Abstract P185: Novel Loci for Blood Pressure Using Gene-alcohol Interactions and 1000g Imputed Data
Alcohol consumption has a complex relationship with blood pressure (BP). Whereas heavy alcohol consumption is associated with high BP, moderate alcohol consumption is associated with unchanged or modestly lower BP. We performed genome-wide meta-analysis of single SNP x alcohol drinking status interaction on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) blood pressure using 1000G imputed data. Our preliminary results comprise 23 European ancestry studies, including 87,098 individuals with known drinking status. Interaction associations were preformed using linear regression with main and interaction effects and accounting for family structure as needed. Meta-analyses were performed with METAL, for a 2 degrees of freedom joint test, after applying study- and meta-based genomic control adjustments. Results were further filtered if the meta-analysis N < 5,000 individuals or if the number of cohorts contributing to meta-analysis were < 3 for each SNP. For DBP, six novel loci (TRAF3IP1, ANKRD36, NLGN1, UBE3D, OFCC1 and C1orf167) were identified (p < 5E-08). Known BP loci were found to be significant using the same interaction model, including MTHFR, CLCN6, NPPB, MECOM, NOS3, CACNB2, SH2B3, ATXN2, ALDH2, ATP2B1, CSK, FURIN and ZNF831. The significant DBP genes are enriched for hypertension (p-FDR=8.5E-08) and cardiac arrhythmias (p-FDR=5.3E-07) disease loci. MAP analyses identified similar loci as for DBP, while for SBP, ANKRD36 SNPs yielded the most significant associations. For PP, MYPN variants were most significant. In general for the joint test, known BP gene variants showed non-significant levels of meta-heterogeneity and common allele frequency (≥5%), whereas the novel loci often presented meta-heterogeneity and low allele frequency (≈1-5%). TRAF3IP1 interacts among others with TRAF3, reported in mice involved in a new pathway TRAF3-TBK1-AKT for cardiac hypertrophy and heart failure. ANKRD36 interacts with PHLPP2, involved in rats in FKBP51-PHLPP2-AKT signaling during cerebral ischemia/reperfusion injury. NLGN1 has been reported to associate with BP in ASCOT study (N=3,802), while in our meta-analysis out of 6 contributing studies, the joint test significance originates only from the GS_SFHS (N=6,504). Another significant result was C1orf167- rs12561919, a missense SNP considered cis-eQTL for neighboring BP known genes CLCN6 and MTHFR. Employing SNP x drinking status interaction for BP traits, we identified both novel and previously known BP genes. Our findings may provide insights into mechanisms underlying BP and inform lifestyle and therapeutic BP interventions.
Author Disclosures: M.F. Feitosa: None. T.W. Winkler: None. A.R. Bentley: None. M.R. Brown: None. T.M. Bartz: None. D.I. Chasman: None. R. Dorajoo: None. M. Fornage: None. N. Franceschini: None. X. Guo: None. S. Aslibekyan: None. C. Hayward: None. S.L.R. Kardia: None. K. Lohman: None. R.J.F. Loos: None. J. Marten: None. B. Tayo: None. D. Vojinovic: None. W. Xu: None. A. Morrison: None. D.C. Rao: None. I.B. Borecki: A. Employment; Significant; Regeneron Pharmaceuticals. M.A. Province: None. A.T. Kraja: None. L.A. Cupples: None.
- © 2016 by American Heart Association, Inc.