INTRODUZIONE
La patogenesi del morbo di Crohn e della Colite Ulcerosa, nonostante numerosi e approfonditi studi in campo immunologico e microbiologico, rimane elusiva. Negli ultimi anni l’ipotesi dominante è che si verifichi un’anomala risposta immunologica/infiammatoria da parte dell’ospite ad antigeni comunemente presenti nel lume intestinale. Probabilmente a causa di una perdita della “tolleranza” o di un’alterata permeabilità intestinale, viene attivata la risposta immune ma soprattutto non si verificano i normali meccanismi di controllo della risposta infiammatoria e pertanto si determina la cronicità del processo infiammatorio (1). 
Questa ipotesi ha necessariamente suggerito che uno dei fondamentali meccanismi di regolazione della risposta immunologica ed infiammatoria dell’ospite risiede nel suo patrimonio genetico (Fig. 1). Questo elemento, unito alle evidenze epidemiologiche preesistenti (es. familiarità) e al progressivo miglioramento tecnologico nel campo della genetica molecolare, ha determinato un formidabile impulso per gli studi di genetica in queste malattie. 

PRESUPPOSTI EPIDEMIOLOGICI
Una serie di elementi clinici ed epidemiologici ha suggerito negli anni ’80 ed all’inizio degli anni ’90 l’esistenza di una predisposizione genetica per il m. di Crohn e la Colite ulcerosa. 
L’incidenza delle malattie non è uniformemente distribuita nel mondo essendo maggiore tra i caucasici rispetto ai neri ed agli asiatici. Ma anche tra i caucasici si registrano sensibili differenze con un picco nel ceppo Ashkenazi di ebrei di origine europea ed americana (Fig. 2). E’ ovvio che l’incidenza è influenzata da una serie di fattori confondenti, soprattutto ambientali, ma non tutte le differenze identificate sono spiegabili solo sulla base di differenze socio-culturali (2). 
L’associazione tra m. di Crohn o Colite Ulcerosa e malattie genetiche (ad es. sindrome di Turner e glicogenosi di tipo IB)(Fig. 3) e malattie autoimmuni (spondilite anchilopoietica, psoriasi, colangite sclerosante, sclerosi multipla, celiachia) è stata più volte documentata. In alcuni casi è stato evidenziato una correlazione con specifici aplotipi HLA (come ad es. nella celiachia e colangite sclerosante)(3). 
La storia familiare, riportata in percentuale variabile nelle diverse casistiche ma attorno ad un range del 10-20%, è un altro importante elemento a favore della predisposizione genetica (Fig. 4). Questo dato è ulteriormente suffragato dall’evidenza che la presenza di una familiarità rappresenta il più importante fattore di rischio conosciuto di sviluppare queste malattie, con un incremento di incidenza di 10-50 volte nei familiari di 1° grado del soggetto affetto (probando)(4,5). E’ stato argomentato che i familiari di 1° grado condividono verosimilmente gli stessi fattori di rischio ambientale (es. fumo). Ma d’altra parte non si è evidenziato un incremento del rischio nei partner dei pazienti. 
Le stesse caratteristiche cliniche dei casi con aggregazione familiare suggeriscono l’importanza della predisposizione genetica. Pur nei limiti delle difficoltà della tipizzazione fenotipica della malattia nel tempo, la maggior parte degli studi hanno posto in rilievo la sorprendente concordanza per diagnosi e talora per sede e caratteristiche cliniche della malattia nei casi familiari (6)(Fig. 5). 
La concordanza nei gemelli, monozigoti, rispetto ai dizigoti ed agli altri fratelli che arriva a valori del 50-60% soprattutto nel caso del m. di Crohn, ha consentito, in analogia a quanto eseguito in altre malattie, di calcolare un coefficiente di ereditabilità che nel m. di Crohn è superiore a quello calcolato ad esempio per il diabete e l’ipertensione arteriosa (7)(Fig. 6). 

MODELLO GENETICO
Il m. di Crohn e la Colite Ulcerosa non vengono trasmesse con un modello mendeliano classico (8). Analisi di segregazione eseguite in Germania e Scandinavia hanno dimostrato che forse un singolo gene autosomico può essere coinvolto in un piccolo sottogruppo di pazienti. L’ipotesi più accreditata è che queste malattie siano geneticamente complesse, con una chiara interazione di fattori ambientali. I geni coinvolti sono sicuramente numerosi (forse addirittura 10-15) ed alcuni potrebbero essere condivisi (9). Questo dato spiegherebbe la più frequente coesistenza di m. di Crohn e Colite Ulcerosa in alcune famiglie rispetto alla possibilità teorica. La diverse combinazione dei genotipi spiegherebbe anche la notevole eterogeneità sul piano clinico di queste malattie. Un’altra ipotesi di lavoro è che la malattia potrebbe essere determinata dall’interazione di 2-3 geni principali (modello multilocus)(2). Questo potrebbe spiegare la presenza di marker sub-clinici (es. alterata permeabilità intestinale) anche nei familiari sani. La coesistenza dell’alterazione di questi geni principali (es. alterata permeabilità ed alterata risposta immune), in presenza di particolari condizioni ambientali potrebbe scatenare la malattia. Un altro possibile modello è quello cosiddetto di eterogeneità. Secondo questa ipotesi il m. di Crohn e la Colite Ulcerosa sono malattie eziologicamente e geneticamente distinte, ma con una simile presentazione clinica. Ciascuna delle diverse componenti della malattia potrebbe essere ereditata con meccanismo distinto. Questo modello, che pure è il più complesso, è anche il più flessibile (2). D’altra parte nessuno di questi modelli spiega il progressivo aumento di queste malattie nelle ultime decadi. 

STUDI GENETICI
Qualunque sia il modello genetico coinvolto, per dimostrare che una malattia presenti almeno in parte una patogenesi genetica, è necessario individuare il gene candidato. Questa strategia, in analogia a quanto fatto per altre patologie, è stata diffusamente utilizzata negli anni ’80 e buona parte dei ’90. Sulla base delle conoscenze della fisiopatologia di queste malattie, si sono studiate le possibili mutazioni di alcuni geni candidati (Tabelle I e II)(10) in studi caso/controllo. Per quanto molto specifica, questa metodologia è tuttora limitata dalla conoscenza della minoranza dei geni (circa un decimo) del nostro patrimonio genetico. I dati sin qui ottenuti sono stati assai contradditori per la possibilità di false positività (errore di stratificazione), linkage disequilibrium o associazione casuale e non possono considerarsi conclusivi. 
Più recentemente, con i notevoli progressi anche metodologici che lo studio del genoma umano ha ottenuto, è stata utilizzata una diversa strategia. Lo studio cioè della segregazione di particolari marcatori (microsatelliti) all’interno di famiglie con due o più soggetti affetti (Fig. 7). Dopo la prima segnalazione di Hugot et al nel 1996 (11), sono apparsi altri sei studi con l’analisi dell’intero genoma con questa metodologia (Tabella III). Questi studi hanno segnalato un progressivo aumento dei cromosomi (e quindi dei possibili geni) coinvolti. I numerosi studi di replicazione eseguiti, anche nella popolazione italiana (12) hanno confermato un linkage soprattutto sul cromosoma 16 (IBD1) per il m. di Crohn e sul cromosoma 12 nella Colite Ulcerosa (IBD2). Sono in corso, anche presso il ns. centro, ulteriori studi per ottenere una migliore definizione dell’area di interesse sul cromosoma (“fine mapping”), di conferma del locus in casi a presentazione sporadica, ed infine di identificazione del possibile gene coinvolto. La strada da percorrere è comunque ancora tanta perchè le aree di interesse descritte nelle varie popolazione spaziano sul cromosoma di circa 30-40 centiMorgan, una superficie che contiene diverse centinaia di geni (13) (Fig. 8). 
Più recentemente una nuova metodologia di studio si va affermando. Sono stati messi a punto dei filtri che contengono fino a 40.000 cloni di cDNA, inclusi tutti i geni noti. Il principio in pratica è lo studio del mRNA tissutale a partire ad esempio dalle cellule delle cripte del colon. Previa estrazione dell’RNA, si esegue una sintesi del cDNA in situ con successiva marcatura radoioattiva ed ibridizzazione con i filtri di cDNA. Successivamente viene eseguite una complessa analisi per evidenziare un’eventuale sovra o sotto-espressione di un particolare gene (14)(Fig. 9). Si tratta di una metodica molto innovativa ma tuttavia promettente, anche in maniera complementare alle altre metodiche suddette. 

