ABSTRACT
Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.
Subject(s)
Blood Pressure , Genetic Predisposition to Disease , Genome-Wide Association Study , Hypertension , Multifactorial Inheritance , Polymorphism, Single Nucleotide , Female , Humans , Male , Blood Pressure/genetics , Genetic Risk Score , Hypertension/genetics , Risk FactorsABSTRACT
BACKGROUND: Disparities in COVID-19 outcomes exist on the basis of ethnicity and comorbidities. Minority ethnic groups in the UK are known to have poorer COVID-19 outcomes, but also an increased prevelance of certain comorbidities associated with severe outcomes. Additionally, despite the prevalence of certain psychiatric disorders there is a lack of research establishing their relationship with COVID-19 outcomes. METHODS: We used UK Biobank data, involving 472,182 participants, to test for an association between comorbidities and COVID-19 diagnosis (n = 30,901); and to test for an association between comorbidities and severe COVID-19 (n = 3182). This was done by performing univariable and multivariable logistic regression analysis, estimating odds ratios (ORs) and their 95% confidence intervals (95% CIs). The comorbidities studied were coronary heart disease (CHD), hypertension, type II diabetes mellitus (T2DM), obesity, chronic kidney disease (CKD), depression and anxiety. Multivariable models were adjusted for various socioeconomic, demographic and health-related confounders. We then performed sub-group analysis by common UK ethnic groups (White, South Asian, and Black). RESULTS: Increased prevalence of all studied comorbidities was seen in both outcomes, compared to the rest of the cohort. All studied comorbidities were associated with an increased risk of COVID-19 infection and severity across all models. For example, the adjusted ORs (95% CI) for depression were 1.112 (1.083 - 1.161) for COVID-19 diagnosis and 2.398 (2.163 - 2.658) for severe COVID-19. Sub-group analysis revealed stronger associations of COVID-19 diagnosis and severe COVID-19 for South-Asian participants for CHD (OR 1.585 [95% CI 1.194-2.105] for COVID-19 diagnosis and 3.021 [1.683-5.390] for severe COVID-19), hypertension (1.488 [1.231-1.799]; 3.399 [1.862-6.206]) and T2DM (1.671 [1.346-2.076]; 5.412 [3.130-9.357]) compared to White participants (1.264 [1.195-1.336] and 1.627 [1.441-1.837] for CHD; 1.131 [1.097-1.116] and 2.075 [1.885-2.284] for hypertension; 1.402 [1.331-1.476] and 2.890 [2.596-3.216] for T2DM). Similar results were seen for Black participants with CKD and hypertension. CONCLUSION: Specific comorbidities are risk factors for poorer COVID-19 outcomes, supporting targeted interventions and policy aimed at individuals with these comorbidities. Although further research is required, there's also a need for targeted policies for ethnic minorities assessing the unique reasons they are at greater risk of poor COVID-19 outcomes.
Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Hypertension , Humans , Ethnicity , Biological Specimen Banks , COVID-19 Testing , Cohort Studies , COVID-19/epidemiology , Hypertension/epidemiology , United Kingdom/epidemiologyABSTRACT
BACKGROUND: COVID-19 manifests with huge heterogeneity in susceptibility and severity outcomes. UK Black Asian and Minority Ethnic (BAME) groups have demonstrated disproportionate burdens. Some variability remains unexplained, suggesting potential genetic contribution. Polygenic Risk Scores (PRS) can determine genetic predisposition to disease based on Single Nucleotide Polymorphisms (SNPs) within the genome. COVID-19 PRS analyses within non-European samples are extremely limited. We applied a multi-ethnic PRS to a UK-based cohort to understand genetic contribution to COVID-19 variability. METHODS: We constructed two PRS for susceptibility and severity outcomes based on leading risk-variants from the COVID-19 Host Genetics Initiative. Scores were applied to 447,382 participants from the UK-Biobank. Associations with COVID-19 outcomes were assessed using binary logistic regression and discriminative power was validated using incremental area under receiver operating curve (ΔAUC). Variance explained was compared between ethnic groups via incremental pseudo-R2 (ΔR2). RESULTS: Compared to those at low genetic risk, those at high risk had a significantly greater risk of severe COVID-19 for White (odds ratio [OR] 1.57, 95% confidence interval [CI] 1.42-1.74), Asian (OR 2.88, 95% CI 1.63-5.09) and Black (OR 1.98, 95% CI 1.11-3.53) ethnic groups. Severity PRS performed best within Asian (ΔAUC 0.9%, ΔR2 0.98%) and Black (ΔAUC 0.6%, ΔR2 0.61%) cohorts. For susceptibility, higher genetic risk was significantly associated with COVID-19 infection risk for the White cohort (OR 1.31, 95% CI 1.26-1.36), but not for Black or Asian groups. CONCLUSIONS: Significant associations between PRS and COVID-19 outcomes were elicited, establishing a genetic basis for variability in COVID-19. PRS showed utility in identifying high-risk individuals. The multi-ethnic approach allowed applicability of PRS to diverse populations, with the severity model performing well within Black and Asian cohorts. Further studies with larger sample sizes of non-White samples are required to increase statistical power and better assess impacts within BAME populations.
