The hepatic nuclear factor-1α G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree
The hepatic nuclear factor-1α G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree
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DOI：
10.1210/jc.84.3.1077
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发表时间：
1999-03-01
影响因子：
5.8
通讯作者：
Zinman, B
中科院分区：
文献类型：
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作者：
Hegele, RA;Cao, HI;Zinman, B
在年轻人的成熟型糖尿病患者中发现了编码肝核因子-1 α（HNF-1 α）的基因突变。我们在患有2型糖尿病的安大略Oji-Cree患者中发现了HNF-1 α基因的一种新变体，即G319 S。G319 S位于HNF-1 α反式激活位点的富含脯氨酸II的结构域内，并改变了在整个进化过程中保守的甘氨酸残基。S319在来自其他六个种族的990个等位基因中不存在，这表明它是Oji-Cree的私有基因。我们发现：1）S319等位基因在糖尿病患者比非糖尿病患者更普遍，（0.209 vs. 0.087; P = 0.000001）; 2）S319/S319纯合子和S319/G319杂合子分别与2型糖尿病的比值比为4.00（95%置信区间，2.65-6.03）和1.97（95%可信区间为1.44-2.70）; 3）2型糖尿病的平均发病年龄存在显著差异，G319/G319、S319/G319和S319/S319受试者在第五、第四、和三十年的生活，分别。在2型糖尿病受试者中，我们还发现与G319/G319受试者相比，S319/S319和S319/G319受试者的体重指数显著降低，攻毒后血糖显著升高。最后，在非糖尿病受试者中，S319/G319杂合子的血浆胰岛素显著低于G319/G319纯合子。在大量患有2型糖尿病的Oji-Cree中存在私有HNF-1 α G319 S变体及其与2型糖尿病易感性的强相关性在人群中是独特的。此外，G319 S与一种独特的2型糖尿病相关，其特征在于发病年龄较早、体重较低和挑战后血糖较高。
Mutations in the gene encoding hepatic nuclear factor-1 alpha (HNF-1 alpha) have been found in patients with maturity-onset diabetes of the young. We identified a new variant in the HNF-1 alpha gene, namely G319S, in Ontario Oji-Cree with type 2 diabetes. G319S is within the proline II-rich domain of the trans-activation site of HNF-1 alpha and alters a glycine residue that is conserved throughout evolution. S319 was absent from 990 alleles taken from subjects representing six other ethnic groups, suggesting that it is private for Oji-Cree. We found that 1) the S319 allele was significantly more prevalent in diabetic than nondiabetic Oji-Cree (0.209 vs. 0.087; P = 0.000001); 2) S319/S319 homozygotes and S319/G319 heterozygotes, respectively, had odds ratios for type 2 diabetes of 4.00 (95% confidence interval, 2.65-6.03) and 1.97 (95% confidence interval, 1.44-2.70) compared with G319/G319 homozygotes; 3) there was a significant difference in the mean age of onset of type 2 diabetes, with G319/G319, S319/G319, and S319/S319 subjects affected in the fifth, fourth, and third decades of life, respectively. In subjects with type 2 diabetes, we also found significantly lower body mass index and significantly higher postchallenge plasma glucose in S319/S319 and S319/G319 compared with G319/G319 subjects. Finally, among nondiabetic subjects, S319/G319 heterozygotes had significantly lower plasma insulin than G319/G319 homozygotes. The presence of the private HNF-1 alpha G319S variant in a large number of Oji-Cree with type 2 diabetes and its strong association with type 2 diabetes susceptibility are unique among human populations. Also, G319S is associated with a distinct Form of type 2 diabetes, characterized by onset at an earlier age, lower body mass, and a higher postchallenge plasma glucose.