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Background: We systematically reviewed Mendelian randomization (MR) studies and summarized evidence on the potential effects of different antihypertensive drugs on health., Methods: We searched PubMed and Embase for MR studies evaluating the effects of antihypertensive drug classes on health outcomes until 22 May 2024. We extracted data on study characteristics and findings, assessed study quality, and compared the evidence with that from randomized controlled trials (RCTs)., Results: We identified 2643 studies in the search, of which 37 studies were included. These studies explored a wide range of health outcomes including cardiovascular diseases and their risk factors, psychiatric and neurodegenerative diseases, cancer, immune function and infection, and other outcomes. There is strong evidence supporting the protective effects of genetically proxied antihypertensive drugs on cardiovascular diseases. We found strong protective effects of angiotensin-converting enzyme (ACE) inhibitors on diabetes whereas beta-blockers showed adverse effects. ACE inhibitors might increase the risk of psoriasis, schizophrenia, and Alzheimer's disease but did not affect COVID-19. There is strong evidence that ACE inhibitors and calcium channel blockers (CCBs) are beneficial for kidney and immune function, and CCBs showed a safe profile for disorders of pregnancy. Most studies have high quality. RCT evidence supports the beneficial effects of ACE inhibitors and CCBs on stroke, diabetes, and kidney function. However, there is a lack of reliable RCTs to confirm the associations with other diseases., Conclusions: Evidence of the benefits and off-target effects of antihypertensive drugs contribute to clinical decision-making, pharmacovigilance, and the identification of drug repurposing opportunities., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Whether vitamin D deficiency causes atrial fibrillation and ischemic stroke of young onset was unknown. We derived a Genetic Risk Score for vitamin D from 3,922 subjects in Hong Kong and applied it in an independent sample ( n  = 1,297) for clinical outcomes. Primary endpoint was a composite of atrial fibrillation and/or ischemic stroke. A second study was performed in the UK Biobank ( n  = 392,010; 46% men; 14,878 atrial fibrillation and 4,050 ischemic stroke cases, vs 374,102 controls). After 76 ± 46 months, 240 primary endpoints (18.5%) were adjudicated. Higher genetically-predicted vitamin D independently predicted reduced primary endpoint [odds ratio = 0.83 (0.72 to 0.95), p  = 0.008]. Mendelian randomization analyses indicated vitamin D was causally protective against the primary endpoint [odds ratio = 0.81 (95% CI: 0.65 to 0.98)]. Independent analyses in the UK Biobank revealed that vitamin D was protective against young-onset ischemic stroke <50 years and atrial fibrillation combined [odds ratio = 0.36 (95% CI 0.14 to 0.94)], with predominant effect amongst men [odds ratio = 0.28 (95% CI 0.09 to 0.91)] compared to women [odds ratio = 0.60 (95% CI: 0.11 to 3.22)]. In conclusion, vitamin D may protect against young-onset ischemic stroke through preventing atrial fibrillation. Investigating the sex-specifc effects of vitamin D deficiency may elucidate sex disparities of atrial fibrillation in the young., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2024 JCBN.)

Background: Acetate, a short-chain fatty acid, has gained attention for its contrasting roles, with evidence suggesting it may offer cardiovascular protection but also promote cancer, particularly those involving sex hormones. However, these influences have been scarcely assessed in epidemiological research., Objective: To investigate the relationship between acetate and ischemic heart disease (IHD), diabetes, and cancers related to sex hormones., Methods: Mendelian randomization (MR) was used to assess potential causal effects, selecting genetic variants without linkage disequilibrium (r 2 < 0.001) and with genome-wide significance for acetate ( p < 5 × 10 -8 ). These variants were applied to large genome-wide association studies (GWAS) for ischemic heart disease (IHD; up to 154,373 cases), diabetes (109,731 cases), and five sex-hormone-related cancers (breast, colorectal, prostate, ovarian, and endometrial cancers, ranging from 8679 to 122,977 cases). We employed various methods for analysis, including penalized inverse variance weighting (pIVW), inverse variance weighting, weighted mode, and weighted median., Results: This study indicates that acetate may be associated with a lower risk of ischemic heart disease (IHD), with an odds ratio (OR) of 0.62 per standard deviation (SD) increase in acetate and a 95% confidence interval (CI) of 0.39 to 0.98. Additionally, acetate was linked to a higher breast cancer risk, with an OR of 1.26 and a 95% CI ranging from 1.08 to 1.46. This association remained robust across multiple sensitivity analyses., Conclusions: Acetate, along with factors that influence its activity, may serve as possible targets for breast cancer treatment and possibly IHD, offering opportunities for new drug development.

