Interleukin-18 and COVID-19.

Vulnerability to coronavirus disease (COVID)-19 varies due to differences in interferon gamma (IFNγ) immunity. We investigated whether a key modifiable interferon precursor, interleukin-18, was related to COVID-19, overall and by severity, using Mendelian randomisation. We used four established genome-wide significant genetic predictors of interleukin-18 applied to the most recent genome-wide association study of COVID-19 (June 2021) to obtain Mendelian randomisation inverse variance weighted estimates by severity, i.e. any (cases = 112 612, non-cases = 2 474 079), hospitalised (cases = 24 274, non-cases = 2 061 529) and very severe (cases = 8779, non-cases = 1 001 875) COVID-19. To be comprehensive, we also conducted an exploratory analysis for IFNγ and two related cytokines with less well-established genetic predictors, i.e. interleukin-12 and interleukin-23. Genetically predicted interleukin-18 was associated with lower risk of any COVID-19 (odds ratio (OR) 0.96 per standard deviation, 95% confidence interval (0.94-0.99, P-value 0.004)) and of very severe COVID-19 (OR 0.88, 95% CI 0.78-0.999, P-value 0.048). Sensitivity analysis and a more liberal genetic instrument selection gave largely similar results. Few genome-wide significant genetic predictors were available for IFNγ, interleukin-12 or interleukin-23, and no associations with COVID-19 were evident. Interleukin-18 could be a modifiable target to prevent COVID-19 and should be further explored in an experimental design.

Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation.

We examined whether specifically statins, of the major lipid modifiers (statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) have pleiotropic effects on ischemic heart disease (IHD) via testosterone in men or women. As a validation, we similarly assessed whether a drug that unexpectedly likely increases IHD also operates via testosterone. Using previously published genetic instruments we conducted a sex-specific univariable and multivariable Mendelian randomization study in the UK Biobank, including 179918 men with 25410 IHD cases and 212080 women with 12511 IHD cases. Of these three lipid modifiers, only genetically mimicking the effects of statins in men affected testosterone, which partly mediated effects on IHD. Correspondingly, genetically mimicking effects of anakinra on testosterone and IHD presented a reverse pattern to that for statins. These insights may facilitate the development of new interventions for cardiovascular diseases as well as highlighting the importance of sex-specific explanations, investigations, prevention and treatment.

Reporting and guidelines for mendelian randomization analysis: A systematic review of oncological studies.

BACKGROUND: Mendelian randomization (MR) analyses have been increasingly used to seek evidence of causal associations. This systematic review aims at characterizing and evaluating the reporting of MR analyses in oncological studies. METHODS: The PubMed database was searched to identify MR cancer studies until December 31, 2017. Two of the authors independently selected and evaluated reporting quality of the studies. Reporting quality in MR studies before 2016 and in 2016/17 was compared. RESULTS: Cancer studies with MR analyses in 2016 and 2017 accounted for 55.8% of the total number of studies identified. In the 77 eligible articles, 39 (50.6%) did not report subjects' characteristics, 53 (68.8%) did not conduct power estimation, 40 (51.9%) did not state all of the first three MR assumptions (i.e., genetic instrument is associated with exposure, is not associated with confounders, and acts on outcome only through exposure), and 31 (40.3%) did not exclude SNPs that diverged from Hardy-Weinberg equilibrium. More studies estimated power in 2016/2017 than before 2016 (p = 0.028). CONCLUSIONS: Some MR cancer studies did not sufficiently report essential information, posing obstacles for critical appraisal. This study proposes for MR analysis a guideline/checklist for future publications in cancer and other biomedical research.

Pattern of mortality after menopausal hormone therapy: long-term follow up in a population-based cohort.

OBJECTIVE: To investigate long-term pattern of mortality in menopausal women according to different modalities of hormone therapy. DESIGN: Population-based prospective cohort study. SETTING: Denmark 1993-2013. POPULATION: A total of 29 243 women aged 50-64 years at entry into the Diet, Cancer and Health Cohort, enrolled 1993-97 and followed through 31 December 2013. METHODS: Cox' proportional hazards models for increasingly longer periods of follow-up time were used to estimate mortality pattern according to baseline hormone use adjusted for relevant potential confounders. MAIN OUTCOME(S): All-cause and cause-specific mortality. Outcome information was obtained from the Danish Register of Causes of Death (linkage 99.6%). RESULTS: A total of 4098 women died during a median follow up of 17.6 years. After adjustment for relevant lifestyle risk factors, hormone use had no impact on all-cause mortality, regardless of modality. Among baseline users, lower cardiovascluar disease mortality was only evident after 5 years [hazard ratio (HR) 0.54; 95% CI 0.32-0.92], but dissipated with additional follow up. Conversely, lower colorectal cancer mortality (HR 0.64; 95% CI 0.46-0.89) and higher breast cancer mortality (HR 1.34; 95% CI 1.05-1.72) only became evident after 15 years of follow up. There were no significant associations for mortality from other types of cancer or from stroke. CONCLUSIONS: In this long-term follow-up study, taking hormones during menopause was not associated with overall mortality among middle-aged women. Investigating cause-specific mortality revealed significant, albeit weak, differential associations according to both causes of death and over time, underlining the importance of carefully considering individual risks and duration of treatment when making decisions on hormone therapy. TWEETABLE ABSTRACT: Long-term follow-up study confirms no association between menopausal hormone therapy and overall mortality.

