Interpreting disease genome-wide association studies and polygenetic risk scores given eligibility and study design considerations.

Genome-wide association studies (GWAS) have been helpful in identifying genetic variants predicting cancer risk and providing new insights into cancer biology. Increasing use of genetically informed care, as well as genetically informed prevention and treatment strategies, have also drawn attention to some of the inherent limitations of cancer genetic data. Specifically, genetic endowment is lifelong. However, those recruited into cancer studies tend to be middle-aged or older people, meaning the exposure most likely starts before recruitment, as opposed to exposure and recruitment aligning, as in a trial or a target trial. Studies in survivors can be biased as a result of depletion of the susceptibles, here specifically due to genetic vulnerability and the cancer of interest or a competing risk. In addition, including prevalent cases in a case-control study will make the genetics of survival with cancer look harmful (Neyman bias). Here, we describe ways of designing GWAS to maximize explanatory power and predictive utility, by reducing selection bias due to only recruiting survivors and reducing Neyman bias due to including prevalent cases alongside using other techniques, such as selection diagrams, age-stratification, and Mendelian randomization, to facilitate GWAS interpretability and utility.

The role of cortisol in ischemic heart disease, ischemic stroke, type 2 diabetes, and cardiovascular disease risk factors: a bi-directional Mendelian randomization study.

BACKGROUND: Cortisol, a steroid hormone frequently used as a biomarker of stress, is associated with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). To clarify whether cortisol causes these outcomes, we assessed the role of cortisol in ischemic heart disease (IHD), ischemic stroke, T2DM, and CVD risk factors using a bi-directional Mendelian randomization (MR) study. METHODS: Single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10-6) and independently (r2 < 0.001) predicting cortisol were obtained from the CORtisol NETwork (CORNET) consortium (n = 12,597) and two metabolomics genome-wide association studies (GWAS) (n = 7824 and n = 2049). They were applied to GWAS of the primary outcomes (IHD, ischemic stroke and T2DM) and secondary outcomes (adiposity, glycemic traits, blood pressure and lipids) to obtain estimates using inverse variance weighting, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. Conversely, SNPs predicting IHD, ischemic stroke, and T2DM were applied to the cortisol GWAS. RESULTS: Genetically predicted cortisol (based on 6 SNPs from CORNET; F-statistic = 28.3) was not associated with IHD (odds ratio (OR) 0.98 per 1 unit increase in log-transformed cortisol, 95% confidence interval (CI) 0.93-1.03), ischemic stroke (0.99, 95% CI 0.91-1.08), T2DM (1.00, 95% CI 0.96-1.04), or CVD risk factors. Genetically predicted IHD, ischemic stroke, and T2DM were not associated with cortisol. CONCLUSIONS: Contrary to observational studies, genetically predicted cortisol was unrelated to IHD, ischemic stroke, T2DM, or CVD risk factors, or vice versa. Our MR results find no evidence that cortisol plays a role in cardiovascular risk, casting doubts on the cortisol-related pathway, although replication is warranted.

Association between genetic variations in GSH-related and MT genes and low-dose methylmercury exposure in children and women of childbearing age: a pilot study.

BACKGROUND: Genetic variations in glutathione (GSH)-related and metallothionein (MT) genes, which are involved in producing enzymes in the methylmercury (MeHg) metabolism pathway, have been proposed as one of the reasons for the individual variability in MeHg toxicokinetics. OBJECTIVE: To investigate the impact of genetic variations in MT and GSH-related genes on the association of fish consumption with body burden of MeHg, as measured by hair Hg concentrations among young children and women of childbearing age. METHODS: A total of 179 unrelated children and 165 mothers with either high or low fish consumption were recruited from the community. Their hair total Hg (tHg) and MeHg levels and genotypes for SNPs located on the GCLC, GCLM, GPX1, GSTA1, GSTP1, MT1A, MT2A, and MT4 genes were determined. Based on their 14-day food records, the amounts of fish consumed and their MeHg intakes were estimated. The impact of genetic variations on hair Hg concentrations was examined by using Mann-Whitney tests and multivariable linear regression analyses. RESULTS: The presence of minor alleles of GCLC-129 (rs17883901), GPX1-198 (rs1050450) and MT1M (rs9936741) were associated with significantly lower hair tHg levels in mothers whereas mothers with minor alleles of GSTP1-105(rs1695) and MT1M (rs2270836) have significantly higher hair tHg levels. After adjustment for fish consumption and other confounding factors, apart from MT1M (rs2270836), all of the above SNPs remain significant in the multivariable linear regression models. CONCLUSIONS: Our results in a group of children and women show that genetic variants of GSH-related and MT genes are associated with hair Hg concentrations. These genetic variations are likely to significantly affect MeHg metabolism and thus influence the accumulation of Hg in the human body.