Subject(s)
COVID-19 , Ethnicity , Humans , Ethnicity/genetics , Biological Specimen Banks , COVID-19/genetics , Risk Factors , United KingdomABSTRACT
DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.
Subject(s)
DNA Methylation , Diabetes Mellitus , Humans , Adipocytes/metabolism , Obesity/metabolism , Diabetes Mellitus/metabolism , Genomics , Epigenesis, GeneticABSTRACT
Background: While increased age is an established risk factor for COVID-19, there is great heterogeneity in outcomes within age groups. This is because chronological age does not reflect health, unlike biological age. We intend to investigate the association between accelerated ageing and COVID-19 outcomes through the lens of three measures, namely phenotypic age acceleration (PhenoAgeAccel), telomere length (Adjusted T/S Ratio) and facial ageing, and to examine whether there are differences across ethnic groups. Methods: Taking participants from the UK Biobank, we associated accelerated ageing with severe COVID-19 outcomes, defined as COVID-related hospitalisation or death. Separate logistic regressions models were created for age and the three accelerated ageing-related variables, adjusting for a variety of covariates in each model. Multivariable logistic regression models were also created within White, Black, Asian and Other ethnic groups to assess for potential differing associations. Forward likelihood ratio logistic regression models were created to evaluate importance of the variables and to assess for patterns of association across the total population and ethnic groups. Results: After adjusting for all covariates, the odds ratio (OR) and 95% confidence interval (95% CI) of COVID-19 severe outcomes for age was 1.080 (1.074-1.086). After further adjusting age for the accelerated ageing variables, the ORs were 1.029 (1.020-1.039) for PhenoAgeAccel and 0.847 (0.772-0.929) for Facial Ageing's "Younger Than You Are" while Adjusted T/S ratio and "Older Than You Are" were statistically insignificant. The OR for age remained similar across ethnic groups. Both PhenoAgeAccel and younger facial ages in the White population and PhenoAgeAccel in the Black population had ORs of 1.031 (1.021-1.042), 0.853 (0.774-0.939), and 1.049 (1.001-1.100), respectively. Both Adjusted T/S Ratio and older facial ages showed statistical insignificance in all ethnicities. In forward logistic regression, age and PhenoAgeAccel were the age-related variables selected most frequently in all models. Interpretation: Accelerated ageing is associated with increased COVID-19 severity. The mechanisms at work here are likely immunosenescence and inflamaging. This association indicates that anti-ageing treatment may improve COVID-19 outcome. The results within ethnic groups and that of telomere length were inconclusive, but point to a need for future, more focused research on the topic.
Subject(s)
COVID-19 , Ethnicity , Humans , COVID-19/epidemiology , Aging , Black People , Risk FactorsABSTRACT
BACKGROUND: South Asians are at high risk of type 2 diabetes (T2D). Lifestyle modification is effective at preventing T2D amongst South Asians, but the approaches to screening and intervention are limited by high costs, poor scalability and thus low impact on T2D burden. An intensive family-based lifestyle modification programme for the prevention of T2D was developed. The aim of the iHealth-T2D trial is to compare the effectiveness of this programme with usual care. METHODS: The iHealth-T2D trial is designed as a cluster randomised controlled trial (RCT) conducted at 120 sites across India, Pakistan, Sri Lanka and the UK. A total of 3682 South Asian men and women with age between 40 and 70 years without T2D but at elevated risk for T2D [defined by central obesity (waist circumference ≥ 95 cm in Sri Lanka or ≥ 100 cm in India, Pakistan and the UK) and/or prediabetes (HbA1c ≥ 6.0%)] were included in the trial. Here, we describe in detail the statistical analysis plan (SAP), which was finalised before outcomes were available to the investigators. The primary outcome will be evaluated after 3 years of follow-up after enrolment to the study and is defined as T2D incidence in the intervention arm compared to usual care. Secondary outcomes are evaluated both after 1 and 3 years of follow-up and include biochemical measurements, anthropometric measurements, behavioural components and treatment compliance. DISCUSSION: The iHealth-T2D trial will provide evidence of whether an intensive family-based lifestyle modification programme for South Asians who are at high risk for T2D is effective in the prevention of T2D. The data from the trial will be analysed according to this pre-specified SAP. ETHICS AND DISSEMINATION: The trial was approved by the international review board of each participating study site. Study findings will be disseminated through peer-reviewed publications and in conference presentations. TRIAL REGISTRATION: EudraCT 2016-001,350-18 . Registered on 14 April 2016. CLINICALTRIALS: gov NCT02949739 . Registered on 31 October 2016.
