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Blood Pressure GWAS Highlights Sex-Specific Risk Variants, Links to Cardiovascular Disease

Blood Pressure

NEW YORK – New research suggests that a subset of genetic loci linked to blood pressure traits have sex-specific effects, providing an avenue for better understanding related cardiovascular conditions that are more prevalent in women than men.

"These data inform our understanding of blood pressure regulation and how biologic sex matters, at a molecular level," Santhi Ganesh, a researcher at the University of Michigan and corresponding author of the study, said in an email, adding that "identification of specific genetic loci and gene regulation effects is an important advance in the field, towards a molecular understanding of BP regulation and the role of biologic sex."

For their research, appearing in Nature Medicine on Friday, Ganesh and colleagues examined genotyping profiles and blood pressure measurements for more than 349,300 participants in the UK Biobank project. They performed a combined genome-wide association study, along with a sex-specific GWAS, searching for variants with overall or sex-specific associations with systolic blood pressure, diastolic blood pressure, and pulse pressure.

In the process, they tracked down 29 new blood pressure loci, along with 1,346 loci linked to the trait in the past. The set included 412 loci that coincided with blood pressure features in female participants and 142 loci that appeared to have male-specific blood pressure effects — results that were subsequently validated with data from more than 144,000 participants in cohorts from the Michigan Genomics Initiative and Kaiser Permanente.

"We confirmed many known associations with blood pressure that were previously defined by analyzing male and female individuals together," Ganesh explained. "By accounting for biologic sex, we identified important sex differences and notable sex-specific associations."

More broadly, the team suspected that female-specific genetic contributors to blood pressure traits might inform efforts to understand the overrepresentation of certain cardiovascular diseases (CVDs) in women.

"Our findings revealed genetic heterogeneity of [blood pressure] effects between sexes, with more pronounced genetic effects in female individuals impacting genome regulation and related CVD risks," the authors wrote, adding that the data "address knowledge gaps in CVDs that disproportionately burden female individuals, contributing to a better understanding of these understudied conditions."

By bringing in additional arterial expression quantitative trait locus data from the Genotype-Tissue Expression project, along with gene colocalization clues and epigenomic tissue enrichment profiles, the team identified a chromosome 13 locus and other parts of the genome that were enriched for female-specific risk variants coinciding with diastolic blood pressure and pulse pressure. Similarly, loci linked to pulse pressure in female participants encompassed sites marked by higher-than-usual levels of specific acetylated histone marks in arterial tissues.

With additional polygenic risk score, fine-mapping, and cross-trait analyses, meanwhile, the investigators delved into ties between female-specific blood pressure loci and traits related to cardiovascular disease (CVD), including a female-biased vascular condition called fibromuscular dysplasia.

"Sex-specific and sex-biased polygenic associations of [blood pressure] traits were associated with multiple cardiovascular traits," the authors reported.

Along with insights into blood pressure architecture, the findings point to the possibility of digging into sex-specific pleiotropy to better understand blood pressure as well as related CVDs, the team explained, while potentially informing future efforts to develop targeted treatments that take sex-specific blood pressure traits influencing CVD risk into account.

"Important next steps of this work will be required to translate these insights into potential targeted therapeutic strategies for [blood pressure]-related CVDs with sex-based manifestations," the authors concluded.