Candidate Gene Regions and Genetic Heterogeneity in Gluten Sensitivity

Overview

Journal Gut

Specialty Gastroenterology

Date 2001 Apr 17

PMID 11302971

Citations 7

Authors

P Holopainen

K Mustalahti

P Uimari

P Collin

M Maki

J Partanen

Affiliations

Soon will be listed here.

Abstract

Background: Gluten sensitivity is a common multifactorial disorder, manifested in the small intestine or on the skin as typical coeliac disease or dermatitis herpetiformis, respectively. The only established genetic risk factor is HLA DQ2.

Aims: We tested genetic linkage of previously reported chromosomal loci 5q and 11q in Finnish families with gluten sensitivity. We also tested if genetic linkage to candidate loci on 5q, 11q, 2q33, and HLA DQ differed with respect to clinical manifestations or sex.

Subjects: We studied 102 Finnish families with affected sibpairs. For heterogeneity analysis, families were divided into subgroups according to sex and the presence of dermatitis herpetiformis, the skin manifestation of gluten sensitivity.

Methods: Non-parametric linkage between microsatellite markers and disease was tested. Linkage heterogeneity between subgroups was tested using the M test. The transmission/disequilibrium test and association analysis were performed.

Results: Evidence of linkage to 11q (MLS 1.37), but not to 5q, was found in the entire dataset of 102 families. Heterogeneity between subgroups was suggested: families with only the intestinal disease showed linkage mainly to 2q33 whereas families with dermatitis herpetiformis showed linkage to 11q and 5q, but not to 2q33. Linkage in all three non-HLA loci was strongest in families with predominantly male patients. HLA DQ2 conferred much stronger susceptibility to females than males.

Conclusions: Independent evidence for the suggested genetic linkage between 11q and gluten sensitivity was obtained. The possible linkage heterogeneity suggests genetic differences between intestinal and skin manifestations, and the gender dependent effect of HLA DQ2.

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Brophy K, Ryan A, Turner G, Trimble V, Patel K, OMorain C BMC Med Genet. 2010; 11:76.

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References

Reunala T, Kosnai I, Karpati S, KUITUNEN P, Torok E, Savilahti E . Dermatitis herpetiformis: jejunal findings and skin response to gluten free diet. Arch Dis Child. 1984; 59(6):517-22. PMC: 1628792. DOI: 10.1136/adc.59.6.517. View

Peltonen L, Jalanko A, Varilo T . Molecular genetics of the Finnish disease heritage. Hum Mol Genet. 1999; 8(10):1913-23. DOI: 10.1093/hmg/8.10.1913. View

de la Chapelle A . Disease gene mapping in isolated human populations: the example of Finland. J Med Genet. 1993; 30(10):857-65. PMC: 1016570. DOI: 10.1136/jmg.30.10.857. View

Kruglyak L, Lander E . Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet. 1995; 57(2):439-54. PMC: 1801561. View

Morahan G, Huang D, Tait B, Colman P, Harrison L . Markers on distal chromosome 2q linked to insulin-dependent diabetes mellitus. Science. 1996; 272(5269):1811-3. DOI: 10.1126/science.272.5269.1811. View

Zhong F, McCombs C, Olson J, Elston R, Stevens F, McCarthy C . An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland. Nat Genet. 1996; 14(3):329-33. DOI: 10.1038/ng1196-329. View

Maki M, Collin P . Coeliac disease. Lancet. 1997; 349(9067):1755-9. DOI: 10.1016/S0140-6736(96)70237-4. View

Houlston R, Tomlinson I, Ford D, Seal S, Marossy A, Ferguson A . Linkage analysis of candidate regions for coeliac disease genes. Hum Mol Genet. 1997; 6(8):1335-9. DOI: 10.1093/hmg/6.8.1335. View

Petronzelli F, Bonamico M, Ferrante P, Grillo R, Mora B, Mariani P . Genetic contribution of the HLA region to the familial clustering of coeliac disease. Ann Hum Genet. 1997; 61(Pt 4):307-17. DOI: 10.1046/j.1469-1809.1997.6140307.x. View

10.

Kuokkanen S, Gschwend M, Rioux J, Daly M, Terwilliger J, Tienari P . Genomewide scan of multiple sclerosis in Finnish multiplex families. Am J Hum Genet. 1997; 61(6):1379-87. PMC: 1716063. DOI: 10.1086/301637. View

11.

Greco L, CORAZZA G, Babron M, Clot F, Percopo S, Zavattari P . Genome search in celiac disease. Am J Hum Genet. 1998; 62(3):669-75. PMC: 1376948. DOI: 10.1086/301754. View

12.

Polvi A, Arranz E, Fernandez-Arquero M, Collin P, Maki M, Sanz A . HLA-DQ2-negative celiac disease in Finland and Spain. Hum Immunol. 1998; 59(3):169-75. DOI: 10.1016/s0198-8859(98)00008-1. View

13.

Brett P, Yiannakou J, Morris M, BRONSON S, Mathew C, Curtis D . A pedigree-based linkage study of coeliac disease: failure to replicate previous positive findings. Ann Hum Genet. 1998; 62(Pt 1):25-32. DOI: 10.1046/j.1469-1809.1998.6210025.x. View

14.

Terwilliger J, Weiss K . Linkage disequilibrium mapping of complex disease: fantasy or reality?. Curr Opin Biotechnol. 1999; 9(6):578-94. DOI: 10.1016/s0958-1669(98)80135-3. View

15.

Schmitz J, Mougenot J, Bach J, Caillat-Zucman S . CTLA-4 gene polymorphism is associated with predisposition to coeliac disease. Gut. 1999; 43(2):187-9. PMC: 1727221. DOI: 10.1136/gut.43.2.187. View

16.

Paterson A, Petronis A . Sex of affected sibpairs and genetic linkage to type 1 diabetes. Am J Med Genet. 1999; 84(1):15-9. DOI: 10.1002/(sici)1096-8628(19990507)84:1<15::aid-ajmg4>3.0.co;2-o. View

17.

Vaidya B, Imrie H, Perros P, Young E, Kelly W, Carr D . The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus. Hum Mol Genet. 1999; 8(7):1195-9. DOI: 10.1093/hmg/8.7.1195. View

18.

Holopainen P, Arvas M, Sistonen P, Mustalahti K, Collin P, Maki M . CD28/CTLA4 gene region on chromosome 2q33 confers genetic susceptibility to celiac disease. A linkage and family-based association study. Tissue Antigens. 1999; 53(5):470-5. DOI: 10.1034/j.1399-0039.1999.530503.x. View

19.

Sollid L, Thorsby E . HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology. 1993; 105(3):910-22. DOI: 10.1016/0016-5085(93)90912-v. View