Disconnect Between Genes Associated With Ischemic Heart Disease and Targets of Ischemic Heart Disease Treatments.

BACKGROUND: Development of pharmacological treatments to mitigate ischemic heart disease (IHD) has encompassed disappointing results and expensive failures, which has discouraged investment in new approaches to prevention and control. New treatments are most likely to be successful if they act on genetically validated targets. We assessed whether existing pharmacological treatments for IHD reduction are acting on genetically validated targets and whether all such targets for IHD are currently being exploited. METHODS: Genes associated with IHD were obtained from the loci of single nucleotide polymorphisms reported in either of two recent genome wide association studies supplemented by a gene-based analysis (accounting for linkage disequilibrium) of CARDIoGRAMplusC4D 1000 Genomes, a large IHD case (n=60,801)-control (n=123,504) study. Treatments targeting the products of these IHD genes and genes with products targeted by current IHD treatments were obtained from Kyoto Encyclopedia of Genes and Genomes and Drugbank. Cohen's kappa was used to assess agreement. RESULTS: We identified 173 autosomal genes associated with IHD and 236 autosomal genes with products targeted by current IHD treatments, only 8 genes (PCSK9, EDNRA, PLG, LPL, CXCL12, LRP1, CETP and ADORA2A) overlapped, i.e. were both associated with IHD and had products targeted by current IHD treatments. The Cohen's kappa was 0.03. Interventions related to another 29 IHD genes exist, including dietary factors, environmental exposures and existing treatments for other indications. CONCLUSIONS: Closer alignment of IHD treatments with genetically validated physiological targets may represent a major opportunity for combating a leading cause of global morbidity and mortality through repurposing existing interventions.

Genetically predicted milk consumption and bone health, ischemic heart disease and type 2 diabetes: a Mendelian randomization study.

BACKGROUND/OBJECTIVES: Milk provides protein and micronutrients, and is recommended by some dietary guidelines, particularly for bone health. Meta-analysis of small randomized controlled trials suggests that milk may increase bone mineral density, but they are very heterogeneous. No randomized controlled trial has assessed the effects of milk on major chronic diseases. Previous Mendelian randomization studies of milk did not consider bone health, found no effects on ischemic heart disease (IHD) or type 2 diabetes (T2D) but higher body mass index. Using larger genetic studies, we estimated the effects of milk on osteoporosis, IHD, T2D, adiposity, lipids and glycemic traits. SUBJECTS/METHODS: Instrumental variable analysis based on a genetic variant endowing lactase persistence (rs4988235 (MCM6)) was used to obtain estimates for osteoporosis (GEFOS), IHD (CARDIoGRAMplusC4D), T2D (DIAGRAM), adiposity (GIANT), lipids (GLGC) and glycaemic traits (MAGIC). Eye color was a negative control for IHD, as it mirrors the distribution of lactase persistence and IHD in Western Europe. RESULTS: Genetically predicted adult milk consumption was not clearly associated with bone mineral density, IHD (odds ratio (OR): 1.03 per s.d., 95% confidence interval (CI): 0.95-1.12) and or T2D (OR: 0.92, 95% CI: 0.83-1.02) but was associated with higher log-transformed fasting insulin (0.05, 95% CI: 0.02-0.07) and body mass index (0.06, 95% CI: 0.03-0.09). Genetically predicted eye color was not associated with IHD. CONCLUSIONS: The lack of association of genetically predicted milk consumption with bone health, IHD or T2D suggests few beneficial effects but is more consistent with milk promoting adiposity.

Testosterone concentrations in young healthy US versus Chinese men.

BACKGROUND: Previous small studies examining differences in testosterone concentrations by ethnicity found mixed results for Caucasians and Chinese men, which might be confounded by age differences and living standards. The aim of the present study is to examine the differences in total, free, and bioavailable testosterone concentrations between healthy young men from the United States (US) and from the most economically developed part of China, i.e., Hong Kong (HK). METHODS: Cross-sectional analysis based on 365 young men from the Third National Health and Nutrition examination Survey (NHANES III) in the US and 299 Chinese men recruited from university students. All participants were aged from 18 to 29 years. Main outcome measures were total testosterone (TT) and calculated bioavailable testosterone (Bio T) and free testosterone (FT). RESULTS: In both US and Chinese men, TT, FT, and Bio T concentration peaked at 20-24 years of age, at 23.19, 0.49, and 12.23 nmol/l in US men, and 20.72, 0.48 and 12.59 nmol/l in Chinese men, respectively. Among those aged 18-24 years, after adjusting for age, US men had higher TT (mean, 95% confidence interval: 21.64, 21.31-21.99 versus 20.20, 20.12-20.28 nmol/l), but not FT (0.47, 0.47-0.48 versus 0.47, 0.47-0.47 nmol/l) or Bio T (11.90, 11.83-11.97 versus 12.39, 12.35-12.42 nmol/l) than Chinese men. CONCLUSIONS: TT, but not FT or Bio T concentrations are lower in young healthy Chinese men than US men. These differences apparent in young men may be important in understanding different patterns of diseases between Western and Asian populations.

