Genetic association and gene-smoking interaction study of carotid intima-media thickness at five GWAS-indicated genes: the Bogalusa Heart Study

Objectives: To examine the associations of five GWAS-identified genes with carotid intima-media thickness (IMT) in a biracial sample from the Bogalusa Heart Study, and evaluate their participation in gene-smoking interactions.

Methods: Far wall IMTs of common carotid arteries were measured using high-resolution B-mode ultrasound. Both the gene-smoking interactions and single-marker associations were evaluated by linear models of carotid IMT levels, while the gene-based analyses were assessed through the truncated product method. A Bonferroni multiple testing correction was applied.

Results: Marker rs7840785 (PINX1) was significantly associated with right carotid IMT (p=0.0003) using all participants; mean levels for the CC, TC, and TT genotypes were 0.74 (0.73 to 0.75), 0.76 (0.75 to 0.78), and 0.78 (0.75, 0.81), respectively. Similar trends were observed in blacks (p=0.0031) and whites (p=0.0118). Marker rs7844465 (ZHX2) was significantly associated with left carotid IMT in whites (p=0.0005); mean IMT levels for the GG, TG, and TT genotypes were 0.73 (0.71 to 0.74), 0.75 (0.74 to 0.77) and 0.78 (0.75 to 0.81), respectively. Marker rs6841473 (EDNRA) modified the association between smoking and left carotid IMT in blacks (p=2.79×10(-5)). In addition, gene-based analysis demonstrated that EDNRA and ZHX2 were associated with left carotid IMT in the white and overall participants, respectively, while PINX1 was associated with right carotid IMT in both blacks and whites.

Conclusion: We identified two novel markers that were associated with IMT in both blacks and whites. One gene-smoking interaction was identified in blacks only. Three genes showed gene-based associations with IMT levels. However, genetic markers with small effects may have been missed due to the limited number of black participants.