Qi L, van Dam R M, Asselbergs F W, Hu F B
Department of Nutrition, Harvard Medical School of Public Health, Boston, MA 02115, USA.
Diabet Med. 2007 Nov;24(11):1187-91. doi: 10.1111/j.1464-5491.2007.02255.x. Epub 2007 Sep 26.
Recent studies indicate transcription factor hepatocyte nuclear factor 4 alpha (HNF-4 alpha, HNF4A) modulates the transcription of the pancreatic B-cell ATP-sensitive K+ (KATP) channel subunit Kir6.2 gene (KCNJ11). Both HNF4A and KCNJ11 have previously been associated with diabetes risk but little is known whether the variations in these genes interact with each other.
We conducted a prospective, nested case-control study of 714 incident cases of Type 2 diabetes and 1120 control subjects from the Nurses' Health Study.
KCNJ11 E23K was significantly associated with an increased diabetes risk (odds ratio 1.26, 95% CI 1.03-1.53) while HNF4A P2 promoter polymorphisms were associated with a moderately increased risk at borderline significance. By using a logistic regression model, we found significant interactions between HNF4A rs2144908, rs4810424 and rs1884613 and KCNJ11 E23K (P for interaction = 0.017, 0.012 and 0.004, respectively). Carrying the minor alleles of the three HNF4A polymorphisms was associated with significantly greater diabetes risk in women carrying the KCNJ11 allele 23K, but not in those who did not carry this allele. Analyses using the multifactor dimensionality reduction (MDR) method confirmed the gene-gene interaction. We identified that the best interaction model included HNF4A rs2144908 and KCNJ11 E23K. Such a two-locus model showed the maximum cross-validation consistency of 10 out of 10 and a significant prediction accuracy of 54.2% (P = 0.01) on the basis of 1000-fold permutation testing.
Our data indicate that HNF4A P2 promoter polymorphisms may interact with KCNJ11 E23K in predicting Type 2 diabetes in women.
近期研究表明，转录因子肝细胞核因子4α（HNF - 4α，HNF4A）可调节胰腺β细胞ATP敏感性钾离子（KATP）通道亚基Kir6.2基因（KCNJ11）的转录。此前，HNF4A和KCNJ11均与糖尿病风险相关，但对于这些基因的变异是否相互作用却知之甚少。
我们对护士健康研究中的714例2型糖尿病新发病例和1120名对照者进行了一项前瞻性巢式病例对照研究。
KCNJ11 E23K与糖尿病风险增加显著相关（比值比1.26，95%可信区间1.03 - 1.53），而HNF4A P2启动子多态性与处于临界显著性的中度风险增加相关。通过使用逻辑回归模型，我们发现HNF4A的rs2144908、rs4810424和rs1884613与KCNJ11 E23K之间存在显著相互作用（交互作用P值分别为0.017、0.012和0.004）。携带三种HNF4A多态性的次要等位基因与携带KCNJ11 23K等位基因的女性患糖尿病风险显著增加相关，但在未携带该等位基因的女性中则不然。使用多因素降维（MDR）方法进行的分析证实了基因 - 基因相互作用。我们确定最佳相互作用模型包括HNF4A rs2144908和KCNJ11 E23K。基于1000次置换检验，这样的双位点模型显示出10次交叉验证一致性中的最大值为10，预测准确率为54.2%（P = 0.01）。
我们的数据表明，HNF4A P2启动子多态性可能与KCNJ11 E23K相互作用以预测女性2型糖尿病。