Background: Antihypertensive drugs are known to lower cardiovascular mortality, but the role of different types of antihypertensive drugs in lifespan has not been clarified. Moreover, the underlying mechanisms remain unclear., Methods and Results: To minimize confounding, we used Mendelian randomization to assess the role of different antihypertensive drug classes in longevity and examined the pathways via proteins. Genetic variants associated with systolic blood pressure (SBP) corresponding to drug-target genes were used as genetic instruments. The genetic associations with lifespan were obtained from a large genome-wide association study including 1 million European participants from UK Biobank and LifeGen. For significant antihypertensive drug classes, we performed sex-specific analysis, drug-target analysis, and colocalization. To examine the mediation pathways, we assessed the associations of 2291 plasma proteins with lifespan, and examined the associations of drug classes with the proteins affecting lifespan. After correcting for multiple testing, genetically proxied beta-blockers (BBs), calcium channel blockers (CCBs), and vasodilators were related to longer life years (BBs: 2.03, 95% CI 0.78-3.28 per 5 mmHg reduction in SBP, CCBs: 3.40, 95% CI 1.47-5.33, and vasodilators: 2.92, 95% CI 1.08-4.77). The beneficial effects of BBs and CCBs were more obvious in men. ADRB1, CACNA2D2, CACNB3, CPT1A, CPT2, and EDNRA genes were related to extended lifespan, with CPT2 further supported by colocalization evidence. Eighty-six proteins were related to lifespan, of which four proteins were affected by CCBs. CDH1 may mediate the association between CCBs and lifespan., Conclusions: Beta-blockers, CCBs, and vasodilators may prolong lifespan, with potential sex differences for BBs and CCBs. The role of CCBs in lifespan is partly mediated by CDH1. Prioritizing the potential protein targets can provide new insights into healthy aging., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Air pollution is increasingly linked to impaired kidney function in adults. However, little is known about how early-life exposure to air pollutants affects kidney function in adolescents., Study Design: Cohort study., Methods: We leveraged data from the 'Children of 1997' Hong Kong population-representative birth cohort (N = 8327). Residential exposure to average ambient levels of four air pollutants, including inhalable particle (PM 10 ), sulfur dioxide (SO 2 ), nitrogen dioxide (NO 2 ), and nitrogen monoxide (NO), during in utero, infancy, and childhood periods was estimated using the inverse distance weighting. Kidney function was assessed using estimated glomerular filtration rate (eGFR) calculated from age-adjusted equations for adolescents. Generalized linear regression was used to examine the association of air pollutant exposure in each period with kidney function at 17.6 years. Two-pollutant models tested the robustness of the association., Results: Of the 3350 participants included, 51.4% were boys. Exposure to PM 10 was associated with poorer kidney function. Each interquartile range increment in PM 10 was inversely associated with eGFR (β: -2.933, 95% confidence interval -4.677 to -1.189) in utero, -2.362 (-3.992 to -0.732) infancy, -2.708 (-4.370 to -1.047) childhood, and -2.828 (-4.409 to -1.247) overall. Exposure to PM 10 and SO 2 in utero had a stronger inverse association with kidney function in males. The associations were robust to PM 10 exposure in two-pollutant models., Conclusions: Our findings suggest that early-life exposure to ambient PM 10 and SO 2 is associated with reduced kidney function in adolescents, especially exposure in utero., (Copyright © 2024 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background: Long-term exposure to ambient air pollution is associated with cardiovascular disease (CVD) risk. Little is known about the impact of early-life exposure to air pollutants on CVD risk factors in late adolescence, which may track into adulthood. To clarify, we examined this question in a unique setting with high air pollution and a high level of economic development., Methods: This study leveraged the "Children of 1997" Hong Kong birth cohort (N = 8327), including here 3350 participants. We estimated ambient air pollutant exposure including inhalable particulate matter (PM 10 ), sulfur dioxide (SO 2 ), nitrogen dioxide (NO 2 ) and nitrogen monoxide (NO) by growth phase (in utero, infancy, childhood) and overall based on residential address. Generalized linear regression was used to assess the associations of air pollutants exposure by growth phase and sex with CVD risk factors (fasting blood glucose, glycosylated hemoglobin, lipid profile, blood pressure, and body mass index) at 17.6 years. We also assessed whether associations varied by sex., Results: Early life exposed had little association with glucose metabolism, blood pressure or body mass index, but after considering multiple comparisons early exposure to PM 10 was associated with low density lipoprotein (LDL) in boys, with β and 95 % confidence intervals (95 % CI) of 0.184 (0.069 to 0.298) mmol/l, 0.151 (0.056 to 0.248) mmol/l, and 0.157 (0.063 to 0.252) mmol/l by per interquartile range (IQR) increment of PM 10 for in utero, infancy, and overall, respectively. No such associations were evident for girls, differences by sex were evident., Conclusions: Our study suggested sex-specific associations of early-life PM 10 exposure with elevated LDL in adolescence, especially exposure in utero and infancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: COVID-19 pandemic poses a heavy burden on public health and accounts for substantial mortality and morbidity. Proteins are building blocks of life, but specific proteins causally related to COVID-19, healthspan and lifespan have not been systematically examined., Methods: We conducted a Mendelian randomization study to assess the effects of 1,361 plasma proteins on COVID-19, healthspan and lifespan, using large GWAS of severe COVID-19 (up to 13,769 cases and 1,072,442 controls), COVID-19 hospitalization (32,519 cases and 2,062,805 controls) and SARS-COV2 infection (122,616 cases and 2,475,240 controls), healthspan ( n = 300,477) and parental lifespan (~0.8 million of European ancestry)., Results: We identified 35, 43, and 63 proteins for severe COVID, COVID-19 hospitalization, and SARS-COV2 infection, and 4, 32, and 19 proteins for healthspan, father's attained age, and mother's attained age. In addition to some proteins reported previously, such as SFTPD related to severe COVID-19, we identified novel proteins involved in inflammation and immunity (such as ICAM-2 and ICAM-5 which affect COVID-19 risk, CXCL9, HLA-DRA and LILRB4 for healthspan and lifespan), apoptosis (such as FGFR2 and ERBB4 which affect COVID-19 risk and FOXO3 which affect lifespan) and metabolism (such as PCSK9 which lowers lifespan). We found 2, 2 and 3 proteins shared between COVID-19 and healthspan/lifespan, such as CXADR and LEFTY2, shared between severe COVID-19 and healthspan/lifespan. Three proteins affecting COVID-19 and seven proteins affecting healthspan/lifespan are targeted by existing drugs., Conclusions: Our study provided novel insights into protein targets affecting COVID-19, healthspan and lifespan, with implications for developing new treatment and drug repurposing.

We assessed the causal relation of four glycemic traits and type 2 diabetes liability with 167 metabolites using Mendelian randomization with various sensitivity analyses and a reverse Mendelian randomization analysis. We extracted instruments for fasting glucose, 2-h glucose, fasting insulin, and glycated hemoglobin from the Meta-Analyses of Glucose and Insulin-related traits Consortium (n = 200,622), and those for type 2 diabetes liability from a meta-analysis of multiple cohorts (148,726 cases, 965,732 controls) in Europeans. Outcome data were from summary statistics of 167 metabolites from the UK Biobank (n = 115,078). Fasting glucose and 2-h glucose were not associated with any metabolite. Higher glycated hemoglobin was associated with higher free cholesterol in small low-density lipoprotein. Type 2 diabetes liability and fasting insulin were inversely associated with apolipoprotein A1, total cholines, lipoprotein subfractions in high-density-lipoprotein and intermediate-density lipoproteins, and positively associated with aromatic amino acids. These findings indicate hyperglycemia-independent patterns and highlight the role of insulin in type 2 diabetes development. Further studies should evaluate these glycemic traits in type 2 diabetes diagnosis and clinical management., (© 2024. The Author(s).)

Objectives: The aim of this study was to assess the association of genetically determined iron status with the risk for non-alcoholic fatty liver disease (NAFLD) using two-sample Mendelian randomization (MR) analysis., Methods: We applied single nucleotide polymorphisms (SNPs) associated at genome-wide significance with iron status proxied by serum iron, ferritin, transferrin, and transferrin saturation from the Genetics of Iron status Consortium (N = 48 793), in a genome-wide association study of 1664 NAFLD cases and 400 055 controls from the United Kingdom Biobank. A SNP associated with multiple markers of iron status was only applied to one marker with the strongest association in the main analysis. Their effects on NAFLD were calculated using inverse variance weighting after excluding SNPs associated with alkaline phosphatase and lipid metabolism., Results: The risk for NAFLD is negatively associated with genetically predicted serum transferrin level with a 20% reduction in NAFLD risk per SD (0.65g/L) increase in transferrin (95% confidence interval [CI], 0.66-0.97), and trending positive association with transferrin saturation (odds ratio [OR], 1.50; 95% CI, 0.96-2.35) but it was not associated with serum iron (OR, 0.90; 95% CI, 0.63-1.29) and ferritin (OR, 1.33; 95% CI, 0.54-3.30)., Conclusions: MR analysis provided evidence that genetically predicted higher serum transferrin, indicating lower iron status, may be protective against NAFLD, whereas higher transferrin saturation, indicating higher iron status, might increase the risk for NAFLD and its pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Few studies have examined the role of outdoor air pollution exposure in sarcopenia in Asia. We aimed to investigate the association of outdoor air pollutants exposure with sarcopenia among Chinese adults., Methods: This nationally population-representative study used data from the China Health and Retirement Longitudinal Study (CHARLS) in 2015, 11,700 participants at least 45 years old from 125 Chinese cities were included. Sarcopenia status was identified according to the Asian Working Group for Sarcopenia 2019 (AWGS 2019) criteria. Ambient annual average air pollutants including fine particulate matter (PM 2.5 ), inhalable particles (PM 10 ), coarse particulate matter (PM coarse ), nitrogen dioxide (NO 2 ), sulfur dioxide (SO 2 ), and carbon monoxide (CO) were estimated by satellite models and ground-based measurements. Multinomial logistic regression models were performed to examine the associations of air pollutants exposure with different status of sarcopenia (including possible sarcopenia and sarcopenia). Stratified analyses were utilized to assess the effect modifiers., Results: Among the 11,700 participants (52.6% women), the average age was 61.0 years. Each 10 μg/m 3 increment of annual PM coarse was associated with a higher risk of possible sarcopenia (odds ratio (OR) = 1.08, 95% confidence interval (CI) 1.04-1.11). Stratified analyses showed a positive risk of possible sarcopenia in women after exposure to PM 10 , PM coarse , and NO 2 . Ambient NO 2 exposure was positively associated with sarcopenia (OR = 1.13, 95% CI 1.04-1.22) in those aged 65 years and older. However, we have not observed differences by sex, age, residence, smoking, and drinking. Robustness results were found for PM coarse in the sensitivity analyses., Conclusion: This nationwide study suggested that long-term exposure to outdoor air pollution, especially for PM coarse , was associated with the risk of sarcopenia among Chinese adults. Our findings provide epidemiological implications for protecting healthy ageing by improving air quality., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Mental disorders are among the top causes of disease burden worldwide. Existing evidence regarding the repurposing of antihypertensives for mental disorders treatment is conflicting and cannot establish causation., Methods: We used Mendelian randomization to assess the effects of angiotensin-converting-enzyme inhibitors (ACEIs), beta blockers (BBs), and calcium channel blockers (CCBs) on risk of bipolar disorder (BD), major depression disorder (MDD), and schizophrenia (SCZ). We used published genetic variants which are in antihypertensive drugs target genes and correspond to systolic blood pressure (SBP) in Europeans and East Asians, and applied them to summary statistics of BD (cases = 41,917; controls = 371,549 in Europeans), MDD (cases = 170,756; controls = 329,443 in Europeans and cases = 15,771; controls = 178,777 in East Asians), and SCZ (cases = 53,386; controls = 77,258 in Europeans and cases = 22,778; controls = 35,362 in East Asians) from the Psychiatric Genomics Consortium. We used inverse variance weighting with MR-Egger, weighted median, weighted mode, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. We performed gene-specific analysis and utilized various methods to address potential pleiotropy., Results: After multiple testing correction, genetically proxied ACEIs were associated with an increased risk of SCZ in Europeans (odds ratio (OR) per 5 mmHg lower in SBP 2.10, 95% CI 1.54 to 2.87) and East Asians (OR per 5 mmHg lower in SBP 2.51, 95% CI 1.38 to 4.58). Genetically proxied BBs were not associated with any mental disorders in both populations. Genetically proxied CCBs showed no benefits on mental disorders., Conclusions: Antihypertensive drugs have no protection for mental disorders but potential harm. Their long-term use among hypertensive patients with, or with high susceptibility to, psychiatric illness needs careful evaluation., (© 2023. The Author(s).)