Systematic differences among never, occasional and moderate alcohol users in southern China, and its use in alcohol research: a cross-sectional study.

BACKGROUND: Western observational studies show moderate alcohol use, compared with never use, positively associated with health. Moderate users differ systematically from others, making these observations vulnerable to confounding. Observations from other contexts may help distinguish whether these associations are confounded. To assess whether southern Chinese would provide a more suitable setting to examine the association of moderate alcohol use with health, we compared never alcohol users with moderate alcohol users and occasional users in this setting. METHODS: We used age-adjusted multinomial regression to assess sex-stratified associations of alcohol use (never, occasional (<1 occasion/week), moderate (≤140 g ethanol/week for women and ≤210 g for men)) with health attributes and indicators in the Guangzhou Biobank Cohort Study (2003-2008) (n=26 361). RESULTS: Among men, moderate alcohol users, when compared with never users, had slightly lower socioeconomic position and unhealthier lifestyle. Conversely, occasional alcohol users, when compared with never users, had higher socioeconomic position and healthier lifestyle. Among women, when compared with never users, both occasional and moderate users had higher socioeconomic position and healthier lifestyle. However, all alcohol users for both sexes, when compared with never users, were more likely to be ever smokers and to be exposed to secondhand smoke. CONCLUSIONS: Observations in alcohol epidemiology may be affected by confounding due to contextually specific systematic differences. Results from a particular setting should not be interpreted as causal unless they are verified in different populations and, preferably, in non-observational studies.

Evaluation of moderate alcohol use and cognitive function among men using a Mendelian randomization design in the Guangzhou biobank cohort study.

Observational studies usually show that moderate alcohol use is associated with better cognitive function. Such studies are vulnerable to residual confounding arising from systematic differences between moderate alcohol users and others. A Mendelian randomization study carried out in a suitable population, such as southern Chinese men, in which alcohol use is low to moderate and is influenced by genotype, offers an alternative and superior approach for clarifying the causal effect of moderate alcohol use on cognitive function. The authors used aldehyde dehydrogenase 2 (ALDH2) genotype (AA, GA, or GG) as an instrumental variable in 2-stage least squares analysis to obtain unbiased estimates of the relation of alcohol consumption (measured in alcohol units (10 g ethanol) per day) with cognitive function, assessed from delayed 10-word recall score (n = 4,707) and Mini-Mental State Examination (MMSE) score (n = 2,284), among men from the Guangzhou Biobank Cohort Study (2003-2008). ALHD2 genotype was strongly associated with alcohol consumption, with an F statistic of 71.0 in 2-stage least squares analysis. Alcohol consumption was not associated with delayed 10-word recall score (-0.03 words per alcohol unit, 95% confidence interval: -0.18, 0.13) or MMSE score (0.06 points per alcohol unit, 95% confidence interval: -0.22, 0.34). Moderate alcohol use is unlikely to be cognitively protective.

Estimated birth weight and adult cardiovascular risk factors in a developing southern Chinese population: a cross sectional study.

BACKGROUND: Birth weight is negatively associated with cardiovascular diseases and diabetes, but the associations are less well-established in developing populations where birth weight is often unavailable. We studied the association of birth weight and cardiovascular risk, using birth rank as an instrumental variable, in Southern China. METHODS: We used published data on birth weight by birth rank from an appropriate population and baseline data from the Guangzhou Biobank Cohort Study phases 2 & 3 (2005-8) to examine the adjusted associations, using instrumental variable analysis, of birth weight with clinically measured cardiovascular risk factors and the metabolic syndrome in older (> or = 50 years) men (n = 5,051) and women (n = 13,907). RESULTS: Estimated birth weight was associated with lower blood pressure (systolic -0.25 mm Hg 95% confidence interval (CI), -0.53 to 0.03 and diastolic -0.33 mm Hg 95% CI -0.48 to -0.18 per standard deviation higher birth weight), but had little association with glucose, lipids, waist-hip ratio, body mass index or the metabolic syndrome, adjusted for age, sex, early environment and number of offspring. CONCLUSION: Birth weight may impact blood pressure; however associations of birth weight with other cardiovascular risk factors may not be related to foetal exposures, but speculatively could be an historical co-incidence, with corresponding implications for prevention.