Population-specific risk of type 2 diabetes conferred by HNF4A P2 promoter variants: a lesson for replication studies.
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.


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 x 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] approximately 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.
Barroso
Inês
I
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. ib1@sanger.ac.uk
Luan
Jian'an
J
Wheeler
Eleanor
E
Whittaker
Pamela
P
Wasson
Jon
J
Zeggini
Eleftheria
E
Weedon
Michael N
MN
Hunt
Sarah
S
Venkatesh
Ranganath
R
Frayling
Timothy M
TM
Delgado
Marcos
M
Neuman
Rosalind J
RJ
Zhao
Jinghua
J
Sherva
Richard
R
Glaser
Benjamin
B
Walker
Mark
M
Hitman
Graham
G
McCarthy
Mark I
MI
Hattersley
Andrew T
AT
Permutt
M Alan
MA
Wareham
Nicholas J
NJ
Deloukas
Panagiotis
P
D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D007585:Jews / Q000235:genetics; D015810:Linkage Disequilibrium; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors; D006113:United Kingdom; D044465:White People / Q000235:genetics
D051557:Hepatocyte Nuclear Factor 4