Background: Observationally, polyunsaturated fatty acids (PUFAs) have health benefits compared with saturated fatty acids (SFAs); randomized controlled trials suggest fewer benefits. We used uni- and multi-variable Mendelian randomization to assess the association of major fatty acids and their sub-species with ischaemic heart disease (IHD) overall and sex-specifically and with lifespan sex-specifically, given differing lifespan by sex., Methods: We obtained strong (P <5x10-8), independent (r2<0.001) genetic predictors of fatty acids from genome-wide association studies (GWAS) in a random subset of 114 999 UK Biobank participants. We applied these genetic predictors to the Cardiogram IHD GWAS (cases = 60 801, controls = 123 504) and to the Finngen consortium GWAS (cases = 31 640, controls = 187 152) for replication and to the UK Biobank for sex-specific IHD and for lifespan based on parental attained age (fathers = 415 311, mothers = 412 937). We used sensitivity analysis and assessed sex differences where applicable., Results: PUFAs were associated with IHD [odds ratio 1.23, 95% confidence interval (CI) 1.05 to 1.44] and lifespan in men (-0.76 years, 95% CI -1.34 to -0.17) but not women (0.20, 95% CI -0.32 to 0.70). Findings were similar for omega-6 fatty acids and linoleic acid. Independent associations of SFAs, mono-unsaturated fatty acids or omega-3 fatty acids with IHD overall or lifespan in men and women were limited., Conclusions: PUFAs, via specific subspecies, may contribute to disparities in lifespan by sex. Sex-specific dietary advice might be a start towards personalized public health and addressing inequities., (© The Author(s) 2023; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objectives: Recalled childhood adiposity is inversely associated with breast cancer observationally, including in Mendelian randomization (MR) studies. Breast cancer studies recruited in adulthood only include survivors of childhood adiposity and breast cancer or a competing risk. We assessed recalled childhood adiposity on participant reported sibling and maternal breast cancer to ensure ascertainment of nonsurvivors., Study Design and Setting: We obtained independent strong genetic predictors of recalled childhood adiposity for women and their associations with participant reported own, sibling and maternal breast cancer from UK Biobank genome wide association studies., Results: Recalled childhood adiposity in women was inversely associated with own breast cancer using Mendelian randomization inverse variance weighting (odds ratio (OR) 0.66, 95% confidence interval (CI) 0.52-0.84) but less clearly related to participant reported sibling (OR 0.89, 95% CI 0.69-1.14) or maternal breast cancer (OR 0.84, 95% CI 0.67-1.05)., Conclusion: Weaker inverse associations of recalled childhood adiposity with breast cancer with more comprehensive ascertainment of cases before recruitment suggests the inverse association of recalled childhood adiposity with breast cancer could be partly selection bias from preferential selection of survivors. Greater consideration of survival bias in public health relevant causal inferences would be helpful., Competing Interests: Declaration of competing interest The authors have no conflicts of interest. Replication can be achieved using MR Base https://www.mrbase.org, publicly available data and R code available on request., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Alanine is an amino acid commonly used as a nutritional supplement and plays a key role in the glucose-alanine cycle. Plasma alanine has been associated in observational studies with a higher risk of coronary artery disease (CAD) and unhealthier lipid profiles. However, evidence from large randomized controlled trials is lacking., Objectives: Using Mendelian randomization (MR), we assessed the unconfounded associations of plasma alanine with CAD and CAD risk factors., Methods: We applied single nucleotide polymorphisms that were strongly (P < 5 ×10 -8 ) associated with plasma alanine as genetic instruments to large genome-wide association studies of CAD (63,108 cases; 296,901 controls), diabetes (90,612 cases; 583,493 controls), glucose (515,538 participants), lipids (low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, total cholesterol, and apolipoprotein B) (>1.1 million participants), blood pressure (BP) (757,601 participants), and body mass index (682,137 participants). Given the potential sex disparity, we also conducted sex-specific analyses. MR estimates per standard deviation increase in alanine concentrations were obtained using inverse variance weighting followed by sensitivity analyses using weighted median, MR-Egger, MR-Pleiotropy RESidual Sum and Outlier, and MR-Robust Adjusted Profile Score., Results: Genetically predicted plasma alanine was not associated with CAD but with a higher risk of diabetes (odds ratio [OR]: 1.35; 95% confidence interval [CI]: 1.06, 1.72), higher glucose (β: 0.11; 95% CI: 0.02, 0.19), LDL cholesterol (β: 0.08; 95% CI: 0.04, 0.12), triglycerides (β: 0.25; 95% CI: 0.13, 0.38), total cholesterol (β: 0.14; 95% CI: 0.08, 0.20), apolipoprotein B (β: 0.12; 95% CI: 0.03, 0.21), and BP (β: 1.17; 95% CI: 0.31, 2.04 for systolic BP: β: 0.97; 95% CI: 0.49, 1.45 for diastolic BP) overall. The positive associations of serum alanine with LDL cholesterol and triglycerides were more notable in women than in men., Conclusions: Alanine or factors affecting alanine may have causal effects on diabetes, blood glucose, lipid profiles, and BP but not on CAD. Further studies are needed to clarify possible mechanisms., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Calcium channel blockers (CCBs) are commonly prescribed antihypertensives. However, concerns exist about potential off-target effects on cancer. This Mendelian randomization (MR) study examined the associations of genetic proxies for CCBs with the risk of cancer. We used published genetic proxies in the target genes of CCBs as instruments, and obtained MR estimates by applying them to large studies of 17 site-specific cancers (non-Hodgkin lymphoma, melanoma, leukemia, thyroid, rectal, pancreatic, oral cavity/pharyngeal, kidney, esophagus/stomach, colon, bladder, endometrial, cervical and breast, prostate, lung and ovarian cancer) from the Pan-Cancer study, with replication for breast cancer (133,384 cases, 113,789 controls from the Breast Cancer Association Consortium), prostate cancer (79,148 cases, 61,106 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium), lung cancer (11,348 cases, 15,861 controls from the International Lung Cancer Consortium), and ovarian cancer (25,509 cases, 40,941 controls from the Ovarian Cancer Association Consortium). We used inverse variance weighting for the main analysis and the weighted median, MR-Egger and Mendelian Randomization Pleiotropy Residual Sum and Outlier as sensitivity analyses. Genetic proxies for CCBs were not associated with any cancer after Bonferroni-correction (at the threshold of p < 0.003). Associations were robust to different MR methods. In conclusion, our study suggests no association of genetic proxies for CCBs with 17 different cancers. While the findings add some support to the safety profile of CCBs in long-term use, future replication is necessary to provide definitive evidence., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Berberine is widely available as a nutraceutical