POTENZIALI APPLICAZIONI CLINICHE 
Al momento gli studi di genetica non hanno ancora consentito progressi sostanziali nel campo dell’eziopatogenesi. Questo tipo di acquisizione sono appunto quelle più importanti per arrivare ad una terapia genetica che possa modificare in maniera definitiva la storia naturale di queste malattie. Quello che invece gli studi di genetica sembrano consentire in tempi più prossimi è quello di poter arrivare ad una tipizzazione su base genotipica di alcune caratteristiche cliniche di queste malattie. Chiunque abbia esperienza clinica conosce la notevole eterogeneità clinica di queste malattie che si modifica anche nel tempo nello stesso soggetto. Questo elemento di per sé complica una classificazione in sottogruppi sulla base delle caratteristiche fenotipiche. Viceversa è noto che alcune caratteristiche cliniche della malattia influenzano la risposta alla terapia e l’evoluzione nel tempo, ad esempio in termini di necessità di interventi chirurgici. Qualora una valutazione del background genetico consentisse una migliore stratificazione dei pazienti e magari consentisse di prevedere alcune caratteristiche della malattia, questo sarebbe estremamente utile nella gestione clinica di questi pazienti. Qualche elemento in questo senso è già disponibile. Ad esempio alcuni aplotipi dell’HLA correlano significativamente con alcune caratteristiche cliniche del m. di Crohn e della Colite Ulcerosa (Fig. 10)(15). Inoltre è stato dimostrato che alcuni aplotipi del TNF correlano più ad una o all’altra delle due malattie, oppure a peculiari caratteristiche cliniche (es. forme fistolizzanti e con localizzazione al colon)(Fig. 11). Questo dato, che sarebbe condizionato da una maggiore o minore produzione del TNF determinata da distinti aplotipi, potrebbe avere anche delle ricadute sulla risposta all’anticorpo anti-TNF in questi pazienti. In effetti è stato dimostrato che alcuni aplotipi correlano con una maggiore o minore risposta all’Infliximab. Questi dati per la verità non sono sempre stati univoci e richiedono definitive conferme, ma hanno aperto il nuovo filone della farmacogenomica, la possibilità cioè che la tipizzazione genetica possa consentire di predire meglio la risposta alla terapia o minimizzarne le complicanze (15). A questo proposito grande interesse hanno trovato gli studi sul gene della tiopurina S-metiltransferasi (TMPT) che determina la mutilazione dell’azatioprina e 6-mercaptopurina. Un allele mutante di questo gene ne ridurrebbe la produzione e nei soggetti eterozigoti per questo allele la possibilità di inibizione midollare indotta dai metaboliti tossici questi farmaci sarebbe molto maggiore. Con il sempre maggiore utilizzo di questi farmaci e la frequenza di circa il 10% di eterozigosi e 0.3% di mozigosi nella popolazione, si comprende quando possa essere importante con un semplice test acquisire questo dato (16). Tuttavia del tutto recentemente è stato segnalato che la mutazione di questo allele era presente solo in 11/40 pazienti con aplasia midollare da azatioprina, (17) sottolineando che forse l’anomalia di questo gene non è l’unico elemento responsabile della tossicità midollare. 

CONCLUSIONI
Le evidenze disponibili confermano che il m. di Crohn e la Colite Ulcerosa sono malattie con evidente predisposizione genetica e sono tra loro correlate per la probabile condivisione di alcuni geni/malattia. Il modello genetico è tuttavia complesso con importante componente di interazione con i fattori ambientali e per il momento gli studi di genetica sono da considerarsi ancora molto preliminari. Potenzialmente saranno molto utili per avvicinarsi ai momenti patogenetici iniziali di queste malattie e di conseguenza potranno sicuramente incidere anche nella terapia (genica ?). Tuttavia la strada per l’identificazione dei geni responsabile sembra ancora lunga e difficile. Al momento questi studi hanno già apportato delle importanti informazioni sulla correlazione tra alcuni genotipi e fenotipi (ad esempio nel caso dell’HLA o degli aplotipi del TNF). Inoltre si espande sempre più l’importanza della farmacogenetica. Lo studio di particolari polimorfismi o mutazioni potrà consentire forse il migliore utilizzo di alcuni farmaci (es. il gene NAT per la mesalazina) o di prevenire possibili gravi complicanze della terapia (es. il gene TMPT per la 6-mercaptopurina). Il formidabile impulso scientifico che il progetto genoma ha avuto non potrà non avere importanti ricadute anche nello studio di queste malattie 

2. Yang H, Rotter JL. Genetics of inflammatory bowel disease. In: Inflammatory bowel disease: from the bench to the bedside. Targan SR, Shanahan F (eds), William & Wilkins, Baltimore 1994; chapt 3, pp.32-64. 

3. Annese V, Andriulli A. Alterazioni genetiche nelle malattie infiammatorie croniche dell’intestino. Giornale di Gastroenterologia. 1997;2:174-88. 

4. Peeters M, Nevens H, Baert F, Hieke M, De Meyer M, Vlietink R, et al. Familial aggregation in Crohn’s disease: increased age-adjusted risk and concordance in clinical characteristics. Gastroenterology 1996;111:597-603. 

5. Orholm M, Fonager K, Sorensen HT. Risk of ulcerative colitis and Crohn’s disease among offsprings of patients with chronic inflammatory bowel disease. Am J Gastroenterol 1999;94:3236-8. 

6. Sachar DB. Crohn’s disease: a family affair. Gastroenterology 1996;111:813-5. 

7. Tysk C, Lindberg E, Jarnerot G, Flodérus-Myrhed B. Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dyzigotic twins. A study of hereditability and the influence of smoking. Gut 1988;29:990-6. 

8. Forabosco P, Collins A, Latiano A, Annese V, Clementi M, Andriulli A, et al. Combined segregation and linkage analysis of inflammatory bowel disease in the IBD1 region using severity to characterise Crohn’s disease and ulcerative colitis. Eur J Hum Genet 2000 (in press). 

9. Mc Connel RB, Shaw JM, Whibley EJ, Mc Connel TH. Inflammatory bowel disease: a review of previous genetics studies and the Liverpool family data. Fron Gastrointest Res 1986;11:1-11. 

10. Annese A. Andriulli A. Genetica delle malattie infiammatorie croniche dell’intestino: esiste un marker generico di rischio ? In: IBD Year Book 1999. Bianchi Porro G, Ardizzone S (eds.) Mediserve 1999, pp. 27-41. 

11. Hugot JP, Puig PL, Gower-Rousseau C, et al. Mapping of susceptibility locus for Crohn’s disease on chromosome 16. Nature 1996;379:821-3. 

12. Annese V, Latiano P, Bovio P et al. Genetic analysis in Italian families with inflammatory bowel disease supports linkage to the IBD1 region - A GISC study. Eur J Hum Genet 1999, 7:567-73. 