Sleep duration and risk of diabetes: Observational and Mendelian randomization studies.

Inadequate sleep could contribute to type 2 diabetes, but observational studies are inconsistent and open to biases, particularly from confounding. We used Mendelian randomization (MR) to obtain an unconfounded estimate of the effect of sleep duration on diabetes, fasting glucose (FG) and hemoglobin A1c (HbA1c), and an observation study to assess differences by sex. Using MR, we assessed the effects of genetically instrumented sleep on diabetes, based on 68 single nucleotide polymorphisms (SNPs), applied to the DIAbetes Genetics Replication and meta-analysis case (n = 26,676)-control (n = 132,532) study and on FG and HbA1c, based on 55 SNPs, applied to the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) study of FG (n = 122,743) and HbA1c (n = 123,665). In the population-representative Hong Kong Chinese "Children of 1997" birth cohort we assessed whether associations of sleep duration at ~17.5 years with FG and HbA1c differed by sex. Using inverse variance weighting with multiplicative random effects, sleep duration was not associated with diabetes (odds ratio (OR) 0.85 per hour of sleep, 95% confidence interval (CI) 0.64 to 1.13), FG (-0.032 mmol/l per hour of sleep, 95% CI -0.126 to 0.063) or HbA1c (-0.022% per hour of sleep, 95% CI -0.069 to 0.024). In "Children of 1997", the associations of sleep duration with FG differed by sex (p for interaction 0.05) but not with HbA1c. Overall sleep duration does not appear to be related to diabetes, FG or HbA1c, but the possibility of sex differences merits investigation.

The influence of hospital accreditation: a longitudinal assessment of organisational culture.

BACKGROUND: A growing body of evidence supports the link between hospital organisational culture and health outcomes. Organisational culture is thus an essential consideration for hospital accreditation, a practice of systematically assessing the quality of hospital care against accepted standards. This study assesses the interplay between accreditation and hospital professional staff perception of organisational culture. METHODS: A prospective cohort study design was used to explore the influence of accreditation on organisational culture within a large, publicly-funded, university teaching hospital in Hong Kong. All full-time hospital and academic physicians, nurses and allied health professionals were invited to participate. Organisational culture was evaluated using the Competing Values Framework through the Quality Improvement Implementation Survey. Organisational culture was assessed longitudinally at 9 months prior to accreditation, 3 months following and 15 months after accreditation. To capture potential shifts in staff perception of organisational culture through the accreditation process, we conducted a between time-point comparison using a linear trend model. RESULTS: 545 clinical staff completed the organisational culture survey pre-accreditation, 378 three- months post-accreditation and 141 15-months post-accreditation. Hierarchical culture was the dominant organisational culture domain pre-accreditation, followed by rational, developmental and group culture, respectively. Following accreditation, hierarchical culture declined but remained dominant, while group and developmental culture increased. However, the decline in hierarchical culture was U-shaped with scores increasing at 15-months post-accreditation, though not to pre-accreditation levels. When stratified by professional group, hierarchical culture declined following accreditation with corresponding increases in group culture and developmental culture among physicians and nurses, respectively. While allied health professionals did not perceive any significant cultural differences directly following accreditation, a significant increase in hierarchical culture and corresponding decrease in group culture was found 15-months post-accreditation. CONCLUSIONS: This study suggests the hospital accreditation process may contribute to shifts in staff perception of organisational culture. Our findings also indicate differential views of organisational culture across professional groups. Finally, we note the striking dominance of hierarchical culture in this Hong Kong hospital across all time points, far surpassing other studies, even those in which hierarchical culture prevailed.

Longitudinal Patterns and Predictors of Depression Trajectories Related to the 2014 Occupy Central/Umbrella Movement in Hong Kong.

