INTRODUCTION:
C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Cigarette smoking is a major risk factor in the development of CVD and has been shown to affect circulating levels of CRP. Therefore, we sought to determine how this important environmental exposure may influence genetic associations with CRP in a multi-ethnic setting.
METHODS:
Using the ITMAT Broad-CARe (IBC) SNP array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate genes for CVD pathways, we performed a meta-analysis of up to 26,065 participants of European descent and 7,584 participants of African descent for association with log-CRP level within smoking status stratum. The 2 smoking strata were: never smokers and ever smokers (comprising of current and former smokers). We conducted IBC-wide association scans for CRP within cohort-, race- and smoking-stratum and meta-analyzed by race. Samples were from the Candidate gene Association Resource (CARe) cohorts (Atherosclerosis Risk in Communities Study, Framingham Heart Study, Cardiovascular Health Study, Cleveland Family Study , Coronary Artery Risk Development in Young Adults Study, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis Study). Results were considered to be panel wide statistically significant if p<2.2×10−6.
RESULTS:
The overall sample size for ever smokers (never smokers) was 11,698 (10,344) in European Americans and 3,448 (4,330) in African Americans. The per-allele beta coefficients for genes previously established to be associated with CRP and present on the IBC chip (
CRP, APOE, GCKR, IL6R, LEPR, HNF1A, NLRP3
) were very similar in magnitude between smoking strata in European Americans. However, in the African Americans, the estimated per-allele
CRP
and
IL6R
betas were 2-times larger for the ever smokers as compared to the never smokers. In the European American analysis, one gene not previously reported for association with CRP reached IBC-wide significance for a CRP-lowering effect in the never smokers (
GSTT1
, p=4.8E-07 for SNP
rs405597
), but not in the ever smokers (p=0.078).
CONCLUSION:
This large scale candidate gene based meta-analysis identified one novel locus for CRP (
GSTT1
) associated with serum CRP levels in those reporting having never regularly smoked. Polymorphisms in
GSTT1
, which plays a role in detoxification, have previously been reported to interact with smoking for other phenotypes including birth weight and colorectal cancer. We also observed evidence that smoking modifies the effects for previously established loci
CRP
and
IL6R
in African Americans. These results may identify important context genetic specific effects that influence chronic inflammation.
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