13. Schreiber S, Hampe J. Genomics and inflammatory bowel disease. Curr Opin Gastroenterol 2000;16:297-305. 

14. Fortina P, Stoeckert C, Annese V, et al. Microarray gene expression analysis to identify candidate genes for IBD. GUT 2000 (in press). 

15. Annese V, Andriulli A. Genetics and genomics of inflammatory bowel diseases. Gastroenterologia Clinica 2001 (in press) 

16. Dubinski MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercapropurine therapy in inflammatory bowel disease. Gastroenterology 2000;118:705-13. 

17. Colombel JF, Ferari N, Debuysere H, Marteau P. Genotypic analysis of thiopurine s-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000;118:1025-30. 

Tabella I - Elenco dei possibili geni candidati
 

Geni candidati	Cromosomi
NRAMP, KM	2
GNAI2, MLH2	3
HLA, TNF, TAP2a, Motilina, Complemento	6
Recettori a b Vb 11 celule T, EGF, HGF, MLH1, MUC3	7
Recettore Vit. D, Citocheratine, IL-1, IFN-g	12
ICAM	13
GM, recettori g d cellule T	14
Integrina CD11, E-caderina, Recettore IL-4	16
Antagonista recettore IL-1, Complemento BF, ICAM	19

Tabella II – Marcatori molecolari in cui è stato ottenuta un’associazione positiva 
 

Marcatori genetici	Malattia	Cromosomi
Antagonista recettore IL-1 (allele 2)	RCU	2q
NRAMP	RCU/MC	2p
HLA, TAP2	RCU/MC	6p
TNF (a2b1c4e1)	MC	6p
TNF a -308 (allele 2)	RCU	6p
Motilina (allele 2)	MC	6p
Recettore b cellule T	RCU/MC	7q
MUC2	RCU/MC	11p
Recettore Vit. D	MC	12
ICAM	RCU/MC	13,19

Tabella III – Elenco studi di linkage sull’intero genoma
 

Autori	Cromosomi con likage
Hugot JP, Nature 1996	16
Satsangi J, Nat Gen 1996	3, 7, 12
Cho J, PNAS 1998	1, 3, 4, 16
Hampè J, Am J Hum Genet 1999	1, 6, 12, 16
Ma Y, Inflamm Bowel Dis 1999	5, 14, 17
Duerr J, Am J Hum Genet 2000	14
Rioux J, Am J Hum Genet 2000	5, 19

Tratto da mybestlife 16/07/2001

Si è recentemente svolto il Congresso mondiale sulle Malattie infiammatorie croniche intestinali organizzato dall'Università di Bologna e durante il quale sono stati presentati i risultati di due ricerche indipendenti, una americana e l'altra francese, che hanno portato all'identificazione di un fattore responsabile dell'insorgenza del Morbo di Crohn.
I ricercatori avrebbero infatti scoperto la mutazione del gene Nod2, presente con il doppio della frequenza in pazienti affetti dalla malattia rispetto ad altri individui sani. Il gene incriminato si trova soprattutto nei monociti, cellule difensive del sistema immunitario congenito, e la modifica renderebbe tali cellule incapaci di riconoscere i batteri scatenando così una reazione infiammatoria esagerata da parte del sistema immunitario adattivo il quale, di conseguenza, reagisce più lentamente. Il Morbo di Crohn non è una vera e propria malattia ereditaria, tuttavia esiste una dimostrata predisposizione familiare; la scoperta potrebbe quindi velocizzare il processo di identificazione di altre mutazioni presenti nella malattia.
Nonostante l'importanza della scoperta, i ricercatori sostengono che sarà necessario del tempo per mettere a punto nuovi trattamenti terapeutici. Le statistiche stimano 300.000 soggetti colpiti dalla malattia con 10.000 nuovi casi ogni anno, gli individui più colpiti sono i bambini tra i 7 e gli 8 anni, i ragazzi al di sotto dei 18 anni e gli adulti tra i 55 ed i 65 anni.

Background & Aims: The technique of genomewide scanning has been applied successfully in inflammatory bowel disease (IBD). A number of putative susceptibility loci have been identified through genomewide searches including replicated regions of linkage on chromosomes 12, 16, 6 (the HLA region), and 14. We have investigated the contribution of the X chromosome in 145 Belgian affected relative pairs.
Methods: In the first stage of the study, 79 (68 CD, 11 mixed) sibling pairs were genotyped at 12 microsatellite markers covering the X chromosome. In the second stage, 10 additional markers in the X-pericentromeric region were studied in the families involved in stage 1 together with 62 additional families (52 sibling pairs, 14 second-degree relative pairs).
Results: In the first stage, evidence for linkage was found over a 30-cM pericentromeric region spanning dXs991, dXs990, and dXs8096 (multipoint maximum LOD score in the CD subgroup, 2.5; P = 0.0003). The remainder of the X chromosome was excluded (exclusion under LOD-2) for a locus with s = 2. Fine mapping in the second stage confirmed linkage, and narrowed and shifted the linked region to Xq21.3 around dXs1203 (nonparametric linkage [NPL], 2.90; P = 0.0017). The NPL-1 interval around the linkage peak comprises 19.7 cM . Conclusions: These data provide suggestive evidence for the presence and chromosomal location of an X-linked susceptibility gene in IBD. 

By identifying more than 150 genes involved in ulcerative colitis and Crohn's disease, scientists have deepened their understanding of the changes that accompany inflammatory bowel disease.
Dr. Shukti Chakravarti and associates from Case Western Reserve University School of Medicine in Cleveland, Ohio, were particularly interested in pinpointing differences between ulcerative colitis and Crohn's disease--two forms of inflammatory bowel disease (IBD). Previous studies had found only four genes involved in IBD.
The investigators used a new genetic technology called DNA microarray to look for differences in the expression of 7,306 genes in tissues taken from the large intestines of six patients with Crohn's disease, six patients with ulcerative colitis, and six healthy individuals. Their results are published in the March issue of Human Molecular Genetics.
A total of 170 genes showed significant differences in their expression levels--the degree to which they were turned on--in ulcerative colitis and Crohn's disease, the researchers note. Most of the genes had not been previously associated directly with IBD, though a number were clustered within chromosome areas already linked to an increased risk of these diseases.
The functions of these genes spanned a broad spectrum of biological functions, the report indicates, including the inflammation control, cancer prevention, infection defense, and cell-cycle regulation.
Chakravarti, now at Johns Hopkins University in Baltimore, Maryland, told Reuters Health that this information can be used both to improve the diagnosis of ulcerative colitis and Crohn's disease, and to understand which genetic changes may lead to the development of these disorders.
"This study is a beginning for this kind of global gene expression profiling. As we and others begin to accumulate this kind of data, we can better classify ulcerative colitis and different types of Crohn's disease," Chakravarti said.
"Ultimately," Chakravarti concluded, "profiling of biopsy tissues will help to follow progression of these chronic diseases and even help to predict disease severity and possible tendencies for (complications)."
Inflammatory bowel diseases involve gastrointestinal symptoms including pain, diarrhea, bleeding, as well as weight loss and fever. Ulcerative colitis affects mainly the colon inner surface while Crohn's often extends to the small and large intestine.

