NEW YORK (GenomeWeb) – An international team led by investigators in the US and UK have identified previously unappreciated blood pressure (BP) contributors using a genome-wide association study approach that took individuals' cigarette smoking status into account.
Within the "Cohorts for Heart and Aging Research in Genomic Epidemiology" (CHARGE) consortium, researchers from a Gene-Lifestyle Interactions Working Group did a two-stage GWAS and meta-analysis involving more than 600,000 participants from up to five ancestry groups. Along with individuals' systolic BP, diastolic BP, and genotype, their analysis, published online today in the American Journal of Human Genetics, included information on smoking status, which is believed to impact BP.
"Cigarette smoking is known to influence BP in both [an] acute and chronic fashion, motivating genetic association studies accounting for potential gene-by-smoking interactions," the authors explained. "This may help identify BP loci, and such BP loci driven by [gene-by-environment] interactions may reveal new biological insights and mechanisms that can be explored for treatment or prevention of hypertension."
Using this approach, the team tracked down 56 known BP risk loci, and dozens of loci that appeared to coincide with BP traits in one or more of the populations considered — a set that spanned regulatory, cardiometabolic, vascular, and addiction-related sites in the genome. Though 10 loci initially showed ties to smoking status, those associations were not validated beyond the first stage of the study.
For the first phase of the study, the researchers considered resting systolic BP and resting diastolic BP measurements, medication status, current or ever smoking status, when available, and Illumina or Affymetrix (Thermo Fisher Scientific) array-based genotyping data for 129,913 individuals from four-dozen cohorts of European, African, Asian, or Hispanic ancestry. The search led to thousands of SNPs with significant or suggestive ties to systolic and/or diastolic BP traits in the first stage of the analysis.
When they took 4,459 of the SNPs forward for testing in another 480,178 individuals from European, African, Asian, Hispanic, or Brazilian-admixed ancestry groups, the researchers validated 15 new loci and many more known associations, including loci with ancestry-specific or across-ancestry links to BP.
By combining data from the first and second stages of the study in a meta-analysis, meanwhile, the team found 66 more candidate loci and 16 loci implicated in BP traits previously. Of those, 13 and 35 of the new BP-associated loci from the meta-analyses appeared to be specific to individuals of European or African ancestry, respectively, while 18 of the loci had BP affects across the ancestry groups considered.
"Among the 81 index variants, 10 variants showed genome-wide significant interactions with smoking exposure status," the authors wrote. "All 10 of these variants, most of which were identified in African ancestry, show larger effects on BP in smokers."
The interactions were not replicated when the researchers incorporated information for all individuals with a history of smoking, rather than just current smokers, perhaps due to heterogeneity in the ever-smoker group, they noted.
Through a series of expression quantitative trait locus, pathway, gene set enrichment, and other functional analyses, the researchers found that the BP-associated loci included variants in genes previously implicated in everything from ciliopathies, telomere maintenance, dopaminergic signaling, and vascular function to pathways implicated in obesity, diabetes, or hypertension.
"Our findings demonstrate how the interplay between genes and environment can help identify loci, open up new avenues for investigation about BP homeostasis, and highlight the promise of gene-lifestyle interactions for more in-depth genetic and environmental dissection of BP and other complex traits," the authors concluded.