Although it has long been recognized that hypertension prevalence increases with aging in both women and men, recent data have clarified how blood pressure (BP) trajectories differ by sex.1 These differences may contribute to sexual dimorphism in hypertension-related disease outcomes and are likely derived in part from genetic origins. Indeed, accumulating evidence indicates that sex bias in gene expression – extending well beyond sex chromosomes – is related to phenotypic variation across organ systems as well as species.2 Therefore, in a large population-wide cohort comprised almost equally of females and males, we conducted a comprehensive a priori sex-specific genome-wide analysis of single nucleotide polymorphisms (SNPs) to further elucidate the genetic architecture underlying sex differences in BP elevation.
Our study sample comprised 218792 genotyped Finnish individuals from FinnGen Data Freeze 5.3 For each participant, biospecimen derived genotype data were linked to clinical data provided by nationwide hospital medical records and death register records (follow-up period 1969-2018), as previously described.3 Sex-specific systolic BP polygenic risk scores (PRS) were calculated using UK Biobank sex-specific genome-wide association study summary statistics for systolic BP on 1098015 SNPs and a PRS continuous shrinkage pipeline.3 We used Cox proportional hazards models to assess the association between the PRS and hypertension separately in women and men. Age was considered the timescale, and we used collection year, genotyping batch, and the first ten genetic principal components as covariates in all models. We considered two-tailed P-values <0.05 as statistically significant and used R v.4.0.2 for all analyses.
Our study sample consisted of 218792 individuals (56% women, mean age at end of follow-up 58±11 years), including 123,579 women and 95,213 men with 27,804 and 28,113 cases of incident hypertension, respectively. We observed 27,361 cases of early-onset hypertension (age <55 years) and 28,556 cases of late-onset hypertension.
The PRS was more profoundly associated with hypertension in women than in men, particularly in the highest and in the lowest ranges of PRS (Table 1). The hazard ratios (HR) per 1-SD increase in the overall PRS were 1.42 (95% confidence interval [CI] 1.40-1.44) in women and 1.27 (95% CI 1.26-1.29) in men, with P for interaction = 4x10−29. This sex difference was especially pronounced for relations of PRS with early-onset hypertension (manifesting at age <55 years): HR 1.56 (95% CI 1.53-1.58) for women, HR 1.35 (95% CI 1.32-1.37) for men; P for interaction = 1x10−28 (Table 1). For late-onset hypertension, the corresponding HRs were 1.31 (95% CI 1.28-1.33) for women and HR 1.21 (95% CI 1.19-1.23) for men; P for interaction = 2x10−9.
Table 1.
Risk of hypertension for women and men by category of genetic risk score.
| Polygenic Risk Score | WOMEN | MEN | Interaction P-value | ||||
|---|---|---|---|---|---|---|---|
| Cases / Controls | HR (95% CI) | P-value | Cases / Controls | HR (95% CI) | P-value | ||
| ANY HYPERTENSION | |||||||
| <2.5% | 340 / 2749 | 0.41 (0.37, 0.45) | 8x10−60 | 485 / 1896 | 0.61 (0.56, 0.67) | 5x10−26 | 9x10−08 |
| 2.5-20% | 3401 / 18221 | 0.64 (0.61, 0.66) | 1x10−126 | 3966 / 12694 | 0.75 (0.72, 0.77) | 2x10−61 | 1x10−08 |
| 20-80% | 16510 / 57621 | 1 (referent) | - | 16661 / 40456 | 1 (referent) | - | - |
| 80-97.5% | 6451 / 15172 | 1.52 (1.48, 1.57) | 7x10−177 | 5978 / 10683 | 1.37 (1.33, 1.41) | 3x10−94 | 1x10−05 |
| >97.5% | 1102 / 1987 | 2.12 (1.99, 2.25) | 2x10−126 | 1023 / 1358 | 1.80 (1.69, 1.92) | 5x10−74 | 0.003 |
| EARLY-ONSET HYPERTENSION (age of onset <55 years) | |||||||
| <2.5% | 111 / 2979 | 0.33 (0.28, 0.40) | 2x10−30 | 213 / 2168 | 0.60 (0.53, 0.69) | 4x10−13 | 1x10−06 |
| 2.5-20% | 1236 / 20389 | 0.54 (0.50, 0.57) | 3x10−91 | 1706 / 14955 | 0.70 (0.66, 0.74) | 1x10−40 | 2x10−10 |
| 20-80% | 7612 / 66530 | 1 (referent) | - | 8150 / 48974 | 1 (referent) | - | - |
| 80-97.5% | 3618 / 18007 | 1.71 (1.65, 1.78) | 2x10−153 | 3353 / 13309 | 1.47 (1.41, 1.53) | 8x10−77 | 5x10−07 |