THE IMMUNE SYSTEM is a complex and highly developed system, yet its mission is simple: to seek and kill invaders. If a person is born with a severely defective immune system, death from infection by a virus, bacterium, fungus or parasite will occur. In severe combined immunodeficiency, lack of an enzyme means that toxic waste builds up inside immune system cells, killing them and thus devastating the immune system. A lack of immune system cells is also the basis for DiGeorge syndrome: improper development of the thymus gland means that T cell production is diminished. Most other immune disorders result from either an excessive immune response or an 'autoimmune attack'. Asthma, familial Mediterranean fever and Crohn disease (inflammatory bowel disease) all result from an over-reaction of the immune system, while autoimmune polyglandular syndrome and some facets of diabetes are due to the immune system attacking 'self' cells and molecules. A key part of the immune system's role is to differentiate between invaders and the body's own cells - when it fails to make this distinction, a reaction against 'self' cells and molecules causes autoimmune disease.

INFLAMMATORY BOWEL DISEASE (IBD) is a group of chronic disorders that cause inflammation or ulceration in the small and large intestines. Most often, IBD is classified either as ulcerative colitis or Crohn disease. While ulcerative colitis affects the inner lining of the colon and rectum, Crohn disease extends into the deeper layers of the intestinal wall. It is a chronic condition and may recur at various times over a lifetime. About 20% of cases of Crohn disease appear to run in families. It is a 'complex trait', which means that several genes at different locations in the genome may contribute to the disease. A susceptibility locus for the disease was recently mapped to chromosome 16. Candidate genes found in this region include several involved in the inflamatory response, including: CD19, involved in B-lymphocyte function; sialophorin, involved in leukocyte adhesion; the CD11 integrin cluster, involved in microbacterial cell adhesion; and the interleukin-4 receptor, which is interesting, as IL-4-mediated functions are altered in IBDs.

INTRODUZIONE
La causa della malattia di Crohn e della Colite Ulcerosa, nonostante numerosi e approfonditi studi in campo immunologico e microbiologico, rimane sconosciuta. Negli ultimi anni l'ipotesi dominante è che si verifichi un'anomala risposta    immunologia/infiammatoria nei confronti di antigeni comunemente presenti nel lume intestinale. Probabilmente a causa di una perdita della "tolleranza" o di un'alterata permeabilità intestinale, viene attivata la risposta immune ma soprattutto non si verificano i normali meccanismi di controllo della risposta stessa e pertanto si determina un
processo infiammatorio che rimane cronicamente attivato. Questa ipotesi ha  necessariamente suggerito che uno dei fondamentali meccanismi dì regolazione della risposta immunologica ed infiammatoria di ogni soggetto risiede nel suo patrimonio genetico. Questo elemento, unito alle evidenze epidemiologiche preesistenti (es. presenza di casi familiari) e al progressivo miglioramento tecnologico nel campo della genetica molecolare (es. progetto genoma), ha determinato un formidabile impulso per gli studi di genetica in queste malattie.

PRESUPPOSTI EPIDEMIOLOGICI
Una serie di elementi clinici ed epidemiologici ha suggerito negli anni '80 ed all'inizio degli anni '90 l'esistenza di una prodisposizione genetica per le M.I.C.I.
L'incidenza delle malattie non è uniformemente distribuita nel mondo essendo maggiore tra i caucasici rispetto ai neri ed agli asiatici. Ma anche tra i caucasici si registrano sensibili differenze con un picco nel ceppo Ashkenazi di ebrei di origine europea ed americana. E' ovvio che l'incidenza è influenzata da una serie di fattori confondenti, soprattutto ambientali, ma non tutte le differenze registrate sono spiegabili solo sulla base di differenze etniche e sociali. L'associazione tra malattia di Crohn o Colite Ulcerosa con malattie genetiche (es. sindrome di Turner) ed autoimmuni (come spondilite anchilopoietica, psoriasi, colangite sclerosante, sclerosi multipla, celiachia) è stata più volte documentata. . La storia familiare. riportata in percentuale variabile nelle diverse casistiche ma con un range di circa il 10-20%, è un altro importante elemento a favore della predisposizione genetica. Inoltre il dato ancora più rilevante è che la presenza di una familiarità rappresenta il più importante fattore di rischio conosciuto di sviluppare queste malattie, con un'incremento di 10-50 volte nei familiari di 1° grado del soggetto affetto rispetto al resto della popolazione. E' stato argomentato che i familiari di 1° grado condividono verosimilmente gli stessi fattori di rischio ambientale (es. fumo). Ma d'altra parte non si è evidenziato un incremento del rischio nei partner dei pazienti. Le stesse caratteristiche cliniche dei casi con aggregazione familiare suggeriscono l'importanza della predisposizione genetica. Pur nei limiti delle difficoltà di classificare la malattia nel tempo, la maggior parte degli studi hanno posto in rilievo la sorprendente concordanza per diagnosi e talora per sede e caratteristiche cliniche della malattia nei casi familiari (ad es. localizzazione ileale della malattia di Crobn o tendenza a formare fistole). La concordanza nei gemelli, monozigoti, rispetto ai dizigoti ed agli altri fratelli che arriva a valori dei 50-60% soprattutto nel caso della malattia di Crohn, ha consentito, in analogia a quanto eseguito in altre malattie, di calcolare un coefficiente di ereditabilità che nella malattia di
Crohn è superiore a quello calcolato ad esempio per il diabete e l’ipertensione arteriosa.

MODELLO GENETICO
La malattia di Crohn e la Colite Ulcerosa non vengono trasmesse come le malattie genetiche classiche con un modello di tipo dominante (es. anemia mediterranea) o recessivo. L'ipotesi più accreditata è che queste malattie siano geneticamente complesse, con una chiara interazione di fattori ambientali. 1 geni coinvolti sono sicuramente numerosi (forse addirittura 10-15) ed alcuni potrebbero essere condivisi nelle due malattie.
Questo dato spiegherebbe la più frequente consistenza di malattia di Crohn e Colite Ulcerosa in alcune famiglie rispetto alla frequenza attesa secondo le leggi della casualità. La possibile diverse combinazione di geni coinvolti potrebbe spiegare anche la notevole differenza sul piano clinico di queste malattie.

STUDI GENETICI
Qualunque sia il modello genetico coinvolto, per dimostrare che una malattia presenti almeno in parte una patogenesi genetica, è necessario individuare il/i gene/i candidato/i. Questa strategia, in analogia a quanto fatto per altre patologie, è stata diffusamente utilizzata negli anni '80 e buona parte dei '90. Sulla base delle conoscenze della fisiopatologia di queste malattie, un gran numero di geni candidati è stato studiato. I dati sin qui ottenuti nelle M.I.C.I. sono stati assai contradditori e nessun gene stato con certezza individuato. Più recentemente, con i notevoli progressi anche metodologici che lo studio del genoma umano ha ottenuto, è stata utilizzata una, diversa strategia. Lo studio cioè delle famiglie con due o più soggetti affetti da M.I.C.I. In queste famiglie si vanno a ricercare particolari marcatori dei DNA denominati microsatelliti e le loro caratteristiche nei soggetti affetti.
Con complicati calcoli è possibile studiare l'intero patrimonio genetico e individuare sui vari cromosomi le aree in cui potrebbero essere presenti i geni-malattia. A partire dal primo studio nel 1996, diversi ricercatori in tutto il mondo hanno raccolto grossi numeri di famiglie e individuati alcuni cromosomi candidati. Maggiori conferme sono state ottenute su due aree rispettivamente sul cromosoma 16 (IBD1, per la malattia di Crohn) e sul cromosoma IBD2 per la Colite Ulcerosa). Da vari anni il nostro centro è impegnato in questo settore di ricerca.
Grazie alla collaborazione determinante dei GISC (Gruppo Italiano per lo Studio del Colon e Retto), del GISMII (Gruppo Italiano per lo Studio delle Malattie Infiammatorie Intestinali) e della stessa Associazione AMICI (in particolare la sezione Puglia) sono state raccolte più di 100 famiglie con M.I.C.I. in tutta Italia. E' stato estratto il DNA con un semplice prelievo di sangue dei soggetti affetti e dei loro familiari e sono stati studiati numerosi cromosomi (3, 6, 7, 12 e 16). Anche nella popolazione italiana è stata confermata un'area significativa sul cromosoma 16. Gli studi continuano per definire ancora meglio quest'area e ricercare il gene candidato, ed allo stesso tempo per evidenziare altri cromosomi interessati.