Subject(s)
Diabetes Mellitus, Type 2 , Prediabetic State , Adult , Aged , Asian People , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/prevention & control , Female , Humans , Male , Middle Aged , Obesity , Obesity, Abdominal/diagnosis , Obesity, Abdominal/prevention & control , Prediabetic State/diagnosis , Prediabetic State/therapy , Sri LankaABSTRACT
BACKGROUND: There are few data to support accurate interpretation of spirometry data in South Asia, a major global region with a high reported burden of chronic respiratory disease. METHOD: We measured lung function in 7453 healthy men and women aged ≥18â years, from Bangladesh, North India, South India, Pakistan and Sri Lanka, as part of the South Asia Biobank study. First, we assessed the accuracy of existing equations for predicting normal forced vital capacity (FVC), forced expiratory volume in 1â s (FEV1) and FEV1/FVC ratio. Then, we used our data to derive (n=5589) and internally validate (n=1864) new prediction equations among South Asians, with further external validation among 339 healthy South Asians living in Singapore. RESULTS: The Global Lung Initiative (GLI) and National Health and Nutrition Examination Survey consistently overestimated expiratory volumes (best fit GLI-African American, mean±sd z-score: FEV1 -0.94±1.05, FVC -0.91±1.10; n=7453). Age, height and weight were strong predictors of lung function in our participants (p<0.001), and sex-specific reference equations using these three variables were highly accurate in both internal validation (z-scores: FEV1 0.03±0.99, FVC 0.04±0.97, FEV1/FVC -0.03±0.99) and external validation (z-scores: FEV1 0.31±0.99, FVC 0.24±0.97, FEV1/FVC 0.16±0.91). Further adjustment for study regions improves the model fit, with highest accuracy for estimation of region-specific lung function in South Asia. CONCLUSION: We present improved equations for predicting lung function in South Asians. These offer the opportunity to enhance diagnosis and management of acute and chronic lung diseases in this major global population.
Subject(s)
Asian People , Lung , Male , Female , Humans , Adolescent , Adult , Nutrition Surveys , Reference Values , Spirometry , Forced Expiratory Volume , India , Vital CapacityABSTRACT
South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10-8 to 5.2 × 10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.
Subject(s)
Diabetes Mellitus, Type 2 , Genome-Wide Association Study , Asian People/genetics , Case-Control Studies , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Genetic Predisposition to Disease , Humans , Polymorphism, Single NucleotideABSTRACT
AIMS/HYPOTHESIS: Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts. METHODS: We conducted a meta-analysis of EWASs in blood collected 7-10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK). RESULTS: The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values <1.1 × 10-7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values <0.05 in an independent cohort of Indian Asians. However, on adjustment for baseline BMI only four CpG sites remained genome-wide significant, and addition of the 76 CpG methylation risk score to a prediction model including established predictors of type 2 diabetes (age, sex, BMI and HbA1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation. CONCLUSIONS/INTERPRETATION: By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development.
Subject(s)
Diabetes Mellitus, Type 2 , Epigenome , CpG Islands/genetics , DNA Methylation/genetics , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Epigenesis, Genetic/genetics , Genome-Wide Association Study , Humans , Prospective StudiesABSTRACT
We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P < 10-14), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961 , chromatin immunoprecipitation followed by sequencing (ChIP-seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8+ T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.