supplement for improving glucose metabolism. Berberine affects sex hormones, raising the possibility that its effects on glycemic traits and insulin sensitivity have sex disparity which has been overlooked., Objective: To assess the overall and sex-specific effects of berberine on glycemic- and insulin-related traits., Methods: We identified randomized trials of berberine versus placebo from Medline, Embase, CNKI, clinical trial registries and previous systematic reviews. Mean differences were estimated using inverse-variance weighting with random effects models. Subgroup analyses were conducted by sex, diabetes diagnosis, trial duration, berberine dose and ethnicity., Results: We identified 20 eligible studies (n = 1761). Berberine lowered fasting glucose (-0.52 mmol/L, 95% CI -0.72 to -0.33; 18 studies, n = 1522), HbA1c (-4.48 mmol/mol, 95% CI -6.53 to -2.44, 7 studies, n = 756), fasting insulin (-2.36 mU/L, 95% CI -3.64 to -1.08, 11 studies, n = 966), HOMA-IR (-0.85, 95% CI -1.16 to -0.53,12 studies, n = 1065), and 2-h postprandial glucose (-1.81 mmol/L, 95% CI -2.37 to -1.24, 4 studies, n = 501). Effects on fasting glucose and HOMA-IR showed potential differences by sex, with larger reductions in women than in men. Comparing 4 studies conducted in women to one study conducted in men, the mean difference was -0.21 mmol/L (95% CI -0.41 to -0.00) for fasting glucose and -0.97 (95% CI -1.84 to -0.10) for HOMA-IR. We also found larger reductions in fasting glucose in participants with diabetes and in Asians., Conclusion: Berberine is effective in improving glucose metabolism and may result in larger effects on fasting glucose in women, in people with diabetes and in Asians, but subgroup comparisons remain to be replicated given the limited number of studies. Berberine can be considered as a complementary intervention in individuals who may benefit from modest improvements in glucose metabolism and who prefer taking a nutraceutical., Study Registration: PROSPERO (CRD42022345172)., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Branch-chain amino acids (BCAAs) are linked to higher risk of diabetes, whilst the evidence on ischemic heart disease (IHD) is limited. Valine metabolite, 3-hydroxyisobutyrate (3-HIB), also plays an important role in metabolism, whilst its effect has been rarely examined. At the situation of no evidence from large trials, we assessed the role of BCAAs and 3-HIB in IHD and diabetes using Mendelian randomization to minimize confounding. Given their potential role in sex hormones, we also examined sex-specific associations., Methods: We used genetic variants to predict BCAAs and 3-HIB, and obtained their associations with IHD and diabetes in large consortia and cohorts, as well as sex-specific association in the UK Biobank and DIAGRAM. We obtained and combined the Wald estimates using inverse variance weighting, and different analytic methods robust to pleiotropy., Results: Genetically predicted BCAAs were associated with higher risk of IHD (odds ratio (OR) 1.19 per standard deviation (SD) increase in BCAAs, 95% confidence interval (CI) 1.05 to 1.35) and diabetes (OR 1.20, 95% CI 1.08 to 1.34). The associations with IHD were stronger in women (OR 1.23, 95% CI 1.03 to 1.48) than men (OR 0.96, 95% CI 0.83 to 1.10). 3-HIB was associated with higher risk of IHD (OR 1.43, 95% CI 1.17 to 1.73) but not diabetes, with no sex disparity., Conclusion: BCAAs and 3-HIB are potential targets for prevention in IHD and/or diabetes. BCAAs may exert a sex-specific role in IHD. Consideration of the sex disparity and exploration of the underlying pathways would be worthwhile., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Observational studies show inconsistent associations of red meat consumption with cardiovascular disease (CVD) and diabetes. Moreover, red meat consumption varies by sex and setting, however, whether the associations vary by sex and setting remains unclear., Methods and Results: This systematic review and meta-analysis was conducted to summarize the evidence concerning the associations of unprocessed and processed red meat consumption with CVD and its subtypes [coronary heart disease (CHD), stroke, and heart failure], type two diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM) and to assess differences by sex and setting (western vs. eastern, categorized based on dietary pattern and geographic region). Two researchers independently screened studies from PubMed, Web of Science, Embase, and the Cochrane Library for observational studies and randomized controlled trials (RCTs) published by 30 June 2022. Forty-three observational studies (N = 4 462 810, 61.7% women) for CVD and 27 observational studies (N = 1 760 774, 64.4% women) for diabetes were included. Red meat consumption was positively associated with CVD [hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.05 to 1.16 for unprocessed red meat (per 100 g/day increment); 1.26, 95% CI 1.18 to 1.35 for processed red meat (per 50 g/day increment)], CVD subtypes, T2DM, and GDM. The associations with stroke and T2DM were higher in western settings, with no difference by sex., Conclusion: Unprocessed and processed red meat consumption are both associated with higher risk of CVD, CVD subtypes, and diabetes, with a stronger association in western settings but no sex difference. Better understanding of the mechanisms is needed to facilitate improving cardiometabolic and planetary health., Competing Interests: Conflict of interest All authors declare no conflict of interest for this contribution., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alzheimer's disease is more prevalent in women, possibly due to sex or growth hormones but existing evidence is inconclusive. We investigated whether genetically predicted sex and growth hormones are associated with risk of Alzheimer's disease. Genetic variants strongly and independently predicting insulin-like growth factor 1 (IGF-1), testosterone and sex hormone-binding globulin (SHBG) were obtained from large, published genome wide associations studies (GWAS) and applied to GWAS of Alzheimer's disease based on clinical diagnosis (cases = 21,982, control = 41,944) from the International Genomics of Alzheimer's Project and the UK Biobank parental (maternal cases = 27,696; paternal cases = 14,338) and siblings' diagnosis (cases = 2,171) as proxy cases. Published GWAS summary statistics were used in our analyses. Estimates were obtained from inverse variance weighting with sensitivity analysis (i.e., MR-Egger, weighted median and MR-PRESSO). Multivariable analyses adjusted for pleiotropic effects and possible sources of selection bias were also performed. Genetically predicted higher total testosterone may reduce the risk of paternal Alzheimer's disease (odds ratio (OR) 0.86, 95% confidence interval (CI) 0.76 to 0.97, per SD increase in testosterone) and in meta-analysis for women (OR 0.92, 95% CI 0.87, 0.98) with directionally similar results from other analyses. SHBG were not associated with Alzheimer's disease. IGF-1 in women was inversely associated with risk of clinical Alzheimer's disease in sensitivity analysis but not in the main analysis. These results suggest genetically predicted higher total testosterone may lower risk of Alzheimer's disease. The role of testosterone and the immune system in Alzheimer's disease could be further investigated., (© 2023. Springer Nature B.V.)

