Polymorphisms in the SEC8L1 (EXOC4) gene encoding a component of the exocyst complex influence BMI, leptin, and insulin levels in the NHLBI Family Heart Study. J.B. Wilk¹, J.M. Laramie¹, S. Williamson¹, C. Leiendecker-Foster², J.H. Eckfeldt², I.B. Borecki³, M.A. Province³, R.H. Myers¹. 1) Department of Neurology, Boston University School of Medicine, Boston, MA; 2) Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN; 3) Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO.
   Linkage to body mass index (BMI) was identified on chromosome 7q in the NHLBI Family Heart Study. Fine-mapping of the region with SNPs was performed in a subset of 730 people from 171 families exhibiting linkage. SEC8L1 is an 800kb gene residing within 660kb of the microsatellite with the peak evidence for linkage. The SEC8L1 protein translocates to the plasma membrane as a component of the exocyst complex (Exo70) where it is thought to influence the docking of GLUT4, an insulin-responsive transporter protein in adipocytes. BMI, glucose, insulin and plasma leptin measurements were studied. All traits were defined separately by sex adjusting for age and study center locations in MA, MN, NC, and UT. Thirty SNPs in the SEC8L1 gene were evaluated using family based association tests (FBAT) and generalized estimating equations (GEE). The best FBAT result was found for insulin (p=0.005), whereas GEE results were strongest for glucose (p=0.004) and BMI traits (p=0.009). Haplotype studies in FBAT identified a 3-SNP haplotype predicting BMI (p=0.002) and 5 and 7-SNP haplotypes predicting insulin levels (p=0.001). In a subset of 237 obese/overweight participants, a dichotomous outcome variable was defined based on the gender specific median of plasma leptin measurements (12.9 ng/mL for men; 36.7 ng/mL for women). This cutoff on leptin levels splits the sample into two groups with a mean BMI difference of 5 units (mean BMI 37 vs. 32 in men and 40 vs. 35 in women). Insulin levels were also different between the two groups. SNPs in SEC8L1 produced odds ratios of 3.2 (p-value=0.004) for a 16% frequent recessive genotype predicting high leptin/high BMI in the obese/overweight subset. These results suggest that polymorphisms in SEC8L1 may influence risk for obesity.