OBJECTIVES: To examine the longitudinal patterns and predictors of depression trajectories before, during, and after Hong Kong's 2014 Occupy Central/Umbrella Movement. METHODS: In a prospective study, between March 2009 and November 2015, we interviewed 1170 adults randomly sampled from the population-representative FAMILY Cohort. We used the Patient Health Questionnaire-9 to assess depressive symptoms and probable major depression. We investigated pre-event and time-varying predictors of depressive symptoms. RESULTS: We identified 4 trajectories: resistant (22.6% of sample), resilient (37.0%), mild depressive symptoms (32.5%), and persistent moderate depression (8.0%). Baseline predictors that appeared to protect against persistent moderate depression included higher household income (odds ratio [OR] = 0.18; 95% confidence interval [CI] = 0.06, 0.56), greater psychological resilience (OR = 0.63; 95% CI = 0.48, 0.82), more family harmony (OR = 0.68; 95% CI = 0.56, 0.83), higher family support (OR = 0.80; 95% CI = 0.69, 0.92), better self-rated health (OR = 0.28; 95% CI = 0.16, 0.49), and fewer depressive symptoms (OR = 0.59; 95% CI = 0.43, 0.81). CONCLUSIONS: Depression trajectories after a major protest are comparable to those after major population events. Health care professionals should be aware of the mental health consequences during and after social movements, particularly among individuals lacking social support.

Effect of l-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine on ischemic heart disease risk: A Mendelian randomization study.

BACKGROUND: l-arginine is a commonly consumed dietary conditional essential amino acid found in food items and supplements, which is closely related to asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). l-arginine is thought to increase nitric oxide and be cardioprotective, whereas ADMA and SDMA may inhibit nitric oxide synthesis and increase cardiovascular disease risk. Unexpectedly, l-arginine increased mortality in a small trial. To clarify the effects of these potential targets of intervention, we assessed the risk of ischemic heart disease (IHD) by genetically determined l-arginine, ADMA, and SDMA. METHODS: Single nucleotide polymorphisms (SNPs) contributing to l-arginine, ADMA, and SDMA, at genome-wide significance, were applied to the CARDIoGRAMplusC4D 1000 Genomes-based genome-wide association study IHD case (n=60,801, ~70% myocardial infarction)-control (n=123,504) study. We obtained unconfounded estimates using instrumental variable analysis by combining the Wald estimators for each SNP, taking into account any correlation between SNPs using weighted generalized linear regression. RESULTS: Higher l-arginine was associated with higher risk of IHD (odds ratio [OR] 1.18 per SD increase, 95% CI 1.03-1.36) and of myocardial infarction (OR 1.29, 95% CI 1.10-1.51), based on 2 SNPs from MED23. Symmetric dimethylarginine had an OR of 1.07 per SD (95% CI 0.99-1.17) for IHD based on 5 SNPs from AGXT2. Asymmetric dimethylarginine had and OR of 1.08 per SD (95% CI 0.99-1.19) for IHD based on 4 SNPs from DDAH1. CONCLUSION: l-arginine could possibly cause IHD. Given that l-arginine occurs in many common dietary items, investigation of its health effect is required.

Estradiol concentrations in young healthy US versus Chinese men.

OBJECTIVES: The role of estrogens among men has rarely been explicitly considered. We examined differences in total, free, and bioavailable estradiol (Bio E) between young men from the United States (US) and the most economically developed part of China, that is, Hong Kong (HK). METHODS: Cross-sectional analysis was conducted based on 365 young men from the Third National Health and Nutrition Examination Survey in the US and 299 young Chinese men. All participants were aged from 18 to 29 years. Main outcome measures were total estradiol (E2) and calculated Bio E and free estradiol (FE). RESULTS: In both young US and Chinese men, E2 concentrations peaked at ages 25-29 years, at 43.3 pg/ml [95% confidence interval (CI) 41.9-44.8] in US men and 29.0 pg/ml (95% CI 26.2-32.0) in Chinese men. After adjustment for age and ethnicity, in all participants, US men had higher average concentrations of E2 [39.0 (95% CI 38.6-39.4) versus 28.3 (95% CI 28.3-28.4) pg/ml], FE [72.9 (95% CI 72.7-73.7) versus 56.8 (95% CI 56.6-56.9) ng/dl], and Bio E [17.9 (95% CI 17.7-18.1) versus 14.9 (95% CI 14.8-14.9) pg/ml] than HK men. Further adjustment for height or body mass index did not change the results. CONCLUSIONS: Estradiol, and free and Bio E concentrations are much lower in young healthy Chinese men than US men. However, these findings based on comparison between the two assays in the two different locations need further confirmation.

