Ruchat Stephanie-May, Weisnagel John S, Rankinen Tuomo, Bouchard Claude, Vohl Marie-Claude, Pérusse Louis
Department of Preventive Medicine, Laval University, Quebec, Canada.
Diabetes Res Clin Pract. 2009 Jun;84(3):211-8. doi: 10.1016/j.diabres.2009.03.012. Epub 2009 Apr 29.
To test for associations between type 2 diabetes mellitus (T2DM)-related traits and polymorphisms (SNPs) in the hepatocyte nuclear factor 4-alpha gene (HNF4A) in the Quebec Family Study cohort, and determine whether these associations are modulated by physical activity (PA).
Two HNF4A SNPs (rs1885088 G>A; rs745975 C>T), previously reported to be associated with T2DM, were studied in 528 non-diabetic subjects who underwent a 75g oral glucose tolerance test (OGTT). Glucose, insulin and C-peptide plasma levels, measured in the fasting state and during the OGTT, were used in the analysis. The amount (hours per week) of PA was assessed by questionnaire.
The HNF4A rs1885088 SNP was not independently associated with T2DM-related traits, whereas the rs745975 was associated with fasting insulin, HOMA-IR and 2-h glucose levels (p<0.05 for all). Genotype by PA interactions were found for glucose homeostasis (p<0.0001) and insulin secretion (p<or=0.03). When subjects were stratified by PA level (according to the median value), we found that high level of PA (>2h/week) was associated with smaller glucose area under the curve (AUC) and 2-h glucose levels in rs1885088 A/A homozygotes and with lower fasting C-peptide and insulin AUC in rs745975 T/T homozygotes.
These results indicate that the associations of HNF4A rs1885088 with glucose tolerance and rs745975 with insulin secretion are modulated by PA. Our finding therefore suggests that the effect of HNF4A polymorphisms on the risk of T2DM is influenced by PA.
在魁北克家族研究队列中检测2型糖尿病（T2DM）相关性状与肝细胞核因子4α基因（HNF4A）多态性（单核苷酸多态性，SNPs）之间的关联，并确定这些关联是否受体力活动（PA）的调节。
在528名接受75g口服葡萄糖耐量试验（OGTT）的非糖尿病受试者中，研究了两个先前报道与T2DM相关的HNF4A SNPs（rs1885088 G>A；rs745975 C>T）。分析中使用了空腹状态及OGTT期间测量的血糖、胰岛素和C肽血浆水平。通过问卷评估PA的量（每周小时数）。
HNF4A rs1885088 SNP与T2DM相关性状无独立关联，而rs745975与空腹胰岛素、HOMA-IR和2小时血糖水平相关（所有p<0.05）。发现PA与基因型的相互作用对葡萄糖稳态（p<0.0001）和胰岛素分泌（p≤0.03）有影响。当根据PA水平（根据中位数）对受试者进行分层时，我们发现高水平的PA（>2小时/周）与rs1885088 A/A纯合子的葡萄糖曲线下面积（AUC）减小和2小时血糖水平相关，与rs745975 T/T纯合子的空腹C肽和胰岛素AUC降低相关。
这些结果表明，PA调节了HNF4A rs1885088与葡萄糖耐量以及rs745975与胰岛素分泌之间的关联。因此，我们的发现表明HNF4A多态性对T2DM风险的影响受PA影响。
