Genetic analysis of the IRS - Pleiotropic effects of genes influencing insulin levels on lipoprotein and obesity measures
Genetic analysis of the IRS - Pleiotropic effects of genes influencing insulin levels on lipoprotein and obesity measures
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DOI：
10.1161/01.atv.16.2.281
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发表时间：
1996-02-01
影响因子：
8.7
通讯作者：
MacCluer, JW
中科院分区：
文献类型：
--
作者：
Mitchell, BD;Kammerer, CM;MacCluer, JW
胰岛素抵抗是代谢综合征的一部分，代谢综合征还包括非胰岛素依赖型糖尿病、血脂异常、肥胖和高血压。据推测，胰岛素抵抗是这种综合征的主要生理缺陷。由于胰岛素抵抗至少部分由遗传决定，我们假设影响胰岛素抵抗的基因对许多其他性状具有多效性效应，包括甘油三酯（TC）和HDL胆固醇水平，体重指数（BMI）和体脂分布以及血压水平。为了研究这一假设，我们分析了从参加圣安东尼奥家庭心脏研究的41个家庭中获得的数据。利用个体间相关性的统计方法被用来区分性状间表型变异的遗传和非遗传（即环境）贡献。空腹和2小时胰岛素的血清水平（分别在767和743名非糖尿病家庭成员中测量）被用作胰岛素抵抗的指标。胰岛素水平（空腹和2小时）与以下各项之间的遗传相关性很高：BMI，HDL水平，腰臀比和肩胛下肱三头肌比，表明相同的基因或一组基因影响每对性状。相反，胰岛素水平与收缩压和舒张压的遗传相关性较低。我们以前已经表明，一个单一的双等位基因位点占31%的表型变异，在2小时的胰岛素水平在这个人群中。我们进行了一个双变量分离分析，以了解胰岛素和其他性状的共同遗传效应是否可以归因于这个单一的基因座。这些结果表明，2小时胰岛素位点对空腹胰岛素水平（P= 0.02）和BMI（P= 0.05）有显著影响，“高"胰岛素等位基因与空腹胰岛素水平较高但BMI水平较低相关。这个位点对HDL水平、TG水平、肩胛下肌与肱三头肌比率或血压没有可检测的影响。总的来说，这些结果表明，一组共同的基因影响胰岛素水平也影响其他胰岛素抵抗综合征相关的性状，虽然在大多数情况下，这种多效性是不归因于2小时胰岛素水平的主要基因座。
Insulin resistance is part of a metabolic syndrome that also includes non-insulin-dependent diabetes mellitus, dyslipidemia, obesity, and hypertension. It has been hypothesized that insulin resistance represents the primary physiological defect underlying this syndrome. Since insulin resistance is at least partially genetically determined, we hypothesized that genes influencing insulin resistance would have pleiotropic effects on a number of other traits, including triglyceride (TC) and HDL cholesterol levels, body mass index (BMI) and body fat distribution, and blood pressure levels. To investigate this hypothesis, we analyzed data obtained from individuals in 41 families enrolled in the San Antonio Family Heart Study. Statistical methods that take advantage of the relatedness among individuals were used to differentiate between genetic and nongenetic (ie, environmental) contributions to phenotypic variation between traits. Serum levels of fasting and 2-hour insulin (measured in 767 and 743 nondiabetic family members, respectively) were used as a measure of insulin resistance. The genetic correlations were high between insulin levels (both fasting and 2-hour) and each of the following: BMI, HDL level, waist-to-hip ratio, and subscapular-to-triceps ratio, indicating that the same gene, or set of genes, influences each pair of traits. In contrast, the genetic correlations of insulin levels with systolic and diastolic blood pressures were low. We have previously shown that a single diallelic locus accounts for 31% of the phenotypic variation in 2-hour insulin levels in this population. We conducted a bivariate segregation analysis to see if the common genetic effects on insulin and these other traits could be attributable to this single locus. These results indicated a significant effect of the 2-hour insulin locus on fasting insulin levels (P=.02) and BMI (P=.05), with the ''high'' insulin allele associated with higher levels of fasting insulin but lower levels of BMI. There was no detectable effect of this locus on HDL level, TG level, subscapular-to-triceps ratio, or blood pressure. Overall, these results suggest that a common set of genes influencing insulin levels also influences other insulin resistance syndrome-related traits, although for the most part this pleiotropy is not attributable to the 2-hour insulin level major locus.