Using genetics and proteomics data to identify proteins causally related to COVID-19, healthspan and lifespan: a Mendelian randomization study.

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.

A two-sample Mendelian randomization study explores metabolic profiling of different glycemic traits.

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.

Long-term exposure to ambient air pollution with sarcopenia among middle-aged and older adults in China.

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 (PM2.5), inhalable particles (PM10), coarse particulate matter (PMcoarse), nitrogen dioxide (NO2), sulfur dioxide (SO2), 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/m3 increment of annual PMcoarse 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 PM10, PMcoarse, and NO2. Ambient NO2 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 PMcoarse in the sensitivity analyses. CONCLUSION: This nationwide study suggested that long-term exposure to outdoor air pollution, especially for PMcoarse, was associated with the risk of sarcopenia among Chinese adults. Our findings provide epidemiological implications for protecting healthy ageing by improving air quality.

Early-life exposure to ambient air pollution with cardiovascular risk factors in adolescents: Findings from the "Children of 1997" Hong Kong birth cohort.

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 (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2) 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 PM10 was associated with low density lipoprotein (LDL) in boys, with ß 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 PM10 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 PM10 exposure with elevated LDL in adolescence, especially exposure in utero and infancy.

Genetic proxies for antihypertensive drugs and mental disorders: Mendelian randomization study in European and East Asian populations.

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.

Iron status and non-alcoholic fatty liver disease: A Mendelian randomization study.

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.

Selection bias as an explanation for the observed protective association of childhood adiposity with breast cancer.

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.

Using genetics to examine the overall and sex-specific associations of branch-chain amino acids and the valine metabolite, 3-hydroxyisobutyrate, with ischemic heart disease and diabetes: A two-sample Mendelian randomization study.

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.

Overall and Sex-Specific Effect of Berberine on Glycemic and Insulin-Related Traits: a Systematic Review and Meta-Analysis of Randomized Controlled Trials.

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).

The Associations of Genetically Predicted Plasma Alanine with Coronary Artery Disease and its Risk Factors: A Mendelian Randomization Study.

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 (ß: 0.11; 95% CI: 0.02, 0.19), LDL cholesterol (ß: 0.08; 95% CI: 0.04, 0.12), triglycerides (ß: 0.25; 95% CI: 0.13, 0.38), total cholesterol (ß: 0.14; 95% CI: 0.08, 0.20), apolipoprotein B (ß: 0.12; 95% CI: 0.03, 0.21), and BP (ß: 1.17; 95% CI: 0.31, 2.04 for systolic BP: ß: 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.

The relationship of fatty acids to ischaemic heart disease and lifespan in men and women using Mendelian randomization.

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.

Red meat consumption, cardiovascular diseases, and diabetes: a systematic review and meta-analysis.

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.

The influence of growth and sex hormones on risk of alzheimer's disease: a mendelian randomization study.

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.

Genetic proxies for calcium channel blockers and cancer: a Mendelian randomization study.

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.

Genome-wide cross-trait analysis and Mendelian randomization reveal a shared genetic etiology and causality between COVID-19 and venous thromboembolism.

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.

Exploration of Metabolic Biomarkers Linking Red Meat Consumption to Ischemic Heart Disease Mortality in the UK Biobank.

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.

Overall and Sex-Specific Effect of Berberine for the Treatment of Dyslipidemia in Adults: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.

BACKGROUND: Berberine is a nutraceutical that can improve lipid metabolism. Berberine may also affect sex hormones and exert sex-specific lipid-modifying effects, which have been overlooked. This study aimed to comprehensively review the efficacy and safety of berberine in adults for the treatment of dyslipidemia with consideration of potential sex disparity. Data Sources We searched Medline, Embase, Wanfang, CNKI, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform from inception to 13 December 2022. No language restrictions were applied. This study was registered in PROSPERO (CRD42021293218) prior to completing the literature search. Study Selection Two blinded reviewers assessed studies for inclusion. Eligible studies were randomized controlled trials in adults that compared berberine versus placebo, and measured blood lipids or lipoproteins. Data Extraction and Synthesis Data extraction was performed by two blinded reviewers using a structured form in Covidence. Risk of bias was assessed using the Cochrane risk of bias tool for randomized trials. Mean differences (MD) were estimated using inverse variance weighting with random effects models for lipid outcomes using R. Adverse events (AEs) were described narratively. Main Outcomes Primary outcomes were low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and apolipoprotein B. Secondary outcomes were gastrointestinal and muscle-related AEs. RESULTS: Eighteen studies (n = 1788 participants), conducted mainly in mainland China and Hong Kong (15 studies [83%]), were included with treatment durations ranging from 4 to 24 weeks. Berberine reduced LDL cholesterol (- 0.46 mmol/L, 95% CI - 0.62 to - 0.30, 14 studies, n = 1447), total cholesterol (- 0.48 mmol/L, 95% CI - 0.63 to - 0.33, 17 studies, n = 1637), triglycerides (- 0.34 mmol/L, 95% CI - 0.46 to - 0.23, 18 studies, n = 1661) and apolipoprotein B (- 0.25 g/L, 95% CI - 0.40 to - 0.11, 2 studies, n = 127). Berberine increased HDL cholesterol by 0.06 mmol/L (95% CI 0.00 to 0.11, 15 studies, n = 1471). Notably, the effect on HDL cholesterol was different in women (0.11 mmol/L, 95% CI 0.09 to 0.13) from that in men (- 0.07 mmol/L, 95% CI - 0.16 to 0.02). Among 16 studies that reported AEs, no serious AEs were reported for berberine. Gastrointestinal AEs were reported in 12 studies and tended to be more frequent in participants allocated to berberine versus placebo (2-23% vs 2-15%). CONCLUSIONS: Berberine produces small reductions in LDL cholesterol, triglycerides, and apolipoprotein B, with potential sex-specific effects on HDL cholesterol. Large-scale trials that consider sex disparity and assess clinical outcomes are required.

Berberine is found naturally in barberry and goldenthread, plants which have long been used in traditional herbal medicine in Asia. Nowadays berberine is used as a purified product and is easy to purchase as a nutraceutical supplement or non-prescription drug. People with dyslipidemia, a medical condition often known as 'high cholesterol', may prefer treatment with a nutraceutical such as berberine to reduce blood cholesterol. In recent years, many studies have contrasted the effects of taking berberine with an inactive placebo. This study aimed to combine all the available randomized controlled trials that assessed berberine's effects on blood lipids and lipoproteins. We included 18 studies that used berberine doses of 900­1500 mg/day, the majority of which were conducted in mainland China and Hong Kong. We found that on average berberine can modestly reduce low-density lipoprotein (LDL) cholesterol by 0.5 mmol/L (18 mg/dL) and triglycerides by 0.3 mmol/L (30 mg/dL). Berberine also increases high-density lipoprotein (HDL) cholesterol by 0.06 mmol/L (2 mg/dL). Interestingly, women may obtain a greater increase in HDL cholesterol than men. The short-term use of berberine appears to be safe. No study participants treated with berberine experienced a serious adverse event. However, berberine may occasionally cause constipation, diarrhea, or nausea. Larger high-quality studies are still needed to determine the long-term effects of berberine for dyslipidemia.

Disentangling the common genetic architecture and causality of rheumatoid arthritis and systemic lupus erythematosus with COVID-19 outcomes: Genome-wide cross trait analysis and bidirectional Mendelian randomization study.

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.

Sex-Specific Associations of Red Meat and Processed Meat Consumption with Serum Metabolites in the UK Biobank.

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.