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

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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.

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Acknowledgments

We thank all of the volunteers for their participation in the GENECARD study. We would also like to acknowledge the essential contributions of the following individuals: the GENECARD Investigators Network, and the faculty and staff at the Center for Human Genetics for their innumerable contributions to this manuscript. This work was supported by NIH grants HL073389 and MH595228 and an award from the Neurosciences Education and Research Foundation. This work was supported in part by an appointment to the Research Participation Program at the Office of Research and Development, US Environmental Protection Agency.

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  1. Center for Human Genetics, School of Medicine, Duke University Medical Center, Box 3382, Durham, NC, 27710, USA

    Cavin Ward-Caviness, Carol Haynes, Colette Blach, Elaine Dowdy, Simon G. Gregory, Svati H. Shah, William E. Kraus & Elizabeth R. Hauser

  2. Division of Cardiovascular Medicine, School of Medicine, Duke University Medical Center, Durham, NC, 27710, USA

    Svati H. Shah & William E. Kraus

  3. Cardiovascular Department, Intermountain Medical Center, University of Utah, 391 Chipeta Way, Suite D, Salt Lake City, UT, 84122, USA

    Benjamin D. Horne

  4. Epidemiologic Research and Information Center, Durham Veterans Affairs Medical Center, Durham, NC, USA

    Elizabeth R. Hauser

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  1. Cavin Ward-Caviness
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  4. Elaine Dowdy
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Correspondence to Cavin Ward-Caviness.

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Ward-Caviness, C., Haynes, C., Blach, C. et al. Gene–smoking interactions in multiple Rho-GTPase pathway genes in an early-onset coronary artery disease cohort. Hum Genet 132, 1371–1382 (2013). https://doi.org/10.1007/s00439-013-1339-7

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