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Background: The purpose of this study was to assess if single nucleotide polymorphisms (SNPs) in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis outcomes., Methods: Independent SNPs in MUC5B and MUC5AC (genotyped by Illumina HumanOmniExpress array) were assessed for associations with tumor necrosis factor (TNF) concentrations (measured by immunoassay) in cerebral spinal fluid (CSF) from tuberculous meningitis (TBM) patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal tuberculosis susceptibility and TBM mortality., Results: MUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF (P = 1.8 × 10-8) and IFN-γ (P = 2.3 × 10-6). In an additive genetic model, rs28737416 T/T genotype was associated with higher susceptibility to TBM (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.03-1.49; P = .02), but not pulmonary tuberculosis (OR, 1.11, 95% CI, .98-1.25; P = .10). TBM mortality was higher among participants with the rs28737416 T/T and T/C genotypes (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank P = .005) in a Vietnam discovery cohort (n = 210), an independent Vietnam validation cohort (n = 87; 9/87, 19.1% vs 1/20, 2.5%; log-rank P = .02), and an Indonesia validation cohort (n = 468, 127/287, 44.3% vs 65/181, 35.9%; log-rank P = .06)., Conclusions: MUC5AC variants may contribute to immune changes that influence TBM outcomes., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors., Methods: We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: (i) GWAS hits for fatty acids, (ii) GWAS hits for cancer and (iii) a 1000 genomes reference set., Results: We collated summary data from 6 fatty acid and 54 cancer GWAS. Metadata errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (11.6%). After resolving metadata errors and analytical issues, we created a data set of 219 842 genetic associations with 90 cancer types, generated in analyses of 566 665 cancer cases and 1 622 374 controls., Conclusions: In this large MR collaboration, 11.6% of included studies were affected by a substantial metadata error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of downstream MR analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats)., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Study Question: Are there genetic variants that interact with smoking to reduce reproductive lifespan in East-Asian women?, Summary Answer: Our study corroborates several recently identified genetic loci associated with reproductive lifespan and highlights specific genetic predispositions that may interact with smoking status to adversely affect reproductive lifespan in East-Asian women., What Is Known Already: Epidemiological data as well as evaluations on genetic predisposition to smoke indicate on the importance of smoking in adverse effects on reproductive lifespan in women. However, there are no previous smoking and gene interaction studies for reproductive traits in East-Asian women., Study Design, Size, Duration: This population-based prospective cohort study comprised 11 643 East-Asian Chinese women with overlapping genome-wide genotyping and reproductive data., Participants/materials, Setting, Methods: We performed a genome-wide association study for reproductive lifespan in women (n = 11 643) from the Singapore Chinese Health Study (SCHS) and carried out a genome-wide interaction study to identify loci that interacted with smoking status to affect age of natural menopause and reproductive-time., Main Results and the Role of Chance: Two known loci associated with menopause, rs113430717 (near HMCES, chromosome 3, Pmeta = 5.72 × 10-15) and rs3020136 (near RAD21, chromosome 8, Pmeta = 1.38 × 10-8) were observed beyond genome-wide levels of association with age at menopause in this study. For reproductive lifespan, the genome-wide association observed at rs79784106 (chromosome 3, Pmeta = 5.05 × 10-12) was in linkage disequilibrium with the menopause lead single-nucleotide polymorphism (SNP) (rs113430717). Four additional loci, first reported to be associated with menopause, were also associated with reproductive lifespan in our study (PAdj between 7.42 × 10-5 to 4.51 × 10-3). A significant interaction was observed between smoking and an East-Asian specific SNP, rs140146885, for reduced reproductive lifespan, per copy of the minor C allele (beta = -1.417 years, Pinteraction = 2.31 × 10-10). This interaction was successfully replicated in additional independent samples (beta = -1.389 years, Pinteraction = 6.78 × 10-3). Another known variant associated with menopause, rs11031006 (near FSHB), was also observed to interact with smoking status to reduce age at menopause in our dataset (beta = -0.450 years, Padj = 0.042)., Limitations, Reasons for Caution: The modest sample size of the replication datasets used likely affected the statistical power to firmly replicate all identified novel loci observed in our smoking interaction analyses., Wider Implications of the Findings: Age of natural menopause and reproductive lifespan have clear genetic predispositions with distinct ethnic differences, and they may be adversely truncated by lifestyle factors such as smoking, which can pose a significant impact on the reproductive lifespan and future health outcomes in women., Study Funding/competing Interest(s): The Singapore Chinese Health Study is funded by the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016), National Institutes of Health (R01 CA144034 and UM1 CA182876) and National Research Foundation, Singapore (Project Number 370062002). W.-P.K. is supported by the National Medical Research Council, Singapore (MOH-CSASI19nov-0001). The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors do not report conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations., Methods and Results: Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43-3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20-80%) PRS., Conclusion: The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Aims: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation., Methods and Results: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro., Conclusions: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background Although numerous phenotype based equations for predicting risk of 'hard' coronary heart disease are available, data on the utility of genetic information for such risk prediction is lacking in Chinese populations. Design Case-control study nested within the Singapore Chinese Health Study. Methods A total of 1306 subjects comprising 836 men (267 incident cases and 569 controls) and 470 women (128 incident cases and 342 controls) were included. A Genetic Risk Score comprising 156 single nucleotide polymorphisms that have been robustly associated with coronary heart disease or its risk factors ( p < 5 × 10 -8 ) in at least two independent cohorts of genome-wide association studies was built. For each gender, three base models were used: recalibrated Adult Treatment Panel III (ATPIII) Model (M 1 ); ATP III model fitted using Singapore Chinese Health Study data (M 2 ) and M 3 : M 2 + C-reactive protein + creatinine. Results The Genetic Risk Score was significantly associated with incident 'hard' coronary heart disease ( p for men: 1.70 × 10 -10 -1.73 × 10 -9 ; p for women: 0.001). The inclusion of the Genetic Risk Score in the prediction models improved discrimination in both genders (c-statistics: 0.706-0.722 vs. 0.663-0.695 from base models for men; 0.788-0.790 vs. 0.765-0.773 for women). In addition, the inclusion of the Genetic Risk Score also improved risk classification with a net gain of cases being reclassified to higher risk categories (men: 12.4%-16.5%; women: 10.2% (M 3 )), while not significantly reducing the classification accuracy in controls. Conclusions The Genetic Risk Score is an independent predictor for incident 'hard' coronary heart disease in our ethnic Chinese population. Inclusion of genetic factors into coronary heart disease prediction models could significantly improve risk prediction performance.