Genetically predicted sex hormone binding globulin and ischemic heart disease in men and women: a univariable and multivariable Mendelian randomization study

Zhao, Jie; Schooling, C. Mary

doi:10.1038/s41598-021-02510-w

Cited by 9 publications

(6 citation statements)

References 63 publications

(85 reference statements)

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“…In addition, significant men-women differences in sex hormone genetic traits [52][53][54], BMI genetic traits (obesity, waist/hip circumference, etc.) [55][56][57][58][59] and insulin/type 2 diabetes genetic traits [59,60] have been demonstrated at the GWAS level, which may be remarkable genetic predictors of sex-specific differences for cardiovascular diseases [61][62][63][64][65].…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Features of the Correlation between GWAS-Noticeable Polymorphisms and Hypertension in Europeans of Russia

Иванова

Churnosova

Abramova

et al. 2023

IJMS

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The aim of the study was directed at studying the sex-specific features of the correlation between genome-wide association studies (GWAS)-noticeable polymorphisms and hypertension (HTN). In two groups of European subjects of Russia (n = 1405 in total), such as men (n = 821 in total: n = 564 HTN, n = 257 control) and women (n = 584 in total: n = 375 HTN, n = 209 control), the distribution of ten specially selected polymorphisms (they have confirmed associations of GWAS level with blood pressure (BP) parameters and/or HTN in Europeans) has been considered. The list of studied loci was as follows: (PLCE1) rs932764 A > G, (AC026703.1) rs1173771 G > A, (CERS5) rs7302981 G > A, (HFE) rs1799945 C > G, (OBFC1) rs4387287 C > A, (BAG6) rs805303 G > A, (RGL3) rs167479 T > G, (ARHGAP42) rs633185 C > G, (TBX2) rs8068318 T > C, and (ATP2B1) rs2681472 A > G. The contribution of individual loci and their inter-locus interactions to the HTN susceptibility with bioinformatic interpretation of associative links was evaluated separately in men’s and women’s cohorts. The men–women differences in involvement in the disease of the BP/HTN-associated GWAS SNPs were detected. Among women, the HTN risk has been associated with HFE rs1799945 C > G (genotype GG was risky; ORGG = 11.15 ppermGG = 0.014) and inter-locus interactions of all 10 examined SNPs as part of 26 intergenic interactions models. In men, the polymorphism BAG6 rs805303 G > A (genotype AA was protective; ORAA = 0.30 ppermAA = 0.0008) and inter-SNPs interactions of eight loci in only seven models have been founded as HTN-correlated. HTN-linked loci and strongly linked SNPs were characterized by pronounced polyvector functionality in both men and women, but at the same time, signaling pathways of HTN-linked genes/SNPs in women and men were similar and were represented mainly by immune mechanisms. As a result, the present study has demonstrated a more pronounced contribution of BP/HTN-associated GWAS SNPs to the HTN susceptibility (due to weightier intergenic interactions) in European women than in men.

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Section: Introductionmentioning

confidence: 99%

Sex-Specific Features of the Correlation between GWAS-Noticeable Polymorphisms and Hypertension in Europeans of Russia

Иванова

Churnosova

Abramova

et al. 2023

IJMS

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“…Inconsistent results have been reported previously for the association of SHBG and MI, though a growing body of evidence has also demonstrated the same directional relationship as we observe. A Mendellian randomisation study also showed genetically predicted higher SHBG was associated with lower risk of ischemic heart disease in men [ 35 ]. The previously mentioned study by Yeap and colleagues also showed men with lower SHBG concentrations have higher risk for MI in their analyses of UK Biobank data [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Sex hormones and the risk of myocardial infarction in women and men: a prospective cohort study in the UK Biobank

