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Background Chronic kidney disease (CKD) has an apparent sex disparity, with a more rapid progress in men than in women. Whether the well-established sex-specific evolutionary biology trade-off between reproduction and longevity might inform CKD has not previously been considered. Relevant evidence from randomized controlled trials (RCTs) is not available. Methods We used a bi-directional Mendelian randomization study to obtain unconfounded estimates using the UK Biobank. Single nucleotide polymorphisms (SNPs) that strongly ( p value < 5 × 10 −8 ) predicted testosterone in a sex-specific manner were applied to 179,916 white British men (6016 CKD cases) and 212,079 white British women (5958 CKD cases) to obtain sex-specific associations with CKD, albuminuria, and estimated glomerular filtration rate (eGFR). We also used multivariable MR to control for sex hormone binding globulin (SHBG). For validation, we similarly examined their role in hemoglobin and high-density lipoprotein cholesterol (HDL-c). We also assessed the role of kidney function in serum testosterone, by applying eGFR-related SNPs to testosterone in the UK Biobank. Results Genetically predicted testosterone was associated with CKD in men (odds ratio (OR) for bioavailable testosterone 1.17 per standard deviation, 95% confidence interval (CI) 1.03 to 1.33) based on 125 SNPs but not in women (OR 1.02, 95% CI 0.92 to 1.14 for total testosterone) based on 254 SNPs. Multivariable MR allowing for SHBG showed consistent patterns. Genetically predicted bioavailable testosterone in men and women and genetically predicted total testosterone in women increased hemoglobin and lowered HDL-c, as seen in RCTs. Genetically predicted eGFR was not related to serum testosterone in men or in women. Conclusions Genetically predicted testosterone was associated with CKD and worse kidney function in men, whilst not affected by kidney function. Identifying drivers of testosterone and the underlying pathways could provide new insights into CKD prevention and treatment.

Background Insulin is known to be associated with a higher risk of coronary artery disease (CAD), but molecular mechanisms remain unclear. This study aimed to explore protein-mediated pathways linking fasting insulin to CAD using Mendelian randomization (MR). Methods This MR study examined the association between fasting insulin and CAD using genome-wide association study (GWAS) data from MAGIC and CARDIoGRAMplusC4D. To investigate underlying mechanisms, a two-step proteome-wide MR analysis was conducted. First, associations of fasting insulin with 2940 circulating proteins were assessed using GWAS of proteomics from UKB-PPP. Proteins affected by insulin were then analyzed for their association with CAD risk. Proteins selected in both steps were considered as potential mediators. Sensitivity analyses to test whether associations are robust to pleiotropy and replication using other GWAS data, including GWAS of proteomics from deCODE and GWAS of CAD from FinnGen Biobank, were performed. Results Genetically predicted insulin was associated with a higher risk of CAD (odds ratio 1.79, 95% confidence interval 1.34 to 2.40). At a false discovery rate of 0.05, insulin affected 355 proteins, ten of which were both increased by insulin and linked to a higher risk of CAD. After sensitivity and replication analyses, PLA2G7, GZMA, LDLR, AGRP, and HHEX were identified as reliable mediators. Mediation analyses using non-pleiotropic instruments showed that PLA2G7, GZMA, LDLR, and AGRP explained 19.50%, 6.91%, 19.31%, and 29.66% of insulin’s total effect on CAD, respectively. Conclusions This study identified five protein mediators linking insulin to CAD. These proteins could be considered as potential targets to mitigate insulin-related cardiovascular risk, providing novel insights for drug repurposing. Graphical Abstract

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.

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.

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.

Background The role of n-6 polyunsaturated fatty acids (PUFAs) in ischemic heart disease (IHD) is controversial, and dietary guidelines vary. Observationally, lower saturated fat intake and higher intake of vegetable oils rich in linoleic acid (LA), the main n-6 PUFA, is associated with lower IHD and diabetes; however, randomized controlled trials have not fully corroborated these benefits. We assessed how genetically predicted LA affected IHD and its risk factors, including diabetes, lipids, and blood pressure. We also assessed the role of LA in reticulocyte count, the red blood cell precursor, which has recently been identified as a possible causal factor in IHD. Methods Two-sample instrumental variable analysis with genetic instruments, i.e., Mendelian randomization, was used to obtain unconfounded estimates using genetic variants strongly ( p value < 5 × 10 −8 ) and solely associated with LA, applied to an IHD case ( n  ≤ 76,014)-control ( n  ≤ 264,785) study (mainly based on the meta-analysis of CARDIoGRAMplusC4D 1000 Genomes and UK Biobank CAD SOFT GWAS), the DIAbetes Genetics Replication And Meta-analysis diabetes case ( n  = 26,676)-control ( n  = 132,532) study, lipids from the Global Lipids Genetics Consortium Results ( n  = 196,475), and reticulocyte count and blood pressure from the UK Biobank ( n  ≤ 361,194). A weighted median and Mendelian randomization Egger were used for sensitivity analysis. Results Genetically predicted LA was not associated with IHD or systolic blood pressure. Genetically predicted higher serum LA was associated with lower diabetes (odds ratio (OR) 0.97 per percentage in total fatty acid increase in LA, 95% confidence interval (CI) 0.96 to 0.99) and lower lipids (low-density lipoprotein, high-density lipoprotein, and total cholesterol), but may be associated with higher diastolic blood pressure. The findings were robust to different single nucleotide polymorphism (SNP) selections, analytic methods, and correction for multiple testing. Conclusions Our novel study suggests a benefit of LA for diabetes and lipids but no benefit for IHD, blood pressure, or reticulocyte count. Explicating these paradoxical findings would facilitate identification of effective new interventions for diabetes and IHD.

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.

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.

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.

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. 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. 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). 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. •Recalled childhood adiposity is inversely associated with breast cancer.•Studies of childhood exposures recruited in adulthood are open to survival bias.•Participant reports about family members include deaths before recruitment.•We tested childhood adiposity on sibling breast cancer using Mendelian randomization.•Recalled childhood adiposity on sibling breast cancer was less marked.