Venous thromboembolism occurs in up to one-third of patients with COVID-19. Venous thromboembolism and COVID-19 may share a common genetic architecture, which has not been clarified. To fill this gap, we leverage summary-level genetic data from the latest COVID-19 host genetics consortium and UK Biobank and examine the shared genetic etiology and causal relationship between COVID-19 and venous thromboembolism. The cross-trait and co-localization analyses identify 2, 3, and 4 shared loci between venous thromboembolism and severe COVID-19, COVID-19 hospitalization, SARS-CoV-2 infection respectively, which are mapped to ABO, ADAMTS13, FUT2 genes involved in coagulation functions. Enrichment analysis supports shared biological processes between COVID-19 and venous thromboembolism related to coagulation and immunity. Bi-directional Mendelian randomization suggests that venous thromboembolism was associated with higher risk of three COVID-19 traits, and SARS-CoV-2 infection was associated with a higher risk of venous thromboembolism. Our study provides timely evidence for the genetic etiology between COVID-19 and venous thromboembolism (VTE). Our findings contribute to the understanding of COVID-19 and VTE etiology and provide insights into the prevention and comorbidity management of COVID-19., (© 2023. The Author(s).)

Growing evidence suggests that red meat consumption is a risk factor for cardiovascular health, with potential sex disparity. The metabolic mechanisms have not been fully understood. Using the UK Biobank, first we examined the associations of unprocessed red meat and processed meat with ischemic heart disease (IHD) mortality overall and by sex using logistic regression. Then, we examined the overall and sex-specific associations of red meat consumption with metabolites using multivariable regression, as well as the associations of selected metabolites with IHD mortality using logistic regression. We further selected metabolic biomarkers that are linked to both red meat consumption and IHD, with concordant directions. Unprocessed red meat and processed meat consumption was associated with higher IHD mortality overall and in men. Thirteen metabolites were associated with both unprocessed red meat and IHD mortality overall and showed a consistent direction, including triglycerides in different lipoproteins, phospholipids in very small very-low-density lipoprotein (VLDL), docosahexaenoic acid, tyrosine, creatinine, glucose, and glycoprotein acetyls. Ten metabolites related to triglycerides and VLDL were positively associated with both unprocessed red meat consumption and IHD mortality in men, but not in women. Processed meat consumption showed similar results with unprocessed red meat. Triglycerides in lipoproteins, fatty acids, and some nonlipid metabolites may play a role linking meat consumption to IHD. Triglycerides and VLDL-related lipid metabolism may contribute to the sex-specific associations. Sex differences should be considered in dietary recommendations.

Coronavirus Disease (COVID-19) may cause a dysregulation of the immune system and has complex relationships with multiple autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, little is known about their common genetic architecture. Using the latest data from COVID-19 host genetics consortium and consortia on RA and SLE, we conducted a genome-wide cross-trait analysis to examine the shared genetic etiology between COVID-19 and RA/SLE and evaluated their causal associations using bidirectional Mendelian randomization (MR). The cross-trait meta-analysis identified 23, 28, and 10 shared genetic loci for severe COVID-19, COVID-19 hospitalization, and SARS-CoV-2 infection with RA, and 14, 17, and 7 shared loci with SLE, respectively. Co-localization analysis identified five causal variants in TYK2, IKZF3, PSORS1C1, and COG6 for COVID-19 with RA, and four in CRHR1, FUT2, and NXPE3 for COVID-19 with SLE, involved in immune function, angiogenesis and coagulation. Bidirectional MR analysis suggested RA is associated with a higher risk of COVID-19 hospitalization, and COVID-19 is not related to RA or SLE. Our novel findings improved the understanding of the genetic etiology shared by COVID-19, RA and SLE, and suggested an increased risk of COVID-19 hospitalization in people with higher genetic liability to RA., (© 2023 Wiley Periodicals LLC.)

Purpose of the Review: This review summarizes major insights into causal risk factors for cardiovascular disease (CVD) by using Mendelian randomization (MR) to obtain unconfounded estimates, contextualized within its strengths and weaknesses., Recent Findings: MR studies have confirmed the role of major CVD risk factors, including alcohol, smoking, adiposity, blood pressure, type 2 diabetes, lipids, and possibly inflammation, but added that the relation with alcohol is likely linear, confirmed the role of diastolic blood pressure, identified apolipoprotein B as the major target lipid, and foreshadowed results of some trials concerning anti-inflammatories. Identifying a healthy diet and the role of early life influences, such as birth weight, has proved more difficult. Use of MR has winnowed empirically driven hypotheses about CVD into a set of genetically validated targets of intervention. Greater inclusion of global diversity in genetic studies and the use of an overarching framework would enable even more informative MR studies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Red meat consumption has been found to closely related to cardiometabolic health, with sex disparity. However, the specific metabolic factors corresponding to red meat consumption in men and women have not been examined previously. We analyzed the sex-specific associations of meat consumption, with 167 metabolites using multivariable regression, controlling for age, ethnicity, Townsend deprivation index, education, physical activity, smoking, and drinking status among ~79,644 UK Biobank participants. We also compared the sex differences using an established formula. After accounting for multiple testing with false discovery rate < 5% and controlling for confounders, the positive associations of unprocessed red meat consumption with branched-chain amino acids and several lipoproteins, and the inverse association with glycine were stronger in women, while the positive associations with apolipoprotein A1, creatinine, and monounsaturated fatty acids were more obvious in men. For processed meat, the positive associations with branched-chain amino acids, several lipoproteins, tyrosine, lactate, glycoprotein acetyls and inverse associations with glutamine, and glycine were stronger in women than in men. The study suggests that meat consumption has sex-specific associations with several metabolites. This has important implication to provide dietary suggestions for individuals with or at high risk of cardiometabolic disease, with consideration of sex difference.

Background: L-carnitine is emerging as an item of interest for cardiovascular disease (CVD) prevention and treatment, but controversy exists. To examine the effectiveness and safety of L-carnitine, we assessed how genetically different levels of L-carnitine are associated with CVD risk and its risk factors. Given higher CVD incidence and L-carnitine in men, we also examined sex-specific associations., Methods: We used Mendelian randomization to obtain unconfounded estimates. Specifically, we used genetic variants to predict L-carnitine, and obtained their associations with coronary artery disease (CAD), ischemic stroke, heart failure, and atrial fibrillation, as well as CVD risk factors (type 2 diabetes, glucose, HbA1c, insulin, lipid profile, blood pressure and body mass index) in large consortia and established cohorts, as well as sex-specific association in the UK Biobank. We obtained the Wald estimates (genetic association with CVD and its risk factors divided by the genetic association with L-carnitine) and combined them using inverse variance weighting. In sensitivity analysis, we used different analysis methods robust to pleiotropy and replicated using an L-carnitine isoform, acetyl-carnitine., Results: Genetically predicted L-carnitine was nominally associated with higher risk of CAD overall (OR 1.07 per standard deviation (SD) increase in L-carnitine, 95% CI 1.02 to 1.11) and in men (OR 1.09, 95% CI 1.02 to 1.16) but had a null association in women (OR 1.00, 95% CI 0.92 to 1.09). These associations were also robust to different methods and evident for acetyl-carnitine., Conclusions: Our findings do not support a beneficial association of L-carnitine with CVD and its risk factors but suggest potential harm. L-carnitine may also exert a sex-specific role in CAD. Consideration of the possible sex disparity and exploration of the underlying pathways would be worthwhile., (© 2022. The Author(s).)

