Portal de Periódicos da CAPES

Sex Differences in Genetic Risk for Hypertension

2021; Lippincott Williams & Wilkins; Volume: 78; Issue: 4 Linguagem: Inglês

10.1161/hypertensionaha.121.17796

1524-4563

Anni Kauko, Jenni Aittokallio, Felix Vaura, Hongwei Ji, Joseph E. Ebinger, Teemu Niiranen, Susan Cheng,

Hormonal Regulation and Hypertension

HomeHypertensionVol. 78, No. 4Sex Differences in Genetic Risk for Hypertension Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBSex Differences in Genetic Risk for Hypertension Anni Kauko, Jenni Aittokallio, Felix Vaura, Hongwei Ji, Joseph E. Ebinger, Teemu Niiranen and Susan Cheng Anni KaukoAnni Kauko Correspondence to: Anni Kauko, Department of Internal Medicine, University of Turku, Kiinamyllynkatu 4–8, Turku 20014, Finland, Email E-mail Address: [email protected] https://orcid.org/0000-0003-1131-3865 Department of Internal Medicine (A.K., F.V., T.N.), University of Turku, Finland. , Jenni AittokallioJenni Aittokallio Department of Anesthesiology and Intensive Care (J.A.), University of Turku, Finland. Division of Perioperative Services, Intensive Care and Pain Medicine (J.A.), Turku University Hospital, Finland. , Felix VauraFelix Vaura https://orcid.org/0000-0002-6036-889X Department of Internal Medicine (A.K., F.V., T.N.), University of Turku, Finland. , Hongwei JiHongwei Ji https://orcid.org/0000-0003-3657-4666 Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (H.J., J.E.E., S.C.). , Joseph E. EbingerJoseph E. Ebinger https://orcid.org/0000-0002-0587-1572 Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (H.J., J.E.E., S.C.). , Teemu NiiranenTeemu Niiranen Department of Internal Medicine (A.K., F.V., T.N.), University of Turku, Finland. Division of Medicine (T.N.), Turku University Hospital, Finland. Department of Public Health Solutions, Finnish Institute for Health and Welfare, Turku, Finland (T.N.). and Susan ChengSusan Cheng Susan Cheng, Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, Email E-mail Address: [email protected] Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (H.J., J.E.E., S.C.). Division of Cardiology, Brigham and Women’s Hospital, Boston, MA (S.C.). Originally published15 Aug 2021https://doi.org/10.1161/HYPERTENSIONAHA.121.17796Hypertension. 2021;78:1153–1155Although 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 to further elucidate the genetic architecture underlying sex differences in BP elevation.Our study sample comprised 218 792 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 described previously.3 Sex-specific systolic BP polygenic risk scores (PRSs) were calculated using UK Biobank sex-specific genome-wide association study summary statistics for systolic BP on 1 098 015 single-nucleotide polymorphisms 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 10 genetic principal components as covariates in all models. We considered 2-tailed P<0.05 as statistically significant and used R v.4.0.2 for all analyses.Our study sample consisted of 218 792 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). The hazard ratios (HRs) per 1-SD increase in the overall PRS were 1.42 (95% CI, 1.40–1.44) in women and 1.27 (95% CI, 1.26–1.29) in men, with P for interaction of 4×10−29. 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 and 1.35 [95% CI, 1.32–1.37] for men; P for interaction, 1×10−28; Table). For late-onset hypertension, the corresponding HRs were 1.31 (95% CI, 1.28–1.33) for women and 1.21 (95% CI, 1.19–1.23) for men (P for interaction, 2×10−9).Table. Risk of Hypertension for Women and Men by Category of Genetic Risk ScorePRSWomenMenInteraction P valueCases/controlsHR (95% CI)P valueCases/controlsHR (95% CI)P valueAny hypertension 97.5%1102/19872.12 (1.99–2.25)2×10−1261023/13581.80 (1.69–1.92)5×10−740.003Early-onset hypertension (age of onset <55 y) 97.5%702/23872.51 (2.32–2.72)7×10−119660/17212.10 (1.94–2.28)2×10−740.005Late-onset hypertension (age of onset ≥55 y) 97.5%400/26901.66 (1.50–1.84)5×10−23363/20181.45 (1.30–1.61)7×10−120.09We used the Cox proportional hazards models to estimate HRs 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 10 genetic principal components. HR indicates hazard ratio; and PRS, polygenic risk score.