CONCLUSIONI
Gli studi di genetica nelle malattie infiammatorie croniche dell'intestino sono ancora molto preliminari. Potenzialmente saranno molto utili per avvicinarsi a spiegare i momenti iniziali che determinano queste malattie e di conseguenza potranno incidere anche nella terapia (forse anche di tipo “genico”). Tuttavia la strada per l'identificazione dei geni responsabili è ancora lunga e difficile. Non vi è indicazione ad eseguire questo studio del DNA se non a scopo di ricerca perché i dati in nostro possesso non ci consentono ancora di prevedere nell'ambito di una famiglia i possibili soggetti a rischio.
E d'altra parte solo circa il 10% dei casi si presenta in forma familiare. Questi studi inoltre stanno fornendo già importanti indicazioni sulle caratteristiche cliniche della malattia. La presenza di alcune combinazioni genetiche possono predire ad es. l'evoluzione più severa o la presenza di manifestazioni extraintestinali. Infine è nato praticamente un nuovo settore di ricerca che è quello della farmacogenetica. Lo studio di particolari geni ci potrà forse consentire di prevedere la migliore o peggiore risposta alla terapia o il maggior rischio di alcune complicanze della malattia. Si affaccia all'orizzonte una nuova era che, anche se non in termini brevissimi, potrà consentirci di cambiare la storia naturale di queste malattie. E' importante al momento, non sovrastimare e vagliare con cura l'importanza degli studi di genetica. Va sottolineato ancora una volta che questi studi sono pura ricerca e a volte richiedono diversi anni per essere validati ed avere dei risvolti clinici per tutti i giorni.

LA RICERCA DELLE FAMIGLIE NON E' FINITA; E' ESTREMAMENTE UTILE CHE GLI OPERATORI SANITARI CHE SEGUONO FAMIGLIE CON PIU’ CASI DI MICI O GLI STESSI PAZIENTI DI QUESTE FAMIGLIE CHE DESIDERINO PARTECIPARE ALLO STUDIO (E’ SUFFICIENTE UN SEMPLICE PRELIEVO DI SANGUE) CI CONTATTINO. SAPREMO INDICARE IL CENTRO IN ITALIA A LORO PIU’ VICINO CHE COLLABORA CON QUESTO STUDIO E LI TERREMO INFORMATI SUI RISULTATI.

Vito Annese, Angelo Andriulli
Unità Operativa di Gastroenterologia e Laboratorio di Ricerca, Ospedale IRCCS "Casa Sollievo della Sofferenza",
San Giovanni Rotondo
vito.annese@tin.it - Fax 0882-411879

Genetics is the study of heredity. The unique set of genes and chromosomes you inherited from your parents determines everything from the color of your eyes to whether you are predisposed to inflammatory bowel disease (IBD).
It is likely that there is more than one gene for both Crohn's disease and ulcerative colitis. But even if you carry one or more of these mutant genes, you may not become ill. Interaction with a specific environmental factor (e.g., a bacterium) probably is required to trigger IBD.
In recent years, geneticists have identified many genetic markers (distinctive DNA segments) and learned their locations on various chromosomes. Now, they are screening people from families with multiple cases of IBD to see whether they carry any of these markers. The presence of such a marker may mean that a disease gene lies near it on the same chromosome. Researchers also are studying specific genes, such as those involved in the immune response, which may play a role in IBD.
When researchers find the genes for IBD, they can identify people at greatest risk. They also can begin to develop therapies that replace, alter, or block the activity of defective genes.

