1418/F Sequence variants in two novel genes and two intergenic regions... on human chromosome 7q36 alter plasma triglyceride levels in the...

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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.
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