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Genes interact with smoking status to influence BP regulation
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Newly identified genetic loci were associated with smoking status and BP regulation, according to a meta-analysis published in The American Journal of Human Genetics.
“Despite tremendous efforts, we continue to have a lot of difficulty controlling blood pressure in many patients,” Lisa de las Fuentes, MD, MS, associate professor of medicine and biostatistics in the division of cardiology at Washington University School of Medicine in St. Louis, said in a press release. “Even when we try every tool in our arsenal, some patients still don’t respond to medications the way we would expect them to. There are probably biological reasons for this that we haven’t tapped into yet. Our study identified potential genes of interest that we should be investigating for potentially new ways to treat high blood pressure.”
Yun J. Sung, PhD, associate professor of biostatistics at Washington University School of Medicine, and colleagues analyzed data from 610,091 participants from studies that included information on smoking, BP and genotypes across the genome. Patients were from five ancestry groups: European, Asian, African, Hispanic and Brazilian admixed.
In stage 1 of the analysis, genome-wide interaction analyses were performed on 129,913 participants from 48 cohorts. Approximately 18.8 million single nucleotide polymorphisms and either deletion or small insertion variants were included in this stage.
The variants identified in stage 1 (n = 4,459) as genome-wide suggestive (P < 10-6) or significant (P < 5 x 10-8) for BP-smoking combinations were used to replicate results in 480,178 participants from 76 cohorts.
Resting systolic and diastolic BP were analyzed separately. Participants were categorized as current smoking, referring to those who smoked in the past year, or ever smoking, defined as those who smoked at least 100 cigarettes during a lifetime.
Sixty-six additional genome-wide significant loci were identified in a combined stage 1 and stage 2 meta-analysis. BP loci were also found in two-step or combined analyses (n = 56; P < 5 x 10-8).
Ten variants significantly interacted genome-wide with smoking exposure status (1 degree of freedom [df] interaction = P < 5 x 10-8), which had a greater effect on patients with African ancestry. Stage 2 analysis did not replicate these results.
The loci that were identified shared pathophysiology with addition and cardiometabolic traits, and they showed strong evidence for regulatory features. They also played a role in BP regulation for biological candidates such as ciliopathies (RPGRIP1L, SDCCAG8), modulators of vascular structure and function (BCAR1-CFDP1, CDKN1B, EEA1, PXDN), central dopaminergic signaling (EBF2, MSRA) and telomere maintenance (PINX1, TNKS, AKTIP).
“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,” Sung and colleagues wrote. – by Darlene Dobkowski
Disclosures: De las Fuentes and Sung report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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