A role for coding functional variants in HNF4A in type 2 diabetes susceptibility

B Jafar-Mohammadi; C J Groves; A P Gjesing; B M Herrera; W Winckler; H M Stringham; A P Morris; Torsten Lauritzen; A S F Doney; A D Morris; M N Weedon; A J Swift; J Kuusisto; M Laakso; D Altshuler; A T Hattersley; F S Collins; M Boehnke; T Hansen; O Pedersen; C N A Palmer; T M Frayling; A L Gloyn; M I McCarthy; DIAGRAM Consortium

doi:10.1007/s00125-010-1916-4

A role for coding functional variants in HNF4A in type 2 diabetes susceptibility

B Jafar-Mohammadi, C J Groves, A P Gjesing, B M Herrera, W Winckler, H M Stringham, A P Morris, Torsten Lauritzen, A S F Doney, A D Morris, M N Weedon, A J Swift, J Kuusisto, M Laakso, D Altshuler, A T Hattersley, F S Collins, M Boehnke, T Hansen, O PedersenC N A Palmer, T M Frayling, A L Gloyn, M I McCarthy, DIAGRAM Consortium

Endocrinology and Metabolism

23 Citationer (Scopus)

Abstract

Aims/hypothesis: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ∼5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ∼0.1%; T130I, MAF ∼3.0%) - known to influence downstream HNF-4A target gene expression - are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. Methods: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. Results: We found no association between V255M and type 2 diabetes in either the initial (p=0.28) or the expanded analysis (p=0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p=1.5×10^-4), which was strengthened in the metaanalysis (OR 1.20 [95% CI 1.10-1.30]; p=2.1×10^-5). Conclusions/ interpretation: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.

Originalsprog	Engelsk
Tidsskrift	Diabetologia
Vol/bind	54
Udgave nummer	1
Sider (fra-til)	111-9
Antal sider	9
ISSN	0012-186X
DOI	https://doi.org/10.1007/s00125-010-1916-4
Status	Udgivet - jan. 2011

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Jafar-Mohammadi, B., Groves, C. J., Gjesing, A. P., Herrera, B. M., Winckler, W., Stringham, H. M., Morris, A. P., Lauritzen, T., Doney, A. S. F., Morris, A. D., Weedon, M. N., Swift, A. J., Kuusisto, J., Laakso, M., Altshuler, D., Hattersley, A. T., Collins, F. S., Boehnke, M., Hansen, T., ... DIAGRAM Consortium (2011). A role for coding functional variants in HNF4A in type 2 diabetes susceptibility. Diabetologia, 54(1), 111-9. https://doi.org/10.1007/s00125-010-1916-4

Jafar-Mohammadi, B, Groves, CJ, Gjesing, AP, Herrera, BM, Winckler, W, Stringham, HM, Morris, AP, Lauritzen, T, Doney, ASF, Morris, AD, Weedon, MN, Swift, AJ, Kuusisto, J, Laakso, M, Altshuler, D, Hattersley, AT, Collins, FS, Boehnke, M, Hansen, T , Pedersen, O, Palmer, CNA, Frayling, TM, Gloyn, AL, McCarthy, MI & DIAGRAM Consortium 2011, 'A role for coding functional variants in HNF4A in type 2 diabetes susceptibility', Diabetologia, bind 54, nr. 1, s. 111-9. https://doi.org/10.1007/s00125-010-1916-4

@article{817b43254a3f42079d0a7ee844d6bb29,

title = "A role for coding functional variants in HNF4A in type 2 diabetes susceptibility",

abstract = "Aims/hypothesis: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ∼5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ∼0.1%; T130I, MAF ∼3.0%) - known to influence downstream HNF-4A target gene expression - are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. Methods: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. Results: We found no association between V255M and type 2 diabetes in either the initial (p=0.28) or the expanded analysis (p=0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p=1.5×10-4), which was strengthened in the metaanalysis (OR 1.20 [95% CI 1.10-1.30]; p=2.1×10-5). Conclusions/ interpretation: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.",

keywords = "Adult, Aged, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Genotype, Hepatocyte Nuclear Factor 4, Humans, Male, Middle Aged, Mutation",

author = "B Jafar-Mohammadi and Groves, {C J} and Gjesing, {A P} and Herrera, {B M} and W Winckler and Stringham, {H M} and Morris, {A P} and Torsten Lauritzen and Doney, {A S F} and Morris, {A D} and Weedon, {M N} and Swift, {A J} and J Kuusisto and M Laakso and D Altshuler and Hattersley, {A T} and Collins, {F S} and M Boehnke and T Hansen and O Pedersen and Palmer, {C N A} and Frayling, {T M} and Gloyn, {A L} and McCarthy, {M I} and {DIAGRAM Consortium}",

year = "2011",

month = jan,

doi = "10.1007/s00125-010-1916-4",

language = "English",

volume = "54",

pages = "111--9",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

number = "1",

}

TY - JOUR

T1 - A role for coding functional variants in HNF4A in type 2 diabetes susceptibility

AU - Jafar-Mohammadi, B

AU - Groves, C J

AU - Gjesing, A P

AU - Herrera, B M

AU - Winckler, W

AU - Stringham, H M

AU - Morris, A P

AU - Lauritzen, Torsten

AU - Doney, A S F

AU - Morris, A D

AU - Weedon, M N

AU - Swift, A J

AU - Kuusisto, J

AU - Laakso, M

AU - Altshuler, D

AU - Hattersley, A T

AU - Collins, F S

AU - Boehnke, M

AU - Hansen, T

AU - Pedersen, O

AU - Palmer, C N A

AU - Frayling, T M

AU - Gloyn, A L

AU - McCarthy, M I

AU - DIAGRAM Consortium

PY - 2011/1

Y1 - 2011/1

N2 - Aims/hypothesis: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ∼5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ∼0.1%; T130I, MAF ∼3.0%) - known to influence downstream HNF-4A target gene expression - are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. Methods: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. Results: We found no association between V255M and type 2 diabetes in either the initial (p=0.28) or the expanded analysis (p=0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p=1.5×10-4), which was strengthened in the metaanalysis (OR 1.20 [95% CI 1.10-1.30]; p=2.1×10-5). Conclusions/ interpretation: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.

AB - Aims/hypothesis: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ∼5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ∼0.1%; T130I, MAF ∼3.0%) - known to influence downstream HNF-4A target gene expression - are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. Methods: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. Results: We found no association between V255M and type 2 diabetes in either the initial (p=0.28) or the expanded analysis (p=0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p=1.5×10-4), which was strengthened in the metaanalysis (OR 1.20 [95% CI 1.10-1.30]; p=2.1×10-5). Conclusions/ interpretation: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.

KW - Adult

KW - Aged

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Hepatocyte Nuclear Factor 4

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

U2 - 10.1007/s00125-010-1916-4

DO - 10.1007/s00125-010-1916-4

M3 - Journal article

C2 - 20878384

SN - 0012-186X

VL - 54

SP - 111

EP - 119

JO - Diabetologia

JF - Diabetologia

IS - 1

ER -

A role for coding functional variants in HNF4A in type 2 diabetes susceptibility

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