1418/F Sequence variants in two novel genes and two intergenic regions within a QTL on human chromosome 7q36 alter plasma triglyceride levels in the human metabolic syndrome. E.M. Smith1, L. Martin2, J. Charlesworth3, J. Blangero3, A.H. Kissebah1,M. Olivier1. 1) HMGC, Medical College of Wisconsin, Milwaukee, WI; 2) Children’s Hospital, Cincinnati, OH; 3) Southwest Foundation for Biomedical Research, San Antonio, TX. We have previously identified a quantitative trait locus on human chromosome 7 LOD = 3.7) linked to plasma triglyceride levels in an obese cohort of 2207 individuals of Northern European descent. The QTL interval spans a region of 5 Mb. Single nucleotide polymorphisms were selected across the region based on the linkage disequilibrium (LD) patterns of the CEPH population of the HapMap. A total of 1,048 SNPs were genotyped using Molecular Inversion Probe technology (Affymetrix). Of the 1,048 SNPs assayed, 109 (10.4%) displayed nominal significance (p<0.05) and nine were significantly associated with triglyceride levels after correction for multiple testing. These SNPs were located in six discrete regions of interest clustered in the center of the QTL, containing two genes (DPP6 and HTR5A) and two additional intergenic regions. Haplotype analysis of these regions suggests that each region of interest independently contributes to the overall effect. Haplotypes in high LD regions around DPP6, which spans 1.1Mb, collectively account for approximately 30% of the initially observed linkage. In addition, a haplotype covering the entire HTR5A gene region, spanning 13.6kb, accounts for 26% of the linkage. The two intergenic regions (46kb in total), both more than 85kb from the nearest gene or hypothetical protein, account for a further 18% of the linkage. These results clearly prove that the initially observed linkage is caused by multiple causal loci each contributing to the observed effect. In addition to two genes, intergenic regions also significantly affect plasma triglyceride levels. However, the physiological mechanisms underlying the genic and non-genic effects remain to be elucidated.