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 the 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 the increasing recognition of sex differences in BP traits, we derived sex-specific PRSs. Our results are distinct from sex-agnostic measures of genetic risk demonstrating no substantial sex differences in relation to outcomes.5Early-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 suggests 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 in 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.AcknowledgmentsWe thank the participants and investigators of the FinnGen and UK Biobank studies for their invaluable contributions to this work.Sources of FundingThis 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 the National Institutes of Health grants R01-HL134168, R01-HL131532, R01-HL143227, R01-HL142983, K23-HL153888, and U54-AG065141.DisclosuresNone.Footnotes*T. Niiranen and S. Cheng contributed equally.For Sources of Funding and Disclosures, see page 1154.Correspondence to: Anni Kauko, Department of Internal Medicine, University of Turku, Kiinamyllynkatu 4–8, Turku 20014, Finland, Email [email protected]fiSusan Cheng, Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, Email susan.[email protected]orgReferences1. Ji H, Kim A, Ebinger JE, Niiranen TJ, Claggett BL, Bairey Merz CN, Cheng S. Sex differences in blood pressure trajectories over the life course.JAMA Cardiol. 2020; 5:19–26. doi: 10.1001/jamacardio.2019.5306CrossrefMedlineGoogle Scholar2. Naqvi S, Godfrey AK, Hughes JF, Goodheart ML, Mitchell RN, Page DC. Conservation, acquisition, and functional impact of sex-biased gene expression in mammals.Science. 2019; 365:eaaw7317. doi: 10.1126/science.aaw7317CrossrefMedlineGoogle Scholar3. Vaura F, Kauko A, Suvila K, Havulinna AS, Mars N, Salomaa V, FinnGen , Cheng S, Niiranen T. Polygenic risk scores predict hypertension onset and cardiovascular risk.Hypertension. 2021; 77:1119–1127. doi: 10.1161/HYPERTENSIONAHA.120.16471LinkGoogle Scholar4. Giri A, Hellwege JN, Keaton JM, Park J, Qiu C, Warren HR, Torstenson ES, Kovesdy CP, Sun YV, Wilson OD, et al.; Understanding Society Scientific Group; International Consortium for Blood Pressure; Blood Pressure-International Consortium of Exome Chip Studies; Million Veteran Program. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.Nat Genet. 2019; 51:51–62. doi: 10.1038/s41588-018-0303-9CrossrefMedlineGoogle Scholar5. Oikonen M, Tikkanen E, Juhola J, Tuovinen T, Seppälä I, Juonala M, Taittonen L, Mikkilä V, Kähönen M, Ripatti S, et al.. Genetic variants and blood pressure in a population-based cohort: the cardiovascular risk in young finns study.Hypertension. 2011; 58:1079–1085. doi: 10.1161/HYPERTENSIONAHA.111.179291LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByVaura F, Palmu J, Aittokallio J, Kauko A and Niiranen T (2022) Genetic, Molecular, and Cellular Determinants of Sex-Specific Cardiovascular Traits, Circulation Research, 130:4, (611-631), Online publication date: 18-Feb-2022.Ji H, Kwan A, Chen M, Ouyang D, Ebinger J, Bell S, Niiranen T, Bello N and Cheng S (2022) Sex Differences in Myocardial and Vascular Aging, Circulation Research, 130:4, (566-577), Online publication date: 18-Feb-2022. October 2021Vol 78, Issue 4Article InformationMetrics Download: 226 © 2021 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.121.17796PMID: 34397277 Originally publishedAugust 15, 2021 Keywordssex differencesgeneticshypertensionepidemiologyblood pressurePDF download SubjectsGeneticsWomen, Sex, and GenderEpidemiologyHypertensionHigh Blood Pressure