Scientists estimate that there may be as many as 100,000 human genes. Over the years, thousands have been identified. Still among the missing: the genes that determine whether you are likely to develop Crohn's disease or ulcerative colitis.
When researchers identify the genes responsible for these inflammatory bowel diseases (IBD), they will be able to pinpoint who is at greatest risk. And one day, advances in gene therapy--which would allow us to replace, delete, or neutralize defective genes--may yield a cure.
That is why researchers worldwide are racing to discover these genetic culprits. In January 1996, CCFA co-sponsored investigators who are sweeping the genome in an effort to find the genes for Crohn's disease. Theodore M. Bayless, M.D., of the Johns Hopkins University Medical Center, is spearheading this major effort. The foundation also is sponsoring two studies that are seeking genetic markers for colon cancer, a possible complication of long-term ulcerative colitis. In February 1996, a French team announced that it had identified a potential marker for Crohn's disease on chromosome 16. Work continues on chromosome 6, where, in 1991, CCFA-sponsored research indicated a marker for ulcerative colitis may reside. And other major medical centers are collecting blood samples from families with a history of IBD for use in genetic studies.
Why is this field bursting with activity? In 1988, the federal government launched the Human Genome Project, which seeks to identify every gene in the human gene pool. Since then, geneticists, funded by both government and private sources, have identified thousands of genes. The Genome Project has spurred extraordinary developments in genetic engineering. Exciting new technologies are enhancing researchers' ability to decode the messages imprinted in our DNA. And every new-found gene or genetic marker offers fresh clues that are helping scientists to unravel a host of other genetic mysteries--including the riddle of IBD.
Compelling Evidence
Of course, even if you carry the gene for a particular disease, you may not necessarily become ill. Many people, for instance, carry the gene marker for Type I diabetes. Yet, they never develop the disease. The same may be true for IBD. In fact, most researchers believe that an unidentified environmental factor (possibly an intestinal bacterium) triggers IBD in people who are genetically susceptible. Clearly, we still have much to learn about the relationship between heredity and environment in IBD. Nevertheless, scientists no longer doubt that genetics plays a central role.
Some of the most compelling evidence has come from epidemiological studies. For example, we know that Jews of European descent are at five times greater risk than the general population. "[These rates] are consistent over different times and geographic areas; social and educational factors do not explain this ethnic difference, suggesting that genetic factors are the primary influence," notes Richard H. Duerr, M.D., in "Genetics of Inflammatory Bowel Disease," an article in the spring 1996 issue of CCFA's scientific journal, Inflammatory Bowel Diseases.
A family history of IBD is the greatest risk factor of all. If someone has a relative with the disease, his risk is estimated to be at least 10 times that of the general population. Multiply that number by three if the relative is a sibling. Studies of identical twins have provided especially dramatic data. (Identical twins are produced by one egg, and therefore have the same genetic profiles.) In 68 percent of the twin pairs studied, both developed Crohn's disease; in 20 percent, both members of the pair were affected by colitis. And if a husband and wife both have IBD, the chances that their children also will have the disease are doubled.
Yet, even within families, inheritance patterns can be perplexing. For instance, if your Aunt Susan has Crohn's, why do you and your brother have ulcerative colitis? And why is it that Aunt Susan's kids have not been affected at all? As these questions suggest, these illnesses present a serious challenge to geneticists.
A Crash Course in Genetics
Before we explore the complex genetics of IBD, we'll need to review a few basic principles. Every human being has 46 chromosomes. (We inherit 23 chromosomes from each of our parents.) Each chromosome is made up of hundreds of genes. Both our genes and our chromosomes are composed of deoxyribonucleic acid (DNA). DNA is a long, chainlike molecule that is made up of four chemicals. These chemicals arrange themselves in a multitude of patterns that determine your individual genetic code. The arrangement of a particular set determines how a gene functions--or malfunctions.
Many hereditary traits are passed along in a straightforward manner, known as Mendelianism. Let's look at a fairly simple example. Beverly's parents both have brown eyes. The corresponding genes on each chromosome that Beverly inherited are exactly alike--two genes for brown eyes. Therefore, Beverly has brown eyes. Now Beverly marries a man with blue eyes. Each of their children's gene pair for eye color may well include a gene for brown eyes and an alternate gene, known as an allele, for blue eyes. Their children might have brown eyes or blue eyes--or the genes might combine to produce a new trait, such as hazel eyes. Some diseases are inherited in this straightforward manner. Unfortunately, IBD is not one of them.
The Crooked Path
IBD researchers are now virtually certain that we are seeking more than one gene--unlike the gene for eye color. They are investigating two theories. The first posits that IBD is caused by a few genes, acting in concert. As Dr. Duerr notes, this could explain why Aunt Susan has Crohn's, but you and your brother have colitis: "One gene may predispose to both [colitis and Crohn's] but be insufficient by itself to result in clinical disease, which would occur only when another [colitis- or Crohn's-specific] gene is present."
The second theory is that there are several different forms of both Crohn's disease and ulcerative colitis. Each of these "subtypes" represents a distinct disease process, with its own set of symptoms and complications. And each subtype might be inherited in a different fashion: one might be caused by a single dominant gene; another might be the product of two genes acting together; and still another might be caused by multiple genes. In other words, IBD might encompass every possible inheritance pattern.
The prospect of investigating these complicated scenarios may seem daunting. But, thanks to advances in the field of genetics, the great IBD gene search is gaining momentum.
How Will We Find the Genes?
Studies that use genetic markers will be key to locating the genes responsible for IBD. A genetic marker is a segment of DNA that has a distinctive, highly variable pattern. Scientists now know the variations and locations of many genetic markers on each human chromosome. They are using these markers in two kinds of studies.
In linkage studies, scientists compare genetic markers in relatives from families in which there are multiple cases of IBD. They are looking for the specific genetic markers that are inherited together--or linked--with the disease genes in these families. Let's look at an example. Researchers find that Paul and Joan Warren, a brother and sister who have Crohn's disease, carry the same genetic marker. Since neighboring segments of DNA tend to be linked and inherited together, disease genes are likely to reside close to the genetic markers that are co-inherited with IBD in families. Thus, the marker that Paul and Joan share could be a flashing neon sign that might help us locate its neighbor: the gene for Crohn's disease. On the other hand, this marker may be linked to a different Warren family trait, such as curly hair. This is why researchers must screen hundreds of families if they are to pinpoint disease-linked markers. Once they have identified these markers, they can search the "neighborhood" for the disease genes.
When geneticists perform association studies, they compare DNA samples from a group of IBD patients who are not related with samples taken from a group of unrelated healthy persons. If a particular genetic variation keeps cropping up within the IBD group--but does not appear in the other group--then we have identified a possible marker or a gene that may be "associated" with the disease and, therefore, merits further study.
Narrowing the Field
Sometimes subclinical markers can help narrow the field. Such markers are specific traits that can be detected before symptoms appear. There are many kinds of subclinical markers: They may range from a family history of disease to a particular antibody that appears in the blood.
Other markers would help researchers define the various subsets of Crohn's disease and ulcerative colitis. For example, ANCAs (anti-neutrophil cytoplasmic antibodies) have been found in some people with colitis, but not in others. (ANCAs do not appear to be associated with Crohn's.) Now, researchers are attempting to differentiate the characteristics of "ANCA positive" colitis from "ANCA negative" colitis. If they are successful, they can begin to design separate genetic studies for each group of patients. Because each study would focus on a "homogeneous" population, the likelihood of finding common markers and/or genes within each group would increase exponentially.
Another approach is to focus on those groups of genes that control critical functions in the disease process. For instance, most researchers agree that IBD is caused by a defect in the body's immune response. For this reason, most association and linkage studies have focused on genes of the immune system (e.g., the HLA complex). The genes for two chemicals that help regulate the immune response also may be implicated: The interleukin-1 receptor antagonist, which resides on chromosome 2, may play a role in colitis, while tumor necrosis factor alpha could be associated with Crohn's. Further studies are needed to determine the exact role that these and other genes may play in IBD. In addition to conducting such "candidate-gene" studies, which select a likely gene or group of genes for analysis, researchers have now developed techniques that allow them to work systematically through the entire genome in an effort to identify possible genetic culprits. These technological advances should lead to exciting discoveries in the years ahead.
James Watson, one of the scientists who broke the DNA code, has said, "We used to think that our fate was in our stars. Now we know that, in large measure, our fate is in our genes." For people with IBD, who must live with pain and uncertainty every day, advances in genetics may lead to a greater control over fate than we ever dreamed possible.

Researchers at the Institut Curie in Paris have identified a potential genetic marker for Crohn's disease on chromosome 16. Geneticists believe that there are probably several genes for both Crohn's disease and ulcerative colitis. The data provided by this study, published in the February 29, 1996 issue of Nature, may help narrow the search for at least one of these genes.
What are Genetic Markers?
Simply put, a genetic marker is a segment of DNA with a highly distinctive pattern which resides on a particular chromosome. In recent years, researchers have identified many such markers (or unique patterns). Now they are trying to determine the significance of these markers. For instance, a specific marker may be related to a trait (e.g., eye color) or a disease (e.g., inflammatory bowel disease or IBD). If it is, it usually resides close to the genes that determine the trait or disease. It follows that if you can find the marker, you can narrow the search for the gene to a region on the chromosome.
The Nature Study
Siblings tend to have very similar genetic makeups. Therefore, the French team searched for markers in pairs of siblings with Crohn's disease. Twenty-five families with multiple cases of Crohn's were screened for 270 markers. Four markers appeared in a sufficient number of these siblings to show some promise. Two were on chromosome 16 and two on chromosome 1. Could any of these markers be inherited (linked) together with a gene for Crohn's disease?
To help answer this question, the team chose a second group, drawn from 53 different families. The members of this group were screened for these four markers. This time, the researchers narrowed the search to a possible marker on chromosome 16. The next step will be to conduct studies in larger numbers of people to determine whether one of the genes for Crohn's actually resides on this chromosome.
Why is this important?
Interestingly, a number of genes involved in the body's immune response have already been found in this region of chromosome 16. Since scientists believe that a defect in the immune system plays a role in IBD, these particular genes also merit further study.
While the French study was limited to Crohn's disease, these markers may be useful in studies of families with ulcerative colitis.

In the past couple of weeks, we have reported on the new studies being funded by CCFA. This week, we will focus on progress made in a study that CCFA began funding in January 1997.

Dr. Richard H. Duerr and colleagues (University of Pittsburgh) have found evidence that there is an ulcerative colitis susceptibility gene on chromosome 12. This research confirms the findings of a British study from 1996. The British study reported that Crohn's disease is also linked to chromosome 12, but Dr. Duerr's study found evidence for a Crohn's disease gene on chromosome 12 only in Jewish families.

Dr. Duerr's team assembled a group of geneticists to search the human genome (the complete set of chromosomes) for regions that contain genes for Crohn's disease. They have so far recruited 707 study subjects from 177 families with more than one member affected by inflammatory bowel disease (IBD). The search for other potential genes continues.

Dr. Duerr took his results on the road to the Workshop on IBD Genotyping at Oxford University in October. This workshop was attended by IBD genetics researchers from the United States, Canada, the United Kingdom, France, Germany, and Australia. The majority of research teams at this workshop reported evidence for IBD genes on chromosomes 12 and 16. (Check out the findings on chromosome 16.) The group hopes to publish its findings en bloc in a medical journal in 1998.

