|Junyent, Mireia - HNRCA-TUFTS UNIVERSITY|
|Smith, Caren - HNRCA-TUFTS UNIVERSITY|
|Garcia-Rios, Antonio - HNRCA-TUFTS UNIVERSITY|
|Mattei, Josiemer - HNRCA-TUFTS UNIVERSITY|
|Lai, Chao Qiang|
Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 11, 2008
Publication Date: November 12, 2008
Citation: Junyent, M., Tucker, K., Smith, C., Garcia-Rios, A., Mattei, J., Lai, C., Parnell, L.D., Ordovas, J.M. 2008. The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study. Journal of Lipid Research. 50:565-573. Interpretive Summary: Low levels of high-density lipoprotein cholesterol (HDL-C, “good” cholesterol) pose a risk for atherosclerosis. Low HDL-C is modulated by genetic and environmental factors such as smoking. The neighboring genes ABCG5 and ABCG8 encode transporters for sterols and limit absorption of sterols such as cholesterol. A panel of genetic variants in these two genes was tested in 845 individuals for association to HDL-C levels. Four variants were found to relate to HDL-C. Importantly, three variants at these genes showed an influence on HDL-C that was modified by smoking, in which smokers exhibited even lower levels of this protective cholesterol. A deeper analysis of the genetic variants in these two genes indicated that the effect of smoking status on HDL-C is global, stretching beyond an single variant tested to include the group of variants as a single unit. In summary, certain ABCG5/G8 genetic variants modulate HDL-C concentrations leading to an HDL-C lowering effect and thereby, a potential increased risk for atherosclerosis, only in smokers.
Technical Abstract: Background-Low high-density lipoprotein cholesterol (HDL-C) is associated with an increased risk for atherosclerosis and concentrations are modulated by genetic and environmental factors such as smoking. Objective- To assess whether the association of common single nucleotide polymorphisms (SNPs) at ABCG5/G8 (i18429G>A, i7892T>C, Gln604GluC>G, 5U145A>C, Tyr54CysA>G, Asp19HisG>C, i14222A>G, and Thr400LysC>A) genes with HDL-C differs according to smoking habit. Results- ABCG5/G8 SNPs were genotyped in 845 participants (243 men and 602 women). ABCG5/G8 (i7892T>C, 5U145A>C, Tyr54CysA>G, Thr400LysC>A) SNPs were significantly associated with HDL-C concentrations (P values ranging from <0.001 to 0.013) by which carriers of the minor alleles at the aforementioned polymorphisms and homozygotes for the Thr400 allele displayed lower HDL-C. A significant gene-smoking interaction was found, in which carriers of the minor alleles at ABCG5/G8 (Gln604GluC>G, Asp19HisG>C, i14222A>G) SNPs displayed lower concentrations of HDL-C, only if they were smokers (P values ranging from 0.001 to 0.025). Also, for ABCG8_Thr400LysC>A SNP, smokers, but not non-smokers, homozygous for the Thr400 allele displayed lower HDL-C (P=0.004). Further analyses supported a significant haplotype global effect on lowering HDL-C (P=0.002) among smokers. Conclusions- ABCG5/G8 genetic variants modulate HDL-C concentrations leading to an HDL-C lowering effect and thereby, a potential increased risk for atherosclerosis, only in smokers.