Background: Calcified coronary plaque (CCP) is a complex trait influenced by both genes and environment, and plausibly an interaction between the two. Because the familial aggregation of CCP has been demonstrated and smoking is a significant, independent predictor of CCP, we assessed the evidence for genotype-by-smoking interaction and conducted linkage analysis of quantitative Agatston CCP scores in participants of the NHLBI Family Heart Study (FHS). Methods: During standardized clinical exams smoking habits were ascertained and CCP was quantified with cardiac computed tomography (CT). Among 4387 relationship pairs from 2128 Caucasian examinees variance component analysis was implemented in SOLAR to examine: (1) additive genotype-by-smoking status interaction using a variance component approach; (2) linkage analysis in the full sample and among smoking subsets defined by individual smoking exposure; (3) QTL-specific genotype-by-smoking interaction in the regions that appeared to differentiate between smoking strata. Results: The prevalence of CCP (and median Agatston score) was 75% (184.6) in men and 48% (51.0) in women. We detected four genome-wide significant logarithm of odds (LOD) scores in samples stratified by individual smoking exposure: chromosome 4 at 122 cM (nearest marker D4S2297; robust adjusted LOD = 3.1; q = 0.053), chromosome 6 at 99 cM (nearest marker D6S1056; robust adjusted LOD = 3.3; q = 0.053), chromosome 11 at 19 cM (nearest marker D11S199; robust adjusted LOD = 4.0; q = 0.02) and chromosome 13 at 77 cM (nearest marker D13S892; robust adjusted LOD = 3.1; q = 0.053). Additive and QTL-specific genotype-by-smoking interaction was detected on chromosomes 4, 6, 11 and 13; all P < 0.05. Three of the four QTLs identified in this report have been previously linked to atherosclerosis and harbor interesting candidate genes. Conclusions: These findings demonstrate the importance of considering complex interactions in the search for genes that influence the pathogenesis of CCP.
|Original language||English (US)|
|Number of pages||9|
|State||Published - Jul 2007|
Bibliographical noteFunding Information:
Support was provided by the National Heart, Lung and Blood Institute cooperative agreement grants U01 HL 67893, U01 HL67894, U01 HL67895, U01 HL67896, U01 HL67897, U01 HL67898, U01 HL67899, U01 HL67900, U01 HL67901 and U01 HL67902. Support was also partially provided by the National Heart, Lung and Blood Institute cooperative agreement grants U01 HL56563, U01 HL56564, U01 HL56565, U01 HL56566, U01 HL56567, U01 HL56568 and U01 HL56569. This report is presented on behalf of the investigators of the NHLBI Family Heart Study. The investigators thank the study participants and staff for their valuable contributions.
Copyright 2008 Elsevier B.V., All rights reserved.