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Gene-smoking interactions in multiple Rho-GTPase pathway genes in an early-onset coronary artery disease cohort.

ABSTRACT: We performed a gene-smoking interaction analysis using families from an early-onset coronary artery disease cohort (GENECARD). This analysis was focused on validating and expanding results from previous studies implicating single nucleotide polymorphisms (SNPs) on chromosome 3 in smoking-mediated coronary artery disease. We analyzed 430 SNPs on chromosome 3 and identified 16 SNPs that showed a gene-smoking interaction at P < 0.05 using association in the presence of linkage--ordered subset analysis, a method that uses permutations of the data to empirically estimate the strength of the association signal. Seven of the 16 SNPs were in the Rho-GTPase pathway indicating a 1.87-fold enrichment for this pathway. A meta-analysis of gene-smoking interactions in three independent studies revealed that rs9289231 in KALRN had a Fisher's combined P value of 0.0017 for the interaction with smoking. In a gene-based meta-analysis KALRN had a P value of 0.026. Finally, a pathway-based analysis of the association results using WebGestalt revealed several enriched pathways including the regulation of the actin cytoskeleton pathway as defined by the Kyoto Encyclopedia of Genes and Genomes.

SUBMITTER: Ward-Caviness C

PROVIDER: S-EPMC3835376 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Gene-smoking interactions in multiple Rho-GTPase pathway genes in an early-onset coronary artery disease cohort.

Ward-Caviness Cavin C Haynes Carol C Blach Colette C Dowdy Elaine E Gregory Simon G SG Shah Svati H SH Horne Benjamin D BD Kraus William E WE Hauser Elizabeth R ER

Human genetics 20130802 12

We performed a gene-smoking interaction analysis using families from an early-onset coronary artery disease cohort (GENECARD). This analysis was focused on validating and expanding results from previous studies implicating single nucleotide polymorphisms (SNPs) on chromosome 3 in smoking-mediated coronary artery disease. We analyzed 430 SNPs on chromosome 3 and identified 16 SNPs that showed a gene-smoking interaction at P < 0.05 using association in the presence of linkage--ordered subset analy ...[more]

PMID: 23907653

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Project description:Many GWAS have identified novel loci associated with common diseases, but have focused only on main effects of individual genetic variants rather than interactions with environmental factors (GxE). Identification of GxE interactions is particularly important for coronary heart disease (CHD), a major preventable source of morbidity and mortality with strong non-genetic risk factors. Atherosclerosis is the major cause of CHD, and coronary artery calcification (CAC) is directly correlated with quantity of coronary atherosclerotic plaque. In the current study, we tested for genetic variants influencing extent of CAC via interaction with smoking (GxS), by conducting a GxS discovery GWAS in Genetic Epidemiology Network of Arteriopathy (GENOA) sibships (N?=?915 European Americans) followed by replication in Framingham Heart Study (FHS) sibships (N?=?1025 European Americans). Generalized estimating equations accounted for the correlation within sibships in strata-specific groups of smokers and nonsmokers, as well as GxS interaction. Primary analysis found SNPs that showed suggestive associations (p?10(-5)) in GENOA GWAS, but these index SNPs did not replicate in FHS. However, secondary analysis was able to replicate candidate gene regions in FHS using other SNPs (+/-250 kb of GENOA index SNP). In smoker and nonsmoker groups, replicated genes included TCF7L2 (p?=?6.0×10(-5)) and WWOX (p?=?4.5×10(-6)); and TNFRSF8 (p?=?7.8×10(-5)), respectively. For GxS interactions, replicated genes included TBC1D4 (p?=?6.9×10(-5)) and ADAMTS9 (P?=?7.1×10(-5)). Interestingly, these genes are involved in inflammatory pathways mediated by the NF-?B axis. Since smoking is known to induce chronic and systemic inflammation, association of these genes likely reflects roles in CAC development via inflammatory pathways. Furthermore, the NF-?B axis regulates bone remodeling, a key physiological process in CAC development. In conclusion, GxS GWAS has yielded evidence for novel loci that are associated with CAC via interaction with smoking, providing promising new targets for future population-based and functional studies of CAC development.

Dataset Information

Gene-smoking interactions in multiple Rho-GTPase pathway genes in an early-onset coronary artery disease cohort.

Publications

Gene-smoking interactions in multiple Rho-GTPase pathway genes in an early-onset coronary artery disease cohort.

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