Subject(s)
DNA Methylation/genetics , Genetic Variation , Arthritis, Rheumatoid/genetics , Asia , Blood Pressure/genetics , Body Mass Index , CD8-Positive T-Lymphocytes/metabolism , CpG Islands , DNA Replication , Europe , Genome-Wide Association Study , Humans , Leukocytes/metabolism , Polymorphism, Single Nucleotide , Quantitative Trait LociABSTRACT
BACKGROUND: People from South Asia are at increased risk of type 2 diabetes (T2D). There is an urgent need to develop approaches for the prevention of T2D in South Asians that are cost-effective, generalisable and scalable across settings. HYPOTHESIS: Compared to usual care, the risk of T2D can be reduced amongst South Asians with central obesity or raised HbA1c, through a 12-month lifestyle modification programme delivered by community health workers. DESIGN: Cluster randomised clinical trial (1:1 allocation to intervention or usual care), carried out in India, Pakistan, Sri Lanka and the UK, with 30 sites per country (120 sites total). Target recruitment 3600 (30 participants per site) with annual follow-up for 3 years. ENTRY CRITERIA: South Asian, men or women, age 40-70 years with (i) central obesity (waist circumference ≥ 100 cm in India and Pakistan; ≥90 cm in Sri Lanka) and/or (ii) prediabetes (HbA1c 6.0-6.4% inclusive). EXCLUSION CRITERIA: known type 1 or 2 diabetes, normal or underweight (body mass index < 22 kg/m2); pregnant or planning pregnancy; unstable residence or planning to leave the area; and serious illness. ENDPOINTS: The primary endpoint is new-onset T2D at 3 years, defined as (i) HbA1c ≥ 6.5% or (ii) physician diagnosis and on treatment for T2D. Secondary endpoints at 1 and 3 years are the following: (i) physical measures: waist circumference, weight and blood pressure; (ii) lifestyle measures: smoking status, alcohol intake, physical activity and dietary intake; (iii) biochemical measures: fasting glucose, insulin and lipids (total and HDL cholesterol, triglycerides); and (iv) treatment compliance. INTERVENTION: Lifestyle intervention (60 sites) or usual care (60 sites). Lifestyle intervention was delivered by a trained community health worker over 12 months (5 one-one sessions, 4 group sessions, 13 telephone sessions) with the goal of the participants achieving a 7% reduction in body mass index and a 10-cm reduction in waist circumference through (i) improved diet and (ii) increased physical activity. Usual care comprised a single 30-min session of lifestyle modification advice from the community health worker. RESULTS: We screened 33,212 people for inclusion into the study. We identified 10,930 people who met study entry criteria, amongst whom 3682 agreed to take part in the intervention. Study participants are 49.2% female and aged 52.8 (SD 8.2) years. Clinical characteristics are well balanced between intervention and usual care sites. More than 90% of follow-up visits are scheduled to be complete in December 2020. Based on the follow-up to end 2019, the observed incidence of T2D in the study population is in line with expectations (6.1% per annum). CONCLUSION: The iHealth-T2D study will advance understanding of strategies for the prevention of diabetes amongst South Asians, use approaches for screening and intervention that are adapted for low-resource settings. Our study will thus inform the implementation of strategies for improving the health and well-being of this major global ethnic group. IRB APPROVAL: 16/WM/0171 TRIAL REGISTRATION: EudraCT 2016-001350-18 . Registered on 14 April 2016. ClinicalTrials.gov NCT02949739 . Registered on 31 October 2016, First posted on 31/10/2016.
Subject(s)
Diabetes Mellitus, Type 2 , Prediabetic State , Adult , Aged , Asian People , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/prevention & control , Female , Humans , Life Style , Male , Middle Aged , Obesity, Abdominal , Prediabetic State/diagnosis , Prediabetic State/therapy , Randomized Controlled Trials as TopicABSTRACT
INTRODUCTION: South Asians are at high risk of type 2 diabetes (T2D). We assessed whether intensive family-based lifestyle intervention leads to significant weight loss, improved glycaemia and blood pressure in adults at elevated risk for T2D. METHODS: This cluster randomised controlled trial (iHealth-T2D) was conducted at 120 locations across India, Pakistan, Sri Lanka and the UK. We included 3684 South Asian men and women, aged 40-70 years, without T2D but with raised haemoglobin A1c (HbA1c) and/or waist circumference. Participants were randomly allocated either to the family-based lifestyle intervention or control group by location clusters. Participants in the intervention received 9 visits and 13 telephone contacts by community health workers over 1-year period, and the control group received usual care. Reductions in weight (aim >7% reduction), waist circumference (aim ≥5 cm reduction), blood pressure and HbA1C at 12 months of follow-up were assessed. Our linear mixed-effects regression analysis was