Smoking and hemorrhagic stroke mortality in a prospective cohort study of older Chinese.

BACKGROUND AND PURPOSE: Hemorrhagic stroke is more common in non-Western settings and does not always share risk factors with other cardiovascular diseases. The association of smoking with hemorrhagic stroke subtypes has not been established. We examined the association of cigarette smoking with hemorrhagic stroke, by subtype (intracerebral hemorrhage and subarachnoid hemorrhage), in a large cohort of older Chinese from Hong Kong. METHODS: Multivariable Cox regression analysis was used to assess the adjusted associations of smoking at baseline with death from hemorrhagic stroke and its subtypes, using a population-based prospective cohort of 66 820 Chinese aged>65 years enrolled from July 1998 to December 2001 at all the 18 Elderly Health Centers of the Hong Kong Government Department of Health and followed until May 31, 2012. RESULTS: After follow-up for an average of 10.9 years (SD=3.1), 648 deaths from hemorrhagic stroke had occurred, of which 530 (82%) were intracerebral hemorrhage. Current smoking was associated with a higher risk of hemorrhagic stroke (hazard ratio, 2.19; 95% confidence interval, 1.49-3.22), intracerebral hemorrhage (1.94; 1.25-3.01), and subarachnoid hemorrhage (3.58; 1.62-7.94), adjusted for age, sex, education, public assistance, housing type, monthly expenditure, alcohol use, and exercise. Further adjustment for hypertension and body mass index slightly changed the estimates. CONCLUSIONS: Smoking is strongly associated with hemorrhagic stroke mortality, particularly for subarachnoid hemorrhage.

Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank.

BACKGROUND: Metformin, a first-line medication for type 2 diabetes, might also have a protective effect against ageing-related diseases, but so far little experimental evidence is available. We sought to assess the target-specific effect of metformin on biomarkers of ageing in the UK Biobank. METHODS: In this drug target mendelian randomisation study, we assessed the target-specific effect of four putative targets of metformin (AMPK, ETFDH, GPD1, and PEN2), involving ten genes. Genetic variants with evidence of causation of gene expression, glycated haemoglobin A1c (HbA1c), and colocalisation were used as instruments mimicking the target-specific effect of metformin via HbA1c lowering. The biomarkers of ageing considered were phenotypic age (PhenoAge) and leukocyte telomere length. To triangulate the evidence, we also assessed the effect of HbA1c on the outcomes using a polygenic mendelian randomisation design and assessed the effect of metformin use on these outcomes using a cross-sectional observational design. FINDINGS: GPD1-induced HbA1c lowering was associated with younger PhenoAge (ß -5·26, 95% CI -6·69 to -3·83) and longer leukocyte telomere length (ß 0·28, 0·03 to 0·53), and AMPKγ2 (PRKAG2)-induced HbA1c lowering was associated with younger PhenoAge (ß -4·88, -7·14 to -2·62) but not with longer leukocyte telomere length. Genetically predicted HbA1c lowering was associated with younger PhenoAge (ß -0·96 per SD lowering of HbA1c, 95% CI -1·19 to -0·74) but not associated with leukocyte telomere length. In the propensity score matched analysis, metformin use was associated with younger PhenoAge (ß -0·36, 95% CI -0·59 to -0·13) but not with leukocyte telomere length. INTERPRETATION: This study provides genetic validation evidence that metformin might promote healthy ageing via targets GPD1 and AMPKγ2 (PRKAG2), and the effect could be in part due to its glycaemic property. Our findings support further clinical research into metformin and longevity. FUNDING: Healthy Longevity Catalyst Award, National Academy of Medicine, and Seed Fund for Basic Research, The University of Hong Kong.

Sex differences in the association of fasting glucose with HbA1c, and their consequences for mortality: A Mendelian randomization study.

