Association of sequence variants in the USF1, ROS1 and ABCA genes with glycohemoglobin levels in the ClinSeq Study

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NHGRI	GEN/GENOM-17

Authors

• H Sung
• M Krischnan
• D Ng
• S Gonsalves
• P Cruz
• J Mullikin
• L Biesecker
• A Wilson

Abstract

ClinSeq is a large-scale-medical-sequencing-study designed to investigate associations of rare sequence-variants(SVs) to risk of developing coronary-heart-disease(CHD). The samples are comprised of non-smoking patients, ages 45-65 with normal-severe coronary-artery-calcification. Forty-three phenotypes including glycohemoglobin-level were measured. Sanger-based sequencing of selected coding-regions across 250 genes was performed at NISC. Each genotype was converted to missing if ambiguous call, Polyphred-score<99 or if either forward or reverse reads was missing. After removing SVs with calling-rate<60% and individuals with genotyping-rate<60%, a total of 8,837 SVs were analyzed in 436 Caucasians. Of 8,837 SVs, 5,035 SVs were novel, not in either dbSNP or 1000 Genomes databases. Tests of association of glycohemoglobin-level (adjusted for age, sex and abdominal-circumference) were performed with simple-linear-regression assuming additive-allelic-effects. Most of 34 significant SVs(p-value<1e-08), minor allele occurred once in entire sample. These findings will be investigated further by collapsing rare-variants by position and by functional domain. Three most significant SVs(p-values<1e-16) were in intronic regions of USF1, ROS1 and ABCA1. USF1 is associated with antilipolytic-insulin-sensitivity and metabolic-risk-factors for cardiovascular disease, ROS1 with myocardial-infarct and ABCA1 with atherosclerosis, CHD and cholesterol. These findings suggest the importance of these genes in determining glycohemoglobin-levels and provide insight into the underlying genetic mechanisms of CHD in ClinSeq study.

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