Harris,

Peters,

Woodward

2023

Biol Sex Differ

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Objectives There is conflicting evidence around the role of sex hormones with cardiovascular outcomes. The aim of this study was to examine the association of sex hormones with the risk of myocardial infarction (MI) in pre- and post-menopausal women, and men in the UK Biobank. Methods The UK Biobank is a prospective population-based cohort study, that recruited over 500,000 (aged 40–69 years) women and men between 2006 and 2010. Sex specific cox regression models, estimating hazard ratios (HRs) and women to men ratio of HRs (RHR) with respective 95% confidence intervals (CI), were used to model the association of sex hormones [oestrogen, testosterone, oestrogen: testosterone (O/T) ratio, sex hormone–binding globulin (SHBG) and the free androgen index (FAI)], measured at study baseline, with incident MI for women and men. Results Data were from 479,797 participants [264,282 (55.1%) women] without a history of MI at study baseline. Over 12.5 years of follow-up, there were 4,908 MI events in women and 10,517 in men. Neither oestrogen nor testosterone were associated with MI in women and men after multiple adjustment. For men, but not women, a unit higher log-transformed O/T ratio was associated with a lower risk of MI 0.79 (0.65, 0.95) after adjustment for traditional CVD risk factors. The corresponding women to men RHR (95% CI) was 1.24 (0.99, 1.56). Higher SHBG (per unit) was also associated with a lower risk of MI in men 0.94 (0.89, 0.99), and not in women 1.02 (0.95, 1.09) after multiple adjustment, the corresponding women to men RHR (95% CI) was 1.09 (1.00, 1.18). Higher FAI was associated with a higher risk of MI in men 1.09 (1.02, 1.15), though not in women 0.97 (0.92, 1.02), the corresponding women to men RHR was 0.89 (0.82, 0.97). Finally, there were differential effects in the association of SHBG and FAI between pre- and post-menopausal women. Conclusions A higher O/T ratio was associated with a lower risk of MI, and a higher FAI with a higher risk of MI after adjustment for CVD risk factors in men, but not in women. Thus, hormone ratios, rather than each alone, may play an important role in modulating the effect of MI.

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“…Studies on the role of sex hormones in men’s health, although scarce, imply that higher levels of testosterone might be associated with a higher risk of CVD [ 76 ]. Also, sex hormone binding globulin (SHBG), which lowers circulating testosterone, might protect against CHD in men [ 65 ]. Future studies are needed to simultaneously assess the effects of multiple sex hormones, and their combinations, on a range of health outcomes in both women and men.…”

Section: Elements Of Sex and Gender-disaggregated Research Methodsmentioning

confidence: 99%

“…A main barrier for sex-specific MR is the limited public availability of sex-specific GWAS results. However, sex-specific MR studies have provided novel insights in the sex-specific effects of risk factors on disease outcomes (Table 6) [64][65][66]. MR can also be used to assess sex differences in the efficacy and safety of drug treatments [67].…”

Section: Sex-specific Mendelian Randomisation To Strengthen Sex-diffe...mentioning

confidence: 99%

A roadmap for sex- and gender-disaggregated health research

Peters,

Woodward

2023

BMC Med

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Sex and gender are fundamental aspects of health and wellbeing. Yet many research studies fail to consider sex or gender differences, and even when they do this is often limited to merely cataloguing such differences in the makeup of study populations. The evidence on sex and gender differences is thus incomplete in most areas of medicine. This article presents a roadmap for the systematic conduct of sex- and gender-disaggregated health research. We distinguish three phases: the exploration of sex and gender differences in disease risk, presentation, diagnosis, treatment, and outcomes; explaining any found differences by revealing the underlying mechanisms; and translation of the implications of such differences to policy and practice. For each phase, we provide critical methodological considerations and practical examples are provided, taken primarily from the field of cardiovascular disease. We also discuss key overarching themes and terminology that are at the essence of any study evaluating the relevance of sex and gender in health. Here, we limit ourselves to binary sex and gender in order to produce a coherent, succinct narrative. Further disaggregation by sex and gender separately and which recognises intersex, non-binary, and gender-diverse identities, as well as other aspects of intersectionality, can build on this basic minimum level of disaggregation. We envision that uptake of this roadmap, together with wider policy and educational activities, will aid researchers to systematically explore and explain relevant sex and gender differences in health and will aid educators, clinicians, and policymakers to translate the outcomes of research in the most effective and meaningful way, for the benefit of all.

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Genetically predicted sex hormone binding globulin and ischemic heart disease in men and women: a univariable and multivariable Mendelian randomization study

Cited by 9 publications

References 63 publications

Sex-Specific Features of the Correlation between GWAS-Noticeable Polymorphisms and Hypertension in Europeans of Russia

Sex-Specific Features of the Correlation between GWAS-Noticeable Polymorphisms and Hypertension in Europeans of Russia

Sex hormones and the risk of myocardial infarction in women and men: a prospective cohort study in the UK Biobank

A roadmap for sex- and gender-disaggregated health research

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