BACKGROUND: Hemoglobin A1c (HbA1c) is used for diabetes diagnosis and management. HbA1c also represents iron-related erythrocyte properties which differ by sex. We investigated erythrocyte properties on HbA1c and glucose, and whether corresponding consequences for mortality differed by sex. METHODS: In this two-sample Mendelian randomization study using the largest publicly available European descent summary statistics, we assessed sex-specific associations of iron (n=163,511) and hemoglobin (188,076 women/162,398 men) with HbA1c (185,022 women/159,160 men) and fasting glucose (73,089 women/67,506 men), of fasting glucose with HbA1c and diabetes (cases=6,589 women/10,686 men, controls=187,137 women/155,780 men), and of fasting glucose (n=140,595), HbA1c (n=146,806) and liability to diabetes (74,124 cases/824,006 controls) with parental attained age (412,937 mothers/415,311 fathers). FINDINGS: Iron and hemoglobin were inversely associated with HbA1c but not fasting glucose. Fasting glucose was more strongly associated with HbA1c and diabetes in women (1.65 standard deviation (SD) per mmol/L [95% confidence interval 1.58, 1.72]; odds ratio (OR) 7.36 per mmol/L [4.12, 10.98]) than men (0.89 [0.81, 0.98]; OR 2.79 [1.96, 4.98]). The inverse associations of HbA1c and liability to diabetes with lifespan were possibly stronger in men (-1.80 years per percentage [-2.77, -0.42]; -0.93 years per logOR [-1.23, -0.59]) than women (-0.80 [-2.69, 0.66]; -0.44 [-0.62, -0.26]). INTERPRETATION: HbA1c underestimates fasting glucose in men compared with women, possibly due to erythrocyte properties. Whether HbA1c and liability to diabetes reduce lifespan more in men than women because diagnostic and management criteria involving HbA1c mean that glycemia in men is under-treated compared to women needs urgent investigation. FUNDING: None.

Do deaths from competing risks influence COPD patterns in China and high socio-demographic index countries?: a cross-sectional analysis of summary statistics from the Global Burden of Disease Study 2017.

OBJECTIVE: To explore possible reasons for the difference in chronic obstructive pulmonary disease (COPD) incidence/mortality rates between China and high socio-demographic index (SDI) countries. DESIGN: A cross-sectional analysis of summary statistics from the Global Burden of Disease Study 2017. PARTICIPANTS: Data were publicly available and de-identified, and individuals were not involved. MEASUREMENT AND METHODS: We extracted the age-standardised and age-specific incidence/mortality rates, and risk factors attributed to COPD in China and high SDI countries from the Global Burden of Disease Study 2017. We first described differences in COPD patterns (ie, incidence and mortality rates) in China and high SDI countries briefly, and then explored possible reasons for driving such differences by comparing rankings for six well-established COPD risk factors and estimating change points in age-specific incidence and mortality rates for COPD and several commonly encountered competing risks using segmented regression models. RESULTS: Differences in age-standardised incidence and mortality rates for COPD between China and high SDI countries converged during 1990-2017 but still differed, particularly for mortality rates. Smoking was the leading attributable risk factor followed by ambient air pollution, with higher rankings for occupational risks in China than in high SDI countries. The change point was ~80 years for age-specific COPD mortality rate in both China and high SDI countries. However, the change point for COPD incidence was 5-year later in China (~65 years) than in high SDI countries (~60 years). The change points for mortality rates due to competing risks (eg, ischaemic heart disease) also varied between settings. CONCLUSION: Differences in risk factors largely shaped the differences in COPD patterns between China and high SDI countries. Varying patterns of mortality due to competing risks might also contribute to the discrepancy in COPD mortality rates, by affecting the survival of the underlying population.

Identifying factors contributing to increased susceptibility to COVID-19 risk: a systematic review of Mendelian randomization studies.

BACKGROUND: To summarize modifiable factors for coronavirus disease 2019 (COVID-19) suggested by Mendelian randomization studies. METHODS: In this systematic review, we searched PubMed, EMBASE and MEDLINE, from inception to 15 November 2021, for Mendelian randomization studies in English. We selected studies that assessed associations of genetically predicted exposures with COVID-19-related outcomes (severity, hospitalization and susceptibility). Risk of bias of the included studies was evaluated based on the consideration of the three main assumptions for instrumental variable analyses. RESULTS: We identified 700 studies through systematic search, of which 50 Mendelian randomization studies were included. Included studies have explored a wide range of socio-demographic factors, lifestyle attributes, anthropometrics and biomarkers, predisposition to diseases and druggable targets in COVID-19 risk. Mendelian randomization studies suggested that increases in smoking, obesity and inflammatory factors were associated with higher risk of COVID-19. Predisposition to ischaemic stroke, combined bipolar disorder and schizophrenia, attention-deficit and hyperactivity disorder, chronic kidney disease and idiopathic pulmonary fibrosis was potentially associated with higher COVID-19 risk. Druggable targets, such as higher protein expression of histo-blood group ABO system transferase (ABO), interleukin (IL)-6 and lower protein expression of 2'-5' oligoadenylate synthetase 1 (OAS1) were associated with higher risk of COVID-19. There was no strong genetic evidence supporting the role of vitamin D, glycaemic traits and predisposition to cardiometabolic diseases in COVID-19 risk. CONCLUSION: This review summarizes modifiable factors for intervention (e.g. smoking, obesity and inflammatory factors) and proteomic signatures (e.g. OAS1 and IL-6) that could help identify drugs for treating COVID-19.