Dr. Duerr expresses great excitement for the work being done on the genetics of IBD. "This corroboration of data is unprecedented," he says. "We are well on our way to discovering the genes that predispose to IBD."

BACKGROUND AND AIMS: Genetic predisposition for inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic linkage studies. Genetic linkage of IBD to chromosome 3 has been observed previously. A high density analysis of chromosome 3p was performed to confirm prior linkages and elucidate potential genetic associations. METHODS: Forty three microsatellite markers on chromosome 3 were genotyped in 353 affected sibling pairs of North European Caucasian extraction (average marker density 2 cM in the linkage interval). Marker order was defined by genetic and radiation hybrid techniques. RESULTS: The maximum single point logarithm of odds (LOD) score was observed for Crohn's disease at D3S3591. Peak multipoint LOD scores of 1.65 and 1.40 for the IBD phenotype were observed near D3S1304 (distal 3p) and near D3S1283 in the linkage region previously reported. Crohn's disease contributed predominantly to the linkage. The transmission disequilibrium test showed significant evidence of association (p=0.009) between allele 4 of D3S1076 and the IBD phenotype (51 transmitted v 28 non-transmitted). Two known polymorphisms in the CCR2 and CCR5 genes were analysed, neither of which showed significant association with IBD. Additional haplotype associations were observed in the vicinity of D3S1076. CONCLUSIONS: This study provides confirmatory linkage evidence for an IBD susceptibility locus on chromosome 3p and suggests that CCR2 and CCR5 are unlikely to be major susceptibility loci for IBD. The association findings in this region warrant further investigation.

The idiopathic inflammatory bowel diseases (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are related, complex genetic disorders. With the completion of the human genomic sequence, identification of genetic variants contributing to IBD susceptibility can now more systematically be identified. Significant genetic linkages have been observed on chromosomes 16, 12, 14, 19, 6, and 1, of which the linkage to CD on chromosome 16 is the most well-established. For many of the other regions, evidence for linkage has been observed for both CD and UC. Candidate gene association studies have largely focused on genes involved in inflammatory pathways, such as cytokines and cytokine receptors. With greater understanding of genetic differences underlying both disease susceptibility and response to medical therapy, the individualization of medical approaches based on this knowledge may soon be possible in patients with IBD.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, both of which are multifactorial diseases involving the interaction of genetic and environmental factors. A region on chromosome 12 centred around the marker locus D12S83 has previously been associated with IBD predisposition. The aim of the study was to investigate this genetic region in an independent panel of European families affected by Crohn's disease. METHODS: A sample of 95 families with two or more affected relatives and 75 simplex nuclear families were genotyped for 19 microsatellite loci located on chromosome 12. A search for linkage and linkage disequilibrium was performed using non-parametric two point and multipoint analyses with the Analyze and Genehunter packages.
RESULTS: No evidence of linkage or linkage disequilibrium was observed for any of the marker loci, including D12S83 (p=0.35 for the two point linkage test). Multipoint linkage analysis also failed to reveal positive linkage on chromosome 12. Power calculations allowed us to reject the hypothesis that the genetic region of chromosome 12 centred on D12S83 contains a susceptibility locus with a relative risk (lambda(s)) equal to or greater than 2.0 in these families. CONCLUSION: Failure to detect linkage or linkage disequilibrium in these families suggests that the chromosome 12 locus previously reported to be associated with genetic predisposition to IBD does not play a role in all European family samples. This observation is compatible with heterogeneity in the genetic basis of susceptibility to the disease and/or exposure to various environmental factors among Caucasian families.

Immune mediated inflammation that culminates in severe tissue necrosis is the hallmark of diseases that result from an inappropriate response to antigen. The inflammatory response becomes chronic when antigen is non-limiting and persists until the reactive tissue is destroyed, or the environment is changed and exposure to antigen is eliminated. The purpose of this review is to: (1) briefly outline common features of immune related inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), and allergic asthma; (2) provide a rationale for the development of gene based drugs for these indications; and (3) describe current experimental results that support the usefulness of this approach for creating novel DNA based therapeutics.

Most vital to the search for the genes for IBD is the participation of people with IBD. Finding even a bit of genetic evidence requires DNA from several hundred people. To actually find the genes for IBD will likely require the participation of several thousands of people with IBD.
We have listed below the names and contact information of researchers throughout the world: Please contact them if you wish to participate.
When you contact researchers, you will receive a packet of information, including a small kit for taking a blood sample. Your doctor, or a lab, can draw the sample. Some studies only require genetic material that can be obtained by brushing cells off the inside of your cheek. These groups will provide you with a kit and instructions. You also will fill out a questionnaire about your medical history and the presence of IBD in your family. Physicians are required to obtain informed consent from patients to use the material in studies.
With your participation, and the groundbreaking cooperation of IBD genetics researchers throughout the world, we can speed up the search for the genes for Crohn's disease and ulcerative colitis. Once found, these genes may bring us closer to the cure for these diseases.

If you would like to participate, please contact these groups:

UNITED STATES OF AMERICA
Dr. Judy Cho, Dr. Steven Hanauer, Dr. Barbara Kirschner
The University of Chicago
(773) 702-2282
(This group is seeking multiplex families, in which more than one person has IBD.)

Drs. Steven Brant, Dr. Theodore M. Bayless
Johns Hopkins University and Hospital, Baltimore
(888) 279-4194
(This group is seeking multiplex families, in which more than one person has IBD. They are particularly interested in Jewish families and Jewish patients whose parents both want to participate.)

Dr. Richard Duerr
University of Pittsburgh
(800) 457-2015
(Dr. Duerr is seeking multiplex families, in which more than one person has IBD.)

Dr. Jack Silver, Dr. Seymour Katz
North Shore University Hospital, New York
(516) 562-1113
(This group is primarily studying multiplex families, in which more than one person has IBD, but appreciates calls from any patients. Participation does not require a blood sample; genetic material is obtained by brushing cells off the inside of your cheek. The group will provide you with a kit and instructions.)

Dr. Hui-Ying Yang, Dr. Jerome Rotter
Cedar-Sinai Hospital, Los Angeles
(310) 855-6453
(This group is primarily studying multiplex families, in which more than one person has IBD.)

CANADA
Dr. Mark Silverberg, Dr. Hillary Steinhart
Dr. Zane Cohen, Dr. Robin McLeod
Mount Sinai Hospital Inflammatory Bowel Disease Unit
University of Toronto
Study Coordinator:(416) 586-8349 (This group is primarily seeking multiplex families, in which more than one person has IBD, however, any IBD patients with parents interested in participating are welcome. They are also particularly interested in Jewish patients and IBD patients who have had colorectal cancer.)

AUSTRALIA
Dr. Paul Pavli, Dr. Juleen Cavanaugh
Gastroenterology Unit
The Canberra Hospital
Garran ACT 2606
Australia
Phone - (011 61) 02 62442195
Fax - (011 61) 02 62815179
E-mail - Paul.Pavli@anu.edu.au; Juleen.Cavanaugh@anu.edu.au

UNITED KINGDOM
Dr. Chris Mathew
Division of Medical & Molecular Genetics
GKT School of Medicine
Guy's Hospital
London SE1 9RT
United Kingdom
Phone - (011 44) 171 955 4653
Fax - (011 44) 171 955 9644
E-mail - c.mathew@umds.ac.uk

Dr. D.P. Jewell
Gastroenterology Unit
Radcliffe Infirmary
Gibson Building, 2nd Floor
Woodstock Road
Oxford OX2 6HE
United Kingdom
Phone - (011 44) 1865 224829
Fax - (011 44) 1865 790792
E-mail - derek.jewell@ndm.ox.ac.uk

FRANCE
Dr. Jean-Pierre Hugot
Foundation Jean Dausset/CEPH
27, rue Juliette Dodu
75010 Paris, France
Phone - (011 33) 1 53 72 50 24
Fax - (011 33) 1 53 72 50 58
E-mail - jean-pierre.hugot@cephb.fr

GERMANY
Dr. Stefan Schreiber, Dr. Jochen Hampe
Christian-Albrechts University
Klinik fur Allgemeine Innere Medizin
Schittenhelmstrasse 12
24105 Kiel
Phone - (011 49) 431-597-1279
Fax - (011 49) 431-597-1842
E-mail - s.schreiber@mucosa.de
(This group is seeking multiplex families, in which more than one person has IBD.)