Background:  Statins have long been suspected to have pleiotropic effects via thrombotic factors. Randomized controlled trials are too limited to be definitive. We examined the associations of genetically mimicking effects of statins, PCSK9 inhibitors, and alternative lipid targets (in genes LDLR , APOC3 , and LPL ) on key indicators of coagulation system function, i.e., prothrombin time (PT) and activated partial thromboplastin time (aPTT)., Methods:  We assessed the effect of established genetic mimics of effects of lipid modifiers and alternative lipid treatment targets on PT ( n  = 58,110) and aPTT ( n  = 37,767), all transformed to z-scores, using Mendelian randomization taking advantage of Biobank Japan. Ischemic heart disease (IHD) was a control outcome., Results:  Genetically mimicked effects of statins increased PT by 0.31 standard deviation (SD) per SD increase in low-density lipoprotein (95% confidence interval [CI]: 0.10-0.51) based on rs12916 but did not affect aPTT. Genetically mimicking effects of targeting LDLR increased PT based on rs688 (0.33 SD per SD increase in triglyceride, 95% CI: 0.03-0.63) but did not affect aPTT. Genetically mimicking effects of PCSK9 inhibitors or targeting APOC3 or LPL had no effect on PT or aPTT. Genetically mimicking effects of statins, PCSK9 inhibitors, and alternative lipid targets reduced risk of IHD in Biobank Japan., Conclusion:  Statins, and possibly targeting LDLR, may also act via a coagulation cascade factor, likely specific to the extrinsic or common pathway. Further elucidation of the mechanistic pathway may facilitate development of new interventions and inform use of statins particularly in relation to use of other anticoagulants., Competing Interests: None declared., (Thieme. All rights reserved.)

Aims/hypothesis: Diabetes and hyperlipidaemia are common comorbidities in people with hypertension. Despite similar protective effects on CVD, different classes of antihypertensive drugs have different effects on CVD risk factors, including diabetes, glucose metabolism and lipids. However, these pleiotropic effects have not been assessed in long-term, large randomised controlled trials, especially for East Asians., Methods: We used Mendelian randomisation to obtain unconfounded associations of ACE inhibitors, β-blockers (BBs) and calcium channel blockers (CCBs). Specifically, we used genetic variants in drug target genes and related to systolic BP in Europeans and East Asians, and applied them to the largest available genome-wide association studies of diabetes (74,124 cases and 824,006 controls in Europeans, 77,418 cases and 356,122 controls in East Asians), blood glucose levels, HbA 1c , and lipids (LDL-cholesterol, HDL-cholesterol and triacylglycerols) (approximately 0.5 million Europeans and 0.1 million East Asians). We used coronary artery disease (CAD) as a control outcome and used different genetic instruments and analysis methods as sensitivity analyses., Results: As expected, genetically proxied ACE inhibition, BBs and CCBs were related to lower risk of CAD in both ancestries. Genetically proxied ACE inhibition was associated with a lower risk of diabetes (OR 0.85, 95% CI 0.78-0.93), and genetic proxies for BBs were associated with a higher risk of diabetes (OR 1.05, 95% CI 1.02-1.09). The estimates were similar in East Asians, and were corroborated by systematic review and meta-analyses of randomised controlled trials. In both ancestries, genetic proxies for BBs were associated with lower HDL-cholesterol and higher triacylglycerols, and genetic proxies for CCBs were associated with higher LDL-cholesterol. The estimates were robust to the use of different genetic instruments and analytical methods., Conclusions/interpretation: Our findings suggest protective association of genetically proxied ACE inhibition with diabetes, while genetic proxies for BBs and CCBs possibly relate to an unfavourable metabolic profile. Developing a deeper understanding of the pathways underlying these diverse associations would be worthwhile, with implications for drug repositioning as well as optimal CVD prevention and treatment strategies in people with hypertension, diabetes and/or hyperlipidaemia., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: High dose vitamin C infusion has been proposed to treat critically ill patients, including patients with pneumonia and severe COVID-19. However, trials have shown mixed findings. Here we assessed the unconfounded associations of vitamin C with COVID-19 and pneumonia using the Mendelian randomisation approach., Methods: This is a separate-sample Mendelian randomisation study using publicly available data. We applied single nucleotide polymorphisms (SNPs) that were associated with plasma vitamin C, in a recent genome-wide association study (GWAS) as genetic instruments to the GWAS of severe COVID-19, COVID-19 hospitalisation and any infection in the COVID-19 host genetics initiative and the GWAS of pneumonia in the UK Biobank, to assess whether people with genetically predicted higher levels of plasma vitamin C had lower risk of severe COVID-19 and pneumonia., Results: Genetically predicted circulating levels of vitamin C was not associated with susceptibility to severe COVID-19, COVID-19 hospitalisation, any COVID-19 infection nor pneumonia. Similar results were obtained when a weighted median and MR-Egger methods were used., Conclusions: Mendelian randomisation analysis provided little evidence for an association of genetically predicted circulating levels of vitamin C with COVID-19 or pneumonia and thus our findings provided little support to the use of vitamin C in prevention and treatment in these patients, unless high dose vitamin C infusion has therapeutic effects via different biological pathways., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Vitamin D (Vit-D) promotes vascular repair and its deficiency is closely linked to the development of type 2 diabetes mellitus (T2DM) and hypertension. Whether genetially predicted vitamin D status (serological 25-hydroxyvitamin D [25(OH)D]) confers secondary protection against cardiovascular diseases (CVD) among high-risk hypertensive-diabetic subjects was unknown., Methods: This is a prospective, individual-data, two-sample Mendelian randomization study. We interrogated 12 prior GWAS-detected SNPs of comprehensive Vit-D mechanistic pathways using high-throughput exome chip analyses in a derivation subcohort (n = 1460) and constructed a genetic risk score (GRS) (rs2060793, rs4588, rs7041; F-statistic = 32, P < 0.001) for causal inference of comprehensive CVD hard clinical endpoints in an independent sample of hypertensive subjects (n = 3746) with prevailing co-morbid T2DM (79%) and serological 25(OH)D deficiency [< 20 ng/mL] 45%., Results: After 55.6 ± 28.9 months, 561 (15%) combined CVD events including myocardial infarction, unstable angina, ischemic stroke, congestive heart failure, peripheral vascular disease, and cardiovascular death had occurred. Kaplan-Meier analysis showed that genetically predicted reduced vitamin D status was associated with reduced event-free survival from combined CVD events (log-rank = 13.5, P = 0.001). Multivariate-adjusted per-allele increase in GRS predicted reduced combined CVD events (HR = 0.90 [0.84 to 0.96], P = 0.002). Mendelian randomization indicates that increased Vit-D exposure, leveraged through each 1 ng/mL genetically instrumented rise of serum Vit-D, protects against combined CVD events (Wald's estimate: OR = 0.86 [95%CI 0.75 to 0.95]), and myocardial infarction (OR = 0.76 [95%CI 0.60 to 0.90]). Furthermore, genetically predicted increase in Vit-D status ameliorates risk of deviation from achieving guideline-directed hypertension control (JNC-8: systolic target < 150 mmHg) (OR = 0.89 [95%CI 0.80 to 0.96])., Conclusions: Genetically predicted increase in Vit-D status [25(OH)D] may confer secondary protection against incident combined CVD events and myocardial infarction in a hypertensive-diabetic population where serological 25(OH)D deficiency is common, through facilitating blood pressure control., (© 2022. The Author(s).)