| >97.5% | 702 / 2387 | 2.51 (2.32, 2.72) | 7x10−119 | 660 / 1721 | 2.10 (1.94, 2.28) | 2x10−74 | 0.005 |
| LATE-ONSET HYPERTENSION (age of onset ≥55 years) | |||||||
| <2.5% | 229 / 2860 | 0.46 (0.40, 0.52) | 2x10−31 | 272 / 2109 | 0.62 (0.55, 0.70) | 9x10−15 | 0.002 |
| 2.5-20% | 2165 / 19458 | 0.71 (0.68, 0.74) | 1x10−45 | 2260 / 14401 | 0.78 (0.75, 0.82) | 1x10−24 | 0.005 |
| 20-80% | 8898 / 65238 | 1 (referent) | - | 8511 / 48609 | 1 (referent) | - | - |
| 80-97.5% | 2833 / 18791 | 1.34 (1.28, 1.39) | 3x10−40 | 2625 / 14036 | 1.26 (1.21, 1.32) | 4x10−25 | 0.1 |
| >97.5% | 400 / 2690 | 1.66 (1.50, 1.84) | 5x10−23 | 363 / 2018 | 1.45 (1.30, 1.61) | 7x10−12 | 0.09 |
We used the Cox proportional hazards models to estimates hazard ratios within categories of the sex-specific genetic risk score for blood pressure. We used age as the timescale and adjusted models for the collection year, genotyping batch, and the first ten genetic principal components. Abbreviations: HR = hazard ratio, CI = confidence interval.
In our study sample of over 200,000 individuals followed for almost 5 decades, we found that sex-specific genetic risk traits are more profoundly associated with risk for hypertension in women than in men, and particularly early-onset hypertension. In effect, our results demonstrate that presence of a low genetic burden offered more protection from hypertension in women than in men.
Numerous prior studies have reported on polygenic risk traits in relation to hypertension in large cohorts.4 Recently, compelling evidence has demonstrated the role of sex-biased gene expression across all chromosomes in determining phenotypic variation across organ systems.2 Thus, given increasing recognition of sex differences in BP traits, we derived sex-specific polygenic risk scores. Our results are distinct from sex-agnostic measures of genetic risk demonstrating no substantial sex differences in relation to outcomes.5
Early-onset hypertension has been related to elevated risk for cardiovascular death and females have a more accelerated rise in BP with aging, a greater sensitivity of BP elevation to the presence of cardiometabolic traits, and higher level of risk for cardiovascular outcomes for a given elevation of BP.1 This suggest that genetic risk traits for hypertension exert effects that are not only more pronounced in women than men but also have repercussions extending to hypertension-related outcomes. Notably, the genetic risk traits studied were not related to loci on sex chromosomes, by convention, which underscores the relative independence of effects from gonadal traits.
Regarding potential limitations, our study sample included data from hospital biobanks and patient cohorts, which can lead to overestimates of absolute risk. In addition, the participants’ menopausal status was not available. As in most genome wide studies, we analyzed only autosomal variants. Furthermore, our sample comprised only individuals of European ancestry.
In conclusion, we found evidence of a sex-specific genetic burden of risk for hypertension, particularly early-onset hypertension, that is more pronounced in women than men. These findings may help to inform clinicians around approaches to communicating with female and male patients with hypertension, prioritizing pharmacotherapy versus lifestyle interventions for managing BP elevation, and considering the potential utility of genetic risk screening tools in the future.
ACKNOWLEDGEMENTS
We thank the participants and investigators of the FinnGen and UK Biobank studies for their invaluable contributions to this work.
SOURCES OF FUNDING
This work has been funded by the Academy of Finland (321351), the Finnish Foundation for Cardiovascular Research, the Paavo Nurmi Foundation, the Finnish Medical Foundation, the Emil Aaltonen Foundation, the Hospital District of Southwest Finland, and National Institutes of Health grants R01-HL134168, R01-HL131532, R01-HL143227, R01-HL142983, K23-HL153888, and U54-AG065141.
Footnotes
DISCLOSURES
The authors declare that they have no conflict of interest.
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