SARA SILBERMAN
Medical Reporter & Editor

Summary Patients with IBD inherit genes which may make them susceptible to the disease.
During their lifetime they may meet an environmental trigger which, because of this genetic susceptibility, allows a chronic inflammatory process to develop. There may be a number of possible genes and possible environmental factors and this may influence disease severity. Crohn's and UC seem to be related, and there may be family members with either.
That we pass some of our characteristics to our children is a self-evident truth. It may be the colour of their hair or eyes, similarity of appearance, and regrettably some disease. The body's instructions about these are encoded in genetic material and these are said to be inherited. However, it is not that simple. Some of the things we pass on to our children are because of the way we live. Sometimes it is a mannerism that is passed from parent to child, or it may be because a family lives in a particular environment, and each is exposed.
If you have inflammatory bowel disease (UC or Crohn's) you may have a family member who also has IBD (15-20% chance of inheriting is generally accepted). You may also be concerned whether IBD can be passed on to a child. These are issues that concern doctors and scientists, and much effort is devoted to the problem of the genetics (inheritance) of IBD. There is definitely evidence of inheritance of IBD proven by studying twins, but simple observation tells us that it is not as simple as passing it on from parent to child.
Many workers in the field gathered together to participate in a symposium on IBD genetics at the 1999 British Society of Gastroenterology Conference in Glasgow. After some general introductions, the real meat of the session concentrated on projects that looked into gene mapping, the relationship between genes and inflammatory substances. Some of the presentations (and other work) are summarised here in an attempt to make sense of highly complex science for the non-expert.
Some diseases are very clearly passed from parent to child. The disease is encoded in the parents DNA (genetic material) and is contributed to the child's DNA. So called dominant genes are always passed on, for example, rare conditions such as acute intermittent porphyria and neurofibromatosis (remember Cliff Barnes from Dallas?) Others depend on so called recessive genes, which come from two unaffected but "carrier" parents. Diseases like cystic fibrosis and sickle cell disease are inherited this way. These kinds of inheritance have a mathematical predictability i.e. for recessive inheritance, one in four offspring are affected.
It is clear that IBD cannot be passed on like a simple dominant or recessive gene - the occurrence is not predictable. However the increased frequency in families, and the even higher frequency in twins allows us to be fairly confident about the genetic influences on the disease. Similarly, because certain racial groups carry genes with them, it is easier to understand why IBD is more common in certain groups e.g. Jews. IBD belongs to a group of inherited diseases called polygenic diseases. This means that several genes may be involved, and environment factors are required for the genes to show themselves as an IBD patient. This creates a complex situation because there may be several genes that might be involved in IBD and the environmental factors are unknown (although we could hazard a few educated guesses - smoking, diet, possibly infection). The implications of this are that not everyone who has genes will develop IBD, and unlike more classical inherited diseases, where the baby is born with the problem, it may take a long time before one meets the environmental trigger. This helps us understand why IBD may not manifest until later in life.
Much of current research is going down two main tracks. Firstly, what is the genetic fault? And if faulty, what are the consequences? Secondly, how many genes are faulty, and can this help explain aspects of the disease? Research work has identified that certain genes (which can be inherited) seem to be associated with abnormal production of substances associated with inflammation. Some that you may have heard of include TNFa (important in Crohn's disease), interleukin, cytokines and chemokines. Mucus production is also closely linked. None are individually responsible for IBD but can play important roles in disease severity. It is logical that if a gene is found that is producing abnormally high quantitites of these harmful substances in an IBD patient, then this may give hope for treatment. It may be possible to switch off the gene with a method like "antisense therapy", or a magic bullet approach such as monoclonal antibody may help by "neutralising" harmful proteins.
Mapping the genetic blueprint has progressed. There doesn't appear to be one single gene responsible (hardly surprising). This helps us understand why some aspects of inflammation tend to dominate in some patients and not others. It may also help us understand why treatments differ in their success from patient to patient. So far susceptible loci (i.e. gene locations) have been identified as chromosomes 12, 1, 3 & 7. In addition there is a susceptibility locus for CD on chromosome 16 and for Ulcerative Colitis there may be loci on chromosomes 2 and 6.
The current perception is that there are genes that seem to be involved, and chemicals controlled by these genes that are responsible for starting and/or continuing the inflammation. We are not sure what triggers the genes, but it does seem very likely that the potential to develop IBD passed on from parent to child but may not show unless something acts as a detonator.

A quick guide to basic genetics
The information about how each human is built is contained in genetic information. This information is encoded into our DNA, about 6 feet of which is squashed into the nucleus of cells which make up the body. The DNA is packaged into 23 pairs of chromosomes. Each chromosome contains thousands of genes, each of which is the recipe for a particular molecule. For each of the 23 pairs, one of each pair comes from each parent. With so much information, the mistakes in encoding or carrying "bad information" from a parent, can give rise to inherited disease. For convenience, scientists number each chromosome, and can identify locations on a chromosome to identify where a gene may be located e.g. an IBD susceptibility gene on chromosome 12 is thought to be near a marker called D12S83.

Many studies have now shown that 15-20% of individuals with either ulcerative colitis or Crohn's disease will have one or more other members of the family affected. Since families tend to share environments, this does not necessarily prove a genetic link, but twin studies have proved a genetic component beyond all reasonable doubt. Recently published family studies from USA and from Oxford have shown that the type of disease and its behaviour tends to run true in a single family, again supporting the suggestion that genetic factors influence susceptibility to getting the disease and also influence the nature of the disease. Furthermore, these studies have found that children develop IBD at a much earlier age than their affected parents, a feature that is often seen in genetic disorders.
NACC members have been kept up-to-date with the genetic programme because of NACC-funded research at St Mark's Hospital, led by Professor Lennard-Jones, and through their enthusiastic co-operation with the genetic studies in Oxford. The oxford team has now collected over 250 families in which two or more members are affected and this has allowed them to demonstrate that these diseases are very closely linked to specific areas on three chromosomes (nos. 3, 7 and 12). Chromosomes are the structures which actually hold the genes. In addition, ulcerative colitis appears to be linked with genes on chromosome 2 and Crohn's disease to genes on chromosome 16. Thus it is possible to understand that there is an overall genetic susceptibility to 'IBD' but that the inheritance of specific genes will determine the type of disease.
What are these genes and how do they function to render individuals susceptible? These questions are fundamental and it is to be hoped that some answers will emerge in the next few years. The exciting finding is that those areas of the chromosomes which are so strongly linked to the diseases are containing genes which control mucus production and some important mechanisms of the body's immune system. Much research has gone into these two areas during the last few years and, within the UK, NACC has been foremost in funding these studies (grants to Dr MacDonald, Professor Allan, Dr Watson, Dr Jewell, Dr Howdle, Mr Durdey and many others). The hunt is now on to define these genetic links more closely and, hopefully, to determine the actual genes responsible for IBD.

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