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Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations.

ABSTRACT: Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes. We performed fine mapping on 446 independent individuals with celiac disease and 641 controls of Dutch origin, testing 872 tagging SNPs in a 22 Mb region of chromosome 6. The 12 most promising SNPs were followed up in 2071 individuals from 284 Finnish and 357 Hungarian celiac disease families to identify risk variants in this region. Multiple markers in the region were significantly associated with celiac disease in the Dutch material. Two SNPs, rs9391227 and rs4946111, were significantly associated with celiac disease in the Finnish population. The association to rs9391227 represents the strongest association signal found in the Finnish (P = 0.003, OR 0.66) as well as the combined Dutch, Finnish and Hungarian populations (P = 3.6 × 10(-5), OR 0.76). The rs9391227 is situated downstream of the HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 (HACE1) gene and is contained within a region of strong linkage disequilibrium enclosing HACE1. Two additional, independent, susceptibility variants in the 6q21-22 region were also found in a meta-analysis of the three populations. The 6q21-22 region was confirmed as a celiac disease susceptibility locus and harbors multiple independent associations, some of which may implicate ubiquitin-pathways in celiac disease susceptibility.

SUBMITTER: Einarsdottir E

PROVIDER: S-EPMC3110053 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations.

Einarsdottir Elisabet E Bevova Marianna R MR Zhernakova Alexandra A Monsuur Alienke A Koskinen Lotta L E LL van't Slot Ruben R Mulder Chris C Mearin M Luisa ML Korponay-Szabo Ilma R IR Kaukinen Katri K Kurppa Kalle K Kere Juha J Mäki Markku M Wijmenga Cisca C Saavalainen Päivi P

European journal of human genetics : EJHG 20110216 6

Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes. We performed fine mapping on 446 independent individuals with celiac disease and 641 controls of Dutch origin, testing 872 ta ...[more]

PMID: 21326284

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Project description:Diabetes mellitus is a major public health problem with a wide range of prevalence among different ethnic groups. Early recognition of pre-diabetes is important to prevent the development of the disease, its complications, co-morbidities, and consequently early death. Insulin resistance (IR) is considered a condition that precedes type 2 diabetes; thus, understanding its underlying causes (genetic and non-genetic factors) will bring us closer to preventing it. The present study aimed to investigate the genetic susceptibility to IR and its impact on estimated longevity in populations with different ethnic origins using randomly selected samples of 372 Hungarian general (HG, as a reference with Caucasian origin) and 334 Roma participants (largest ethnic minority in Europe, with a northern India origin). In the present study, we used the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) to identify people with IR (>3.63) at the population level. To investigate the genetic predisposition to IR, 29 single nucleotide polymorphisms (SNPs) identified in a systematic literature search were selected and genotyped in sample populations. In the analyses, the adjusted p < 0.0033 was considered significant. Of these 29 SNPs, the commutative effects of 15 SNPs showing the strongest association with HOMA-IR were used to calculate an optimized genetic risk score (oGRS). The oGRS was found nominally significantly (p = 0.019) higher in the Roma population compared to HG one, and it was more strongly correlated with HOMA-IR. Therefore, it can be considered as a stronger predictor of the presence of IR among the Roma (AUCRoma = 0.673 vs. AUCHG = 0.528). Furthermore, oGRS also showed a significant correlation with reduced estimated longevity in the Roma population (β = -0.724, 95% CI: -1.230--0.218; p = 0.005), but not in the HG one (β = 0.065, 95% CI: -0.388-0.518; p = 0.779). Overall, IR shows a strong correlation with a genetic predisposition among Roma, but not in the HG population. Furthermore, the increased genetic risk of Roma is associated with shorter estimated longevity, whereas this association is not observed in the HG one. Increased genetic susceptibility of Roma to IR should be considered in preventive programs targeting the development of type 2 diabetes, which may also reduce the risk of preventable premature death among them.

Dataset Information

Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations.

Publications

Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations.

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