SEX DIFFERENCES IN THE GENETIC RISK FOR HYPERTENSION

Abstract

Abstract Objective: The development of hypertension differs markedly between men and women. The genetic drivers of this difference have not been fully studied. Genome-wide polygenic risk scores (PRSs), consisting of data from up to 6 M single nucleotide polymorphisms have been shown to considerably improve hypertension risk prediction, particularly in early-onset disease. However, the sex differences in the ability of PRSs to predict hypertension has not been studied previously. Figure Survival curves from Cox proportional hazards models illustrate the cumulative risk of hypertension by systolic blood pressure PRS categories in FinnGen for women and men. We observed 123 579 women and 95 213 men with 27 804 and 28 113 cases of incident hypertension, respectively. Design and method: Our study sample comprised 218792 FinnGen Study participants with lifetime register-based follow-up for incident hypertension (56% women, mean age 58 years). We used publicly available genome-wide association results from UK Biobank to compute sex-specific PRSs for systolic blood pressure. We categorized SBP PRS into five bins according to percentiles (<2.5, 2.5–20, 20–80, 80–97.5, > 97.5) and used middle bin as the reference. We used multivariable-adjusted Cox proportional hazards models to measure the association between the PRSs and incident hypertension. Results: The PRS was more strongly associated with incident hypertension in women than in men (Figure). The hazard ratios (HR) per 1 SD increase in PRSs were 1.42 (95% CI, 1.40–1.44) for women and 1.27 (95% CI, 1.26–1.29) with an interaction P-value of 4x10–29. The difference between women (HR, 1.56; 95% CI, 1.53–1.58) and men (HR, 1.35; 95% CI, 1.32–1.37) was even greater for early-onset hypertension (onset at age < 55 years). Men and women in the top 2.5 PRS percentile had 2.1-fold (95% CI, 2.0–2.3) and 1.8-fold (95% CI, 1.7–1.9) greater risks of developing hypertension than the reference group. Conclusions: The genetic risk of hypertension appears to be more distinctive in women than in men, which may reflect physiological differences starting already at an early age. These results emphasize the use of sex-specific PRSs in clinical prediction of hypertension.