Population-Specific Risk of Type 2 Diabetes Conferred by HNF4A P2 Promoter Variants
| Autor: | Benjamin Glaser, Andrew T. Hattersley, Jing Hua Zhao, Mark I. McCarthy, Nicholas J. Wareham, Graham A. Hitman, Ranganath Venkatesh, Eleftheria Zeggini, Panagiotis Deloukas, Michael N. Weedon, Sarah E. Hunt, Eleanor Wheeler, M. Alan Permutt, Richard Sherva, Marcos Delgado, Pamela Whittaker, Jian'an Luan, Timothy M. Frayling, Rosalind J. Neuman, Jon Wasson, Inês Barroso, Mark Walker |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Linkage disequilibrium
Genotype Endocrinology Diabetes and Metabolism Population Single-nucleotide polymorphism Type 2 diabetes Biology Polymorphism Single Nucleotide Linkage Disequilibrium White People Gene Frequency Risk Factors Internal Medicine medicine Genetics Odds Ratio Humans Genetic Predisposition to Disease Risk factor education Promoter Regions Genetic Allele frequency education.field_of_study Odds ratio medicine.disease United Kingdom Diabetes Mellitus Type 2 Hepatocyte Nuclear Factor 4 Jews |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | OBJECTIVE—Single nucleotide polymorphisms (SNPs) in the P2 promoter region of HNF4A were originally shown to be associated with predisposition for type 2 diabetes in Finnish, Ashkenazi, and, more recently, Scandinavian populations, but they generated conflicting results in additional populations. We aimed to investigate whether data from a large-scale mapping approach would replicate this association in novel Ashkenazi samples and in U.K. populations and whether these data would allow us to refine the association signal. RESEARCH DESIGN AND METHODS—Using a dense linkage disequilibrium map of 20q, we selected SNPs from a 10-Mb interval centered on HNF4A. In a staged approach, we first typed 4,608 SNPs in case-control populations from four U.K. populations and an Ashkenazi population (n = 2,516). In phase 2, a subset of 763 SNPs was genotyped in 2,513 additional samples from the same populations. RESULTS—Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and type 2 diabetes in the Ashkenazim (n = 991; P < 1.6 × 10−6). Importantly, these associations are significant in a subset of Ashkenazi samples (n = 531) not previously tested for association with P2 SNPs (odds ratio [OR] ∼1.7; P < 0.002), thus providing replication within the Ashkenazim. In the U.K. populations, this association was not significant (n = 4,022; P > 0.5), and the estimate for the OR was much smaller (OR 1.04; [95%CI 0.91–1.19]). CONCLUSIONS—These data indicate that the risk conferred by HNF4A P2 is significantly different between U.K. and Ashkenazi populations (P < 0.00007), suggesting that the underlying causal variant remains unidentified. Interactions with other genetic or environmental factors may also contribute to this difference in risk between populations. |
| Databáze: | OpenAIRE |
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