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.

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.

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.

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.

Using genetics to understand the role of antihypertensive drugs modulating angiotensin-converting enzyme in immune function and inflammation.

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.

Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank.

OBJECTIVE: To determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction. DESIGN: Two sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence. SETTING: Reduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study. PARTICIPANTS: 3225 men of European ancestry aged 50-75 in REDUCE; 392 038 white British men and women aged 40-69 from the UK Biobank; and 171 875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation. MAIN OUTCOME MEASURES: Thromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death. RESULTS: Of the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes. CONCLUSIONS: Endogenous testosterone was positively associated with thromboembolism, heart failure, and myocardial infarction in men. Rates of these conditions are higher in men than women. Endogenous testosterone can be controlled with existing treatments and could be a modifiable risk factor for thromboembolism and heart failure.

How Might Bromodomain and Extra-Terminal (BET) Inhibitors Operate in Cardiovascular Disease?

Bromodomain and extra-terminal (BET) inhibitors, acting via epigenetic mechanisms, have been developed recently as potential new treatments for cancer, including prostate cancer, and inflammatory conditions. Some BET inhibitors, such as RVX-208, also raise high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 levels. A recent meta-analysis of three small trials (n = 798) found that RVX-208 protected against major adverse cardiovascular events (MACE), raising the question as to whether this protective effect was an artefact, a chance finding, or mediated by HDL-C, anti-inflammatory pathways, or other factors. Notably, the effect of RVX-208 on MACE was largely driven by revascularizations, but fewer interventions in the treatment arm could have arisen accidently from favorable effects of RVX-208 on HDL-C and C-reactive protein influencing decisions about patient care. A larger (n = 2400) trial of RVX-208, BETonMACE (NCT02586155), with a more restricted definition of MACE, excluding hospitalizations, will shortly provide clarity. A successful BETonMACE trial would raise the question as to whether RVX-208 operates via lipids, inflammation, or other means, because several previous HDL-C modulators and anti-inflammatories have not provided effective means of treating cardiovascular disease and reducing overall mortality. Re-conceptualizing cardiovascular disease within the well-established evolutionary biology theory that growth and specifically reproduction trade-off against longevity might provide a more comprehensive explanation. Drivers of the gonadotropic axis, particularly androgens, suppress both HDL-C and the immune system while promoting ischemic heart disease and stroke. As such, any effects of RVX-208 on cardiovascular disease might be the result of reducing androgens, of which higher HDL-C and reduced inflammation are biomarkers. Notably, several other effective treatments for cardiovascular disease, such as statins and spironolactone, are known anti-androgens. Results of the BETonMACE trial, and corresponding insight about the mechanism of BET inhibitors in cardiovascular disease, are eagerly awaited.

Endogenous androgen exposures and ischemic heart disease, a separate sample Mendelian randomization study.

BACKGROUND: Evolutionary biology suggests growth and reproduction trade-off against longevity. Correspondingly estrogen supplementation failed to increase lifespan. Testosterone supplementation is widely used by older men, although regulators have warned of its cardiovascular risk. No large trial of testosterone exists. We examined how genetic determinants of up-regulation (follicle-stimulating hormone (FSH)) and down-regulation (anti-Müllerian hormone (AMH) and testicular dysgenesis syndrome (TDS)) of mainly the male reproductive system are associated with ischemic heart disease (IHD). METHODS: Separate sample instrumental variable analysis with genetic instruments, i.e., Mendelian randomization, was used to obtain unconfounded estimates using large case-control studies of coronary artery disease/myocardial infarction (CAD/MI) with extensive genotyping, i.e., CARDIoGRAMplusC4D (64,374 CAD/MI cases, 130,681controls), or CARDIoGRAMplusC4D 1000 Genomes (60,801 cases, 123,504 controls). RESULTS: Genetically predicted FSH was positively associated with CAD/MI (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.03 to 1.13 per mIU/mL FSH). Genetically predicted AMH and TDS were inversely associated with CAD/MI (OR 0.93, 95% CI 0.87 to 0.998 per ng/mL log AMH and OR 0.89, 95% CI 0.81 to 0.98 per log OR higher risk of TDS). CONCLUSIONS: As expected from evolutionary biology, genetically predicted FSH, related to higher androgens in men and women, was positively associated with IHD, while genetically predicted AMH and TDS, related to lower androgens in men, were inversely associated with IHD. Androgens might be a modifiable causal factor underlying men's greater vulnerability to IHD, with corresponding implications for use of testosterone supplementation as well as for prevention and treatment of IHD.

A Mendelian randomization study of testosterone and cognition in men.

Testosterone replacement for older men is increasingly common, with some observations suggesting a protective effect on cognitive function. We examined the association of endogenous testosterone with cognitive function among older men in a Mendelian randomization study using a separate-sample instrumental variable (SSIV) analysis estimator to minimize confounding and reverse causality. A genetic score predicting testosterone was developed in 289 young Chinese men from Hong Kong, based on selected testosterone-related single nucleotide polymorphisms (rs10046, rs1008805 and rs1256031). The association of genetically predicted testosterone with delayed 10-word recall score and Mini-Mental State Examination (MMSE) score was assessed at baseline and follow-up using generalized estimating equation among 4,212 older Chinese men from the Guangzhou Biobank Cohort Study. Predicted testosterone was not associated with delayed 10-word recall score (-0.02 per nmol/L testosterone, 95% confidence interval (CI) -0.06-0.02) or MMSE score (0.06, 95% CI -0.002-0.12). These estimates were similar after additional adjustment for age, education, smoking, use of alcohol, body mass index and the Framingham score. Our findings do not corroborate observed protective effects of testosterone on cognitive function among older men.