Atypical adaptive postural responses in children with developmental coordination disorder: Implications for rehabilitation.

BACKGROUND: Adaptive postural control is an important yet underexamined area in children with developmental coordination disorder (DCD). This study compared adaptive postural responses between children with DCD and those with typical development. METHODS: This was an exploratory cross-sectional study. Fifty-two children with DCD (aged 6-9 years) and 52 age- and sex-matched children with typical development participated in the study. Their adaptive postural (motor) responses were assessed using the Adaptation Test (ADT) on a computerized dynamic posturography machine. The sway energy score (SES) for each ADT trial and the average SES of five trials for both toes-up and toes-down platform inclination conditions were recorded. RESULTS: The SESs were lower in the DCD group than in the control group in ADT toes-up trial 1 (p = 0.009) and on average (p = 0.044). In the control group, the SES decreased from trial 1 to trial 2 for both the ADT toes-up (p = 0.005) and toes-down conditions (p < 0.001). SIGNIFICANCE: Adaptive postural responses were absent in children with DCD, and these children used less force (i.e., sway energy) to overcome postural instability. Therefore, both adaptive balance and neuromuscular training should be factored into rehabilitation programs for children with DCD.

Tai chi-muscle power training for children with developmental coordination disorder: a randomized controlled trial.

This study compared the effectiveness of tai chi (TC) muscle power training (MPT), TC alone, MPT alone, and no training for improving the limits of stability (LOS) and motor and leg muscular performance and decreasing falls in children with developmental coordination disorder (DCD). One hundred and twenty-one children with DCD were randomly assigned to the TC-MPT, TC, MPT, or control group. The three intervention groups received TC-MPT, TC, or MPT three times per week for 3 months. Measurements were taken before and after the intervention period. The primary outcomes were the LOS completion time and dynamic LOS scores. The secondary outcomes included the Movement Assessment Battery for Children-Second Edition total test score and percentile rank, knee muscle peak force and time to peak force, and the number of falls. None of the interventions affected the LOS test scores. Improvements in the peak forces of the knee extensors and flexors were demonstrated in the TC (p = 0.006) and MPT groups (p = 0.032), respectively. The number of falls also decreased in these two groups (p < 0.001). Thus, clinicians may prescribe TC or MPT for children with DCD to increase their knee muscle strength and reduce their risk of falls.

Mendelian randomization study on atrial fibrillation and cardiovascular disease subtypes.

Atrial fibrillation (AF) has been associated with numerous diseases. However, whether AF is a cause or consequence of these diseases is uncertain. To clarify, we assessed the causal role of AF on ischemic heart disease (IHD), stroke, other cardiovascular disease (CVD) subtypes, type 2 diabetes mellitus (T2DM), and late-onset AD using bi-directional two-sample Mendelian randomization (MR) among people primarily of European descent. Genetically predicted log odds of AF was associated with any stroke (odds ratio (OR) 1.22, 95% CI 1.18 to 1.27), particularly cardioembolic stroke and possibly subdural hemorrhage, with sensitivity analyses showing similar positive findings. Genetically predicted AF was also associated with arterial thromboembolism (1.32, 1.13 to 1.53), and heart failure (1.26, 1.21 to 1.30). No association of genetically predicted AF with IHD, T2DM, cognitive function, or late-onset AD was found. Conversely, genetically predicted IHD, heart failure and possibly ischemic stroke, particularly cardioembolic stroke, were positively associated with AF. Atrial fibrillation plays a role in any stroke, arterial thromboembolism, and heart failure, corroborating current clinical guidelines on the importance of preventing these complications by effective AF management. In addition, patients with IHD, heart failure or possibly ischemic stroke might be predisposed to developing AF, with implications for management.

