Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16

doi:10.1016/S0016-5085(98)70075-7

Gastroenterology

Volume 115, Issue 5, November 1998, Pages 1066-1071

https://doi.org/10.1016/S0016-5085(98)70075-7 Get rights and content

Abstract

Background & Aims: Inflammatory bowel disease (IBD) is a complex disorder of unknown etiology. Epidemiological investigations suggest a genetic basis for IBD. Recent genetic studies have identified several IBD linkages. The significance of these linkages will be determined by studies in large patient collections. The aim of this study was to replicate IBD linkages on chromosomes 12 and 16 in a large European cohort. Methods: Three hundred fifty-nine affected sibling pairs from 274 kindreds were genotyped using microsatellite markers spanning chromosomes 12 and 16. Affection status of the sibling pairs was defined as Crohn's disease (CD) or ulcerative colitis (UC). Results: Nonparametric statistical analyses showed linkage for both chromosomes. Two-point results for chromosome 12 peaked at D12S303 (logarithm of odds [LOD], 2.15; P = 0.003) for CD and at D12S75 (LOD, 0.92; P = 0.03) for UC. Multipoint analyses produced a peak LOD of 1.8 for CD. Chromosome 16 showed linkage for CD at marker D16S415 (LOD, 1.52; P = 0.007). Multi-point support peaked above markers D16S409 and D16S411 (LOD, 1.7). Conclusions: These data are consistent with linkage of IBD to chromosomes 12 and 16. The replication of genetic risk loci in a large independent family collection indicates important and common susceptibility genes in these regions and will facilitate identification of genes involved in IBD.

GASTROENTEROLOGY 1998;115:1066-1071

Section snippets

Patient recruitment and phenotyping

Individual kindreds consisting of at least two siblings with a diagnosis of either CD or UC were identified and collected in collaboration with IBD programs located at the following European institutions: King's College School of Medicine, Guy's Hospital, and St. Mark's Hospital (London, England), Charité University Hospital (Berlin, Germany), Academic Medical Center (Amsterdam, The Netherlands), Tabea IBD Center (Hamburg, Germany), Kalk Hospital (Cologne, Germany), and other central European

Results

MLS curves for CD, UC, and all IBD pairs for chromosome 12 are shown in Figure 1A.

. Multipoint MLS curves for (A) chromosome 12 and (B) chromosome 16. Multipoint analyses were performed using the MAPMAKER/SIBS program. Results for CD (thick solid line), UC (thin solid line), and all pairs (dashed line) are shown. Genetic distances between markers, estimated from the data set, are shown in Table 2. Marker allele frequencies were calculated from the full sample. Average heterozygosity was 0.77 for

Discussion

Genome-wide linkage analyses have implicated multiple candidate regions for IBD.24, 25 The strongest evidence for linkage in the initial studies was provided for the susceptibility regions on chromosomes 12 and 16. To evaluate the importance of these linkages in IBD, it is important to replicate these findings in a large, independent sample. In this study, we demonstrate support for IBD susceptibility regions on both chromosomes 12 and 16. Interestingly, these data show strongest support for

Acknowledgements

The authors thank the physicians, patients with inflammatory bowel disease, and the patients' families for participating in this study. The authors gratefully acknowledge the cooperation of the German Crohn's and Colitis Foundation (DCCV e. V.); Dr. Wewalka, Linz, and Dr. Knofloch, Wels, Austria; Prof. Lochs, Dr. Wedel, and Dr. Nürnberg, Berlin, Germany; Dr. Herchenbach, Recklinghausen, Germany; Prof. Scheurlen, Würzburg, Germany; Dr. Simon, Marburg, Germany; Dr. Demharter, Augsburg, Germany;

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^☆: Address requests for reprints to: Mark E. Curran, Ph.D., AxyS Pharmaceuticals Inc., 11099 North Torrey Pines Road, La Jolla, California 92037. e-mail: [email protected]; fax: (619) 452-6653.

^☆☆: Supported by AxyS Pharmaceuticals Inc; the National Association for Colitis & Crohn's Disease (United Kingdom); Merckle GmbH; Crohn's in Childhood Research Association (UK); the Sir Halley Stewart Trust; and the Deutsche Forschungsgemeinschaft (Schr 512/1-3 and SFB415), a Training and Mobility of Research (TMR) Network of the European Union (ERB-4061-PL-97-0389) and Mukosaimmunologie Forschungsgesellschaft.

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Alimentary TractGenetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16☆,☆☆

Abstract

Section snippets

Patient recruitment and phenotyping

Results

Discussion

Acknowledgements

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Surgery

Lancet

Familial occurrence of inflammatory bowel disease

N Engl J Med

Clinical patterns of familial inflammatory bowel disease

Gut

Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking

Gut

Genetics versus environment in inflammatory bowel disease: results of a British twin study

BMJ

Human leucocyte antigens in Crohn's disease and ulcerative colitis

Gut

Histocompatibility antigens and other genetic markers in ankylosing spondylitis and inflammatory bowel diseases

J Immunogenet

HLA-A and -B antigens in inflammatory bowel disease

Gut

Alimentary Tract
Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16☆,☆☆