Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; the NHLBI Family Heart Study.

Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; the NHLBI Family Heart Study.

The chromosome 7q32 region is linked to metabolic syndrome and obesity related traits in the Family Heart Study. As part of a fine mapping study of the region, we evaluated the relationship of polymorphisms to fasting glucose levels and Type 2 diabetes. Thirty-nine HapMap defined tag SNPs in a 1.08 Mb region and a novel deletion polymorphism were genotyped in 2,603 participants of the NHLBI Family Heart Study (FHS). Regression modeling, adjusting for BMI, age, sex, smoking and the TCF7L2 polymorphism, was used to evaluate the association of these polymorphisms with T2D and fasting glucoses levels. The deletion polymorphism confers a protective effect for T2D, with homozygous deletion carriers having a 53% reduced risk compared to non-deleted carriers. Among non-diabetics, the deletion was significantly associated with lower fasting glucose levels in men (p = 0.038) but not women (p = 0.118). In addition, seven SNPs near the deletion were significantly associated (p < 0.01) to diabetes. Chromosome 7q32 contains both SNPs and a deletion that were associated to T2D. Although the deletion region contains several islands of strongly conserved sequence, it is not known to contain a transcribed gene. The closest nearby gene, EXOC4, is involved in insulin-stimulated glucose transport and may be a candidate for this association. Further work is needed to determine if the deletion represents a functional variant or may be in linkage disequilibrium with a functional mutation influencing EXOC4 or another nearby gene.

在家庭心脏研究中，7q32染色体区域与代谢综合征以及肥胖相关性状有关联。作为该区域精细定位研究的一部分，我们评估了多态性与空腹血糖水平和2型糖尿病之间的关系。 在国家心肺血液研究所（NHLBI）家庭心脏研究（FHS）的2603名参与者中，对1.08 Mb区域内的39个国际人类基因组单体型图（HapMap）定义的标签单核苷酸多态性（tag SNPs）以及一种新的缺失多态性进行了基因分型。采用回归模型，并对体重指数（BMI）、年龄、性别、吸烟和转录因子7类似物2（TCF7L2）多态性进行调整，以评估这些多态性与2型糖尿病（T2D）和空腹血糖水平之间的关联。 这种缺失多态性对2型糖尿病具有保护作用，与无缺失的携带者相比，纯合缺失携带者的患病风险降低了53%。在非糖尿病患者中，男性的缺失与较低的空腹血糖水平显著相关（p = 0.038），但女性中无此相关性（p = 0.118）。此外，缺失附近的7个单核苷酸多态性与糖尿病显著相关（p < 0.01）。 7q32染色体既包含与2型糖尿病相关的单核苷酸多态性，也包含一种缺失。尽管缺失区域包含几个高度保守序列的区域，但据了解该区域不包含转录基因。距离最近的基因EXOC4参与胰岛素刺激的葡萄糖转运，可能是这种关联的一个候选基因。需要进一步的研究来确定这种缺失是否代表一种功能性变异，或者是否与影响EXOC4或附近其他基因的功能性突变处于连锁不平衡状态。