Association of novel variants in the hepatocyte nuclear factor 4A gene with maturity onset diabetes of the young and early onset type 2 diabetes
Association of novel variants in the hepatocyte nuclear factor 4A gene with maturity onset diabetes of the young and early onset type 2 diabetes
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DOI：
10.1111/j.1399-0004.2010.01577.x
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发表时间：
2011-12-01
影响因子：
3.5
通讯作者：
Mohan, V.
中科院分区：
文献类型：
--
作者：
Anuradha, S.;Radha, V.;Mohan, V.
肝细胞核因子4A（HNF 4A）的变异体导致年轻人的成熟型糖尿病（MODY 1）。本研究的目的是筛选编码和启动子区的HNF 4A突变在87个无关的南印度受试者临床诊断为MODY与严重形式的糖尿病转介到三级糖尿病中心。此外，我们还研究了HNF 4 A基因常见多态性与MODY（n = 199）、早发2型糖尿病（n = 505）、晚发2型糖尿病（n = 287）和正常葡萄糖耐量（NGT）（n = 247）受试者的相关性。我们在HNF 4A的P2启动子区发现了三个新的突变，即-1009 G/C，-129 T/C和-79 C/T。在一个MODY家系中，-1009 G/C和-129 T/C与糖尿病共分离。我们还研究了HNF 4A基因的8个单核苷酸多态性（SNPs）。rs 2144908的次要等位基因频率在MODY受试者中显著较高（p < 0.01），rs736823的次要等位基因频率在早发T2 DM受试者中显著较高（p = 0.001）。rs 1884614和rs 2071197的次要等位基因频率在早发T2 DM中显著低于NGT受试者（p < 0.01）。与NGT受试者相比，MODY、早发T2 DM和晚发T2 DM中Val 255 Met的次要等位基因频率显著降低（p < 0.01）。这是来自印度的第一份MODY 1突变报告，并显示3.4%的临床诊断MODY受试者患有MODY 1。此外，我们报告了HNF 4A的SNPs，这些SNPs对MODY和早发性T2 DM易感，并具有保护作用。
Variants in hepatocyte nuclear factor 4A (HNF4A) cause maturity onset diabetes of the young (MODY 1). The objective of the study was to screen the coding and the promoter regions of HNF4A mutations in 87 unrelated South Indian subjects with clinically diagnosed MODY with severe forms of diabetes referred to a tertiary diabetes centre. In addition, we looked at the association of common polymorphisms in HNF4 A gene in subjects with MODY (n = 199), early onset type 2 diabetes (T2DM) (n = 505), late onset T2DM (n = 287) and normal glucose tolerance (NGT) (n = 247). We identified three novel mutations in the P2 promoter region of HNF4A, namely -1009 G/C, -129 T/C and -79 C/T. Co-segregation with diabetes was noted with the -1009 G/C and -129 T/C in one MODY family. We also studied eight single nucleotide polymorphisms (SNPs) of HNF4A gene. The frequency of the minor allele of the rs2144908 was significantly higher in subjects with MODY (p < 0.01) and that of rs736823 was significantly higher in early onset T2DM (p = 0.001). Minor allele frequency of rs1884614 and rs2071197 was significantly lower in early onset T2DM when compared to NGT subjects (p < 0.01). Minor allele frequency of Val255Met was significantly lower in MODY, early onset T2DM and late onset T2DM compared to NGT subjects (p < 0.01). This is the first report of MODY 1 mutations from India and shows that 3.4% of clinically diagnosed MODY subjects have MODY 1. In addition, we report SNPs of HNF4A that are both susceptible to, and protective against, MODY and early onset T2DM.