The Common HNF1A Variant I27L Is a Modifier of Age at Diabetes Diagnosis in Individuals With HNF1A-MODY.
The Common HNF1A Variant I27L Is a Modifier of Age at Diabetes Diagnosis in Individuals With HNF1A-MODY.
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作者：
Locke JM;Saint-Martin C;Laver TW;Patel KA;Wood AR;Sharp SA;Ellard S;Bellanné-Chantelot C;Hattersley AT;Harries LW;Weedon MN
由于HNF1A基因突变，成熟型糖尿病（MODY）患者的糖尿病诊断年龄存在很大差异。我们假设与2型糖尿病易感性相关的HNF1A基因座（rs1169288, I27L; rs1800574, A98V）的常见变异可能会改变HNF1A- mody个体的糖尿病诊断年龄。两个独立队列的荟萃分析，包括781名HNF1A-MODY个体，发现基因型和诊断年龄之间没有显著关联。然而，在根据突变类型（蛋白质截断变异（PTV）或错义）进行分层后，我们发现每个27L等位基因与诊断时年龄减少1.6年（95% CI -2.6, -0.7）相关，特别是在具有PTV的HNF1A-MODY个体的亚组（n=444）中。在HNF1A-MODY个体的两个独立队列中，效应大小相似且显著。我们报告了诊断时HNF1A- mody年龄的强大遗传修饰因子，进一步说明了HNF1A遗传变异对糖尿病表型的强烈影响。
There is wide variation in the age at diagnosis of diabetes in individuals with Maturity-Onset Diabetes of the Young (MODY) due to a mutation in the HNF1A gene. We hypothesised that common variants at the HNF1A locus (rs1169288, I27L; rs1800574, A98V), which are associated with type 2 diabetes susceptibility, may modify age at diabetes diagnosis in HNF1A-MODY individuals. Meta-analysis of two independent cohorts, comprising 781 HNF1A-MODY individuals, found no significant associations between genotype and age at diagnosis. However after stratifying according to type of mutation (protein-truncating variant (PTV) or missense), we found each 27L allele to be associated with a 1.6 year decrease (95% CI -2.6, -0.7) in age at diagnosis, specifically in the subset (n=444) of HNF1A-MODY individuals with a PTV. The effect size was similar and significant across the two independent cohorts of HNF1A-MODY individuals. We report a robust genetic modifier of HNF1A-MODY age at diagnosis that further illustrates the strong effect of genetic variation within HNF1A upon diabetes phenotype.
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影响因子：
30.8
作者：
Flannick J;Beer NL;Bick AG;Agarwala V;Molnes J;Gupta N;Burtt NP;Florez JC;Meigs JB;Taylor H;Lyssenko V;Irgens H;Fox E;Burslem F;Johansson S;Brosnan MJ;Trimmer JK;Newton-Cheh C;Tuomi T;Molven A;Wilson JG;O'Donnell CJ;Kathiresan S;Hirschhorn JN;Njølstad PR;Rolph T;Seidman JG;Gabriel S;Cox DR;Seidman CE;Groop L;Altshuler D
通讯作者：
Altshuler D
影响因子：
8.2
作者：
Holmkvist, J.;Cervin, C.;Groop, L.
通讯作者：
Groop, L.
影响因子：
5.8
作者：
Babaya, N;Ikegami, H;Ogihara, T
通讯作者：
Ogihara, T
影响因子：
4.8
作者：
Vaxillaire, M;Abderrahman, A;Pontoglio, M
通讯作者：
Pontoglio, M
影响因子：
7.7
作者：
Bellanne-Chantelot, Christine;Carette, Claire;Timsit, Jose
通讯作者：
Timsit, Jose