Men are more vulnerable to ischemic heart disease (IHD) than women, possibly due to testosterone. Correspondingly, sex hormone binding globulin (SHBG) which lowers circulating testosterone might protect men against IHD. SHBG may also affect IHD independent of testosterone, which has not previously been examined. To assess the sex-specific role of SHBG in IHD, in univariable Mendelian randomization (MR), we used sex-specific, genome-wide significant genetic variants to predict SHBG, and examined their association with IHD in the UK Biobank. We also replicated using genetic instruments from Japanese men and applied to Biobank Japan. To assess the role of SHGB independent of testosterone in men, we used multivariable MR controlling for testosterone. Genetically predicted SHBG was associated with lower IHD risk in men [odds ratio (OR) 0.78 per standard deviation, 95% confidence interval (CI) 0.70 to 0.87], and the association was less clear in women. The estimates were similar in Japanese. The inverse association remained after controlling for testosterone in men (OR 0.79, 95% CI 0.71 to 0.88). SHBG might lower the risk of IHD in men, with a role independent of testosterone. Exploring intervention strategies that increase SHBG is important for targeting IHD treatments., (© 2021. The Author(s).)

Background: Kidney dysfunction occurs in severe COVID-19, and is a predictor of COVID-19 mortality. Whether kidney dysfunction causes severe COVID-19, and hence is a target of intervention, or whether it is a symptom, is unclear because conventional observational studies are open to confounding. To obtain unconfounded estimates, we used Mendelian randomization to examine the role of kidney function in severe COVID-19., Methods: We used genome-wide significant, uncorrelated genetic variants to predict kidney function, in terms of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), and then assessed whether people with genetically instrumented higher eGFR or lower UACR, an indication of better kidney function, had a lower risk of severe COVID-19 (8779 cases, 1,001,875 controls), using the largest available cohorts with extensive genotyping. For comprehensiveness, we also examined their role in COVID-19 hospitalization (24,274 cases, 2,061,529 controls) and all COVID-19 (1,12,612 cases, 2,474,079 controls)., Results: Genetically instrumented higher eGFR was associated with lower risk of severe COVID-19 (odds ratio (OR) 0.90, 95% confidence interval (CI) 0.83, 0.98) but not related to COVID-19 hospitalization or infection. Genetically instrumented UACR was not related to COVID-19., Conclusions: Kidney function appears to be one of the key targets for severe COVID-19 treatment. Use of available medications to improve kidney function, such as antihypertensives, might be beneficial for COVID-19 treatment, with relevance to drug repositioning., (© 2021. The Author(s).)

Cardiovascular disease (CVD) is a major contributor to the global burden of disease. Berberine, a long-standing, widely used, traditional Chinese medicine, is thought to have beneficial effects on CVD risk factors and in women with polycystic ovary syndrome. The mechanisms and effects, specifically in men, possibly via testosterone, have not been examined previously. To assess the effect of berberine on CVD risk factors and any potential pathway via testosterone in men, we conducted a randomized, double-blind, placebo-controlled, parallel trial in Hong Kong. In total, 84 eligible Chinese men with hyperlipidemia were randomized to berberine (500 mg orally, twice a day) or placebo for 12 weeks. CVD risk factors (lipids, thromboxane A2, blood pressure, body mass index and waist-hip ratio) and testosterone were assessed at baseline, and 8 and 12 weeks after intervention. We compared changes in CVD risk factors and testosterone after 12 weeks of intervention using analysis of variance, and after 8 and 12 weeks using generalized estimating equations (GEE). Of the 84 men randomized, 80 men completed the trial. Men randomized to berberine had larger reductions in total cholesterol (-0.39 mmol/L, 95% confidence interval (CI) -0.70 to -0.08) and high-density lipoprotein cholesterol (-0.07 mmol/L, 95% CI -0.13 to -0.01) after 12 weeks. Considering changes after 8 and 12 weeks together, berberine lowered total cholesterol and possibly low-density lipoprotein-cholesterol (LDL-c), and possibly increased testosterone. Changes in triglycerides, thromboxane A2, blood pressure, body mass index and waist-hip ratio after the intervention did not differ between the berberine and placebo groups. No serious adverse event was reported. Berberine is a promising treatment for lowering cholesterol. Berberine did not lower testosterone but instead may increase testosterone in men, suggesting sex-specific effects of berberine. Exploring other pathways and assessing sex differences would be worthwhile, with relevance to drug repositioning and healthcare.

Life expectancy in the developed West is currently stagnated and remains shorter in men than women. Well-established evolutionary biology theory suggests lifespan trades-off against reproductive success, possibly sex-specifically. We examined whether a key driver of reproductive success, testosterone, affected survival using a Mendelian randomization longevity study in the UK Biobank to obtain unbiased estimates, along with control exposures. We applied published genetic instruments for testosterone to obtain inverse variance weighted estimates of associations with survival to (i.e., age at) recruitment, in 167,020 men and 194,174 women. We similarly obtained estimates for a positive control (smoking initiation), and a negative control (absorbate), a marker of vitamin C metabolism. Testosterone was associated with poorer survival (0.10 years younger at recruitment per effect size of testosterone, 95% confidence interval (CI) 0.004 to 0.20). As expected, smoking initiation was also associated with poorer survival (0.37 years younger, 95% CI 0.25 to 0.50), but not absorbate (0.01 years younger, 95% CI - 0.09 to 0.11). Several aspects of a healthy lifestyle (low animal fat diet) and several widely used medications (statins, metformin, dexamethasone and possibly aspirin) may modulate testosterone. Explicitly designing interventions sex-specifically based on these insights might help address stagnating life expectancy and sexual disparities.

APOE genotypes are associated with ischemic heart disease (IHD), several other cardiovascular diseases and dementia. Previous studies have not comprehensively considered all genotypes, especially ε2ε2, nor associations by age and sex, although IHD incidence differs by sex. In the UK Biobank, including 391,992 white British participants, we compared effects of APOE genotypes on IHD and its risk factors. Compared to the ε3ε3 genotype, ε2ε2 was not clearly associated with IHD but was associated with lower plasma apolipoprotein B (apoB). The ε2ε3 genotype conferred lower IHD risk, systolic blood pressure (SBP), pulse pressure and plasma apoB than ε3ε3. ε3ε4 and ε4ε4 conferred higher IHD risk, higher pulse pressure and plasma apoB, but lower glycated haemoglobin (HbA1c) than ε3ε3. The associations by age and sex were fairly similar, except ε2ε2 compared to ε3ε3 was marginally positively associated with IHD in the younger age group and nominally inversely associated with SBP in men. ε3ε4 compared to ε3ε3 was nominally positively associated with SBP in women. APOE genotypes affect IHD risk increasingly from ε2ε3, ε3ε3, ε3ε4 to ε4ε4, with similar patterns for pulse pressure and plasma apoB, but not for diabetes. Associations with blood pressure differed by sex. Greater understanding of products of APOE and their effects might generate targets of intervention.

