Genetic studies of obesity in the NHLBI Family Heart Study.

摘要

The prevalence of obesity (body mass index (BMI) > 30 kg/m2) has increased at an alarming rate and is an important cause of mortality and morbidity. The NHLBI Family Heart Study (FHS) genome-wide linkage scan identified a region of chromosome 7q with strong evidence (LOD=4.9) for a quantitative trait locus influencing BMI. Using the FHS population, we sought to identify the gene(s) under the area of genetic linkage (7q31-34) that influence BMI.; To locate the gene(s) that influence BMI, we divided the FHS population into three independent study samples. Using various genetic linkage and single SNP association methodologies, we estimated that there are at least two genes in our linkage region influencing BMI. Furthermore, we have identified numerous SNPs in the genes plexin-A4 (PLXNA4) and diacylglycerol kinase iota (DGKI) that consistently replicated among study samples and across different association statistical methodologies.; To extend the single SNP association studies, linkage disequilibrium (LD) differences were examined between an unrelated obese (BMI ≥ 30) and control (BMI ≤ 25) subset of the FHS population. The gene PLXNA4 demonstrated a significant (p= 0.009) increase in LD in the obese subpopulation. In contrast, DGKI demonstrated a significant (p= 0.046) increase in LD among the thin subpopulation. Both areas of differing LD localize to the regions of replicated association found for each gene.; To facilitate haplotype analysis in areas of dense genotyping, the software program, HaploBuild, was developed for constructing and testing haplotypes for SNPs that are not necessarily contiguous. When HaploBuild was applied to our data using a recessive genetic model, further evidence for PLXNA4 influencing BMI was revealed.; Finally, we genotyped a large deletion on chromosome 7q32 in a subset of the FHS population and examined its association to BMI and other obesity related phenotypes. Our study indicates that the deletion polymorphism confers a protective effect for Type 2 diabetes (T2D), with homozygous deletion carriers having a 58% reduced risk of T2D (p = 0.0082). Furthermore, in men we demonstrate T2D protection could be due, in part, to non-diabetic homozygous carriers having significantly lower fasting glucose levels (p= 0.031).