Impact of urinary sodium on cardiovascular disease and risk factors: A 2 sample Mendelian randomization study.

BACKGROUND: Although sodium increases the risk of coronary artery disease and hypertension, whether sodium also impacts other cardiovascular disease (CVD) and its risk factors is less clear. We examined the causal role of urinary sodium in these CVDs and risk factors using Mendelian randomization. METHODS: We identified strong, independent single nucleotide polymorphisms (SNPs) of urinary sodium from the most up to date genome wide association studies (GWAS) (n = 446,237) and applied them to GWAS of stroke and its subtypes (40,585 cases and 406,111 non-cases), atrial fibrillation (60,620 cases and 970,216 non-cases) and heart failure (47,309 cases and 930,014 non-case). We assessed the impact of sodium on these diseases and associated risk factors using inverse variance weighting. Sensitivity analyses included weighted median, contamination mixture method, MR-PRESSO, and multivariable Mendelian randomization. RESULTS: Higher log transformed urinary sodium was associated with higher risk of stroke (odds ratio (OR) 1.45, 95% confidence interval (CI) 1.01 to 2.08), ischemic stroke (OR 1.60 95% CI 1.12 to 2.30), heart failure (OR 1.77 95% CI 1.19 to 2.62), and type 2 diabetes (OR 4.17 95% CI 1.53 to 11.35). Sensitivity analyses produced directionally similar estimates. CONCLUSION: Higher sodium likely increases stroke, heart failure and type 2 diabetes risk. Our study further supports public health policies to minimize population sodium intake, so as to reduce the associated disease burden.

Herpes simplex virus and Alzheimer's disease: a Mendelian randomization study.

This study assessed if any herpes simplex virus (HSV) infection was a genetically valid target for late-onset Alzheimer's disease (AD) using 2-sample Mendelian randomization. We applied strong (p-value <5×10-6) and independent (r2 < 0.05) genetic variants for any HSV infection (n = 450,581) to genome wide association studies of cognitive function (n = 300,486), and late-onset AD (n = 455,258) to obtain estimates. Genetically predicted log odds of any HSV infection was not associated with cognitive function (mean difference 0.0004 per any HSV infection, 95% confidence interval (CI) -0.001 to 0.001), or late-onset AD (odds ratio (OR) 0.999, 95% CI 0.998-1.001). Different genetic variant selections produced similar results. Any HSV infection does not appear to be a genetically valid target of intervention in late-onset AD, suggesting a rethink of the relevance of any HSV infection to late-onset AD.

Investigating Effects of Plasma Apolipoprotein E on Ischemic Heart Disease Using Mendelian Randomization Study.

BACKGROUND: Observationally plasma apolipoprotein E (apoE) is positively associated with ischemic heart disease (IHD). A Mendelian randomization (MR) study suggesting apoE is unrelated to cardiovascular mortality did not consider specific isoforms. We used MR to obtain estimates of plasma apoE2, apoE3 and apoE4 on IHD, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and apolipoprotein B (apoB). METHODS: We obtained independent genetic instruments from proteome genome-wide association studies (GWAS) and applied them to large outcome GWAS. We used univariable MR to assess the role of each isoform and multivariable MR to assess direct effects. RESULTS: In univariable MR, apoE4 was positively associated with IHD (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01 to 1.09), but apoE2 and apoE3 were less clearly associated. Using multivariable MR an association of apoE2 with IHD (OR 1.16, 95% CI 0.98 to 1.38) could not be excluded, and associations of apoE3 and apoE4 with IHD were not obvious. In univariable MR, apoE2 and apoE4 were positively associated with apoB, and a positive association of apoE2 with LDL cholesterol could not be excluded. Using multivariable MR apoE2 was positively associated with LDL cholesterol, and associations with apoB could not be excluded. After adjusting for apoB, no direct effects of apoE isoforms on IHD were evident. CONCLUSIONS: Plasma apoE2 and apoE4 may play a role in lipid modulation and IHD. Whether apoE could be a potential therapeutic target requires further clarification when larger genetic studies of apoE isoforms are available.

Effect of Berberine on Cardiovascular Disease Risk Factors: A Mechanistic Randomized Controlled Trial.

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.