Aim: Angiotensin-converting enzyme 2 (ACE 2) is the binding domain for severe acute respiratory syndrome coronavirus (SARS-CoV) and SARSCoV-2. Some antihypertensive drugs affect ACE2 expression or activity (ACE inhibitors and angiotensin II receptor blockers [ARBs]), suggesting use of other hypertensives might be preferable, such as calcium channel blockers (CCBs). Given the limited evidence, the International Society of Hypertension does not support such a policy., Methods: We used a Mendelian randomization study to obtain unconfounded associations of antihypertensives, instrumented by published genetic variants in genes regulating target proteins of these drugs, with immune (lymphocyte and neutrophil percentage) and inflammatory (tumour necrosis factor alpha [TNF-α]) markers in the largest available genome-wide association studies., Results: Genetically predicted effects of ACE inhibitors increased lymphocyte percentage (0.78, 95% confidence interval [CI] 0.35, 1.22), decreased neutrophil percentage (-0.64, 95% CI -1.09, -0.20) and possibly lowered TNF-α (-4.92, 95% CI -8.50, -1.33). CCBs showed a similar pattern for immune function (lymphocyte percentage 0.21, 95% CI 0.05 to 0.36; neutrophil percentage -0.23, 95% CI -0.39 to -0.08) but had no effect on TNF-α, as did potassium-sparing diuretics and aldosterone antagonists, and vasodilator antihypertensives. ARBs and other classes of hypertensives had no effect on immune function or TNF-α., Conclusion: Varying effects of different classes of antihypertensives on immune and inflammatory markers do not suggest antihypertensive use based on their role in ACE2 expression, but instead suggest investigation of the role of antihypertensives in immune function and inflammation might reveal important information that could optimize their use in SARSCoV-2., (© 2020 British Pharmacological Society.)

Background: Angiotensin-converting enzyme (ACE) inhibitors and/or in combination with calcium channel blockers (CCBs) are generally recommended as the first-line antihypertensive therapy for people with hypertension and kidney dysfunction. Evidence from large randomized controlled trials comprehensively comparing renal effects of different classes of antihypertensive drugs is lacking., Methods: We used a Mendelian randomization study to obtain unconfounded associations of genetic proxies for antihypertensives with kidney function. Specifically, we used published genetic variants in genes regulating target proteins of these drugs and then applied to a meta-analysis of the largest available genome-wide association studies of kidney function (estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and albuminuria). Inverse variance weighting was used as the main analysis and to combine estimates from different sources., Results: Genetically predicted ACE inhibition was associated with higher eGFR (effect size 0.06, 95% confidence interval (CI) 0.008, 0.11), while genetic proxies for beta-blockers were associated with lower eGFR (- 0.02, 95% CI - 0.04, - 0.004) when meta-analyzing the UK Biobank and CKDGen. Genetic proxies for CCBs were associated with lower UACR (- 0.15, 95% CI - 0.28, - 0.02) and lower risk of albuminuria (odds ratio 0.58, 95% CI 0.37, 0.90) in CKDGen. The associations were robust to using different analysis methods and different genetic instruments., Conclusions: Our findings suggest the reno-protective associations of genetically proxied ACE inhibitors and CCBs, while genetic proxies for beta-blockers may be related to lower eGFR. Understanding the underlying mechanisms would be valuable, with implications for drug development and repositioning of treatments for kidney disease.

Background: Observational studies suggest poorer glycemic traits and type 2 diabetes associated with coronavirus disease 2019 (COVID-19) risk although these findings could be confounded by socioeconomic position. We conducted a two-sample Mendelian randomization to clarify their role in COVID-19 risk and specific COVID-19 phenotypes (hospitalized and severe cases)., Method: We identified genetic instruments for fasting glucose (n = 133,010), 2 h glucose (n = 42,854), glycated hemoglobin (n = 123,665), and type 2 diabetes (74,124 cases and 824,006 controls) from genome wide association studies and applied them to COVID-19 Host Genetics Initiative summary statistics (17,965 COVID-19 cases and 1,370,547 population controls). We used inverse variance weighting to obtain the causal estimates of glycemic traits and genetic predisposition to type 2 diabetes in COVID-19 risk. Sensitivity analyses included MR-Egger and weighted median method., Results: We found genetic predisposition to type 2 diabetes was not associated with any COVID-19 phenotype (OR: 1.00 per unit increase in log odds of having diabetes, 95%CI 0.97 to 1.04 for overall COVID-19; OR: 1.02, 95%CI 0.95 to 1.09 for hospitalized COVID-19; and OR: 1.00, 95%CI 0.93 to 1.08 for severe COVID-19). There were no strong evidence for an association of glycemic traits in COVID-19 phenotypes, apart from a potential inverse association for fasting glucose albeit with wide confidence interval., Conclusion: We provide some genetic evidence that poorer glycemic traits and predisposition to type 2 diabetes unlikely increase the risk of COVID-19. Although our study did not indicate glycemic traits increase severity of COVID-19, additional studies are needed to verify our findings.

Background: Kidney function declines faster in men. Testosterone levels may mediate the sex disparity. Correspondingly, levels of sex hormone binding globulin (SHBG), which modulates sex hormones, might also be relevant to the lower kidney function in men. The sex-specific role of SHBG is unclear., Methods: A sex-specific, Mendelian randomization (MR) study provided unconfounded estimates of SHBG levels among the United Kingdom Biobank population. Univariable MR applied 357 single nucleotide polymorphisms (SNPs) in men and 359 SNPs in women. These published SNPs strongly ( P <5×10 -8 ) predict SHBG level. They were profiled in 179,916 white British men (6016 patients with CKD) and 212,079 white British women (5958 patients with CKD), to obtain the effect of SHBG on CKD, albuminuria, and eGFR. Multivariable MR controlling for testosterone was used to assess the effect of SHBG on CKD and kidney function independent of testosterone in men., Results: Genetically predicted higher SHBG was associated with a lower risk of CKD in men (odds ratio [OR], 0.78 per SD; 95% confidence interval [95% CI], 0.65 to 0.93) but had no benefit in women. The effect in men remained in multivariable MR, allowing for testosterone (OR, 0.61; 95% CI, 0.45 to 0.82)., Conclusions: Genetically predicted higher SHBG was associated with a lower risk of CKD and better kidney function in men, but not in women, suggesting that SHBG may play a role in CKD specifically in men. Identifying drivers of SHBG and the underlying pathways could provide new insights into CKD prevention and treatment., (Copyright © 2021 by the American Society of Nephrology.)

Background: Mendelian randomization (MR) provides unconfounded estimates. MR is open to selection bias when the underlying sample is selected on surviving to recruitment on the genetically instrumented exposure and competing risk of the outcome. Few methods to address this bias exist. Methods: We show that this selection bias can sometimes be addressed by adjusting for common causes of survival and outcome. We use multivariable MR to obtain a corrected MR estimate for statins on stroke. Statins affect survival, and stroke typically occurs later in life than ischemic heart disease (IHD), making estimates for stroke open to bias from competing risk. Results: In univariable MR in the UK Biobank, genetically instrumented statins did not protect against stroke [odds ratio (OR) 1.33, 95% confidence interval (CI) 0.80-2.20] but did in multivariable MR (OR 0.81, 95% CI 0.68-0.98) adjusted for major causes of survival and stroke [blood pressure, body mass index (BMI), and smoking initiation] with a multivariable Q-statistic indicating absence of selection bias. However, the MR estimate for statins on stroke using MEGASTROKE remained positive and the Q statistic indicated pleiotropy. Conclusion: MR studies of harmful exposures on late-onset diseases with shared etiology need to be conceptualized within a mechanistic understanding so as to identify any potential bias due to survival to recruitment on both genetically instrumented exposure and competing risk of the outcome, which may then be investigated using multivariable MR or estimated analytically and results interpreted accordingly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schooling, Lopez, Yang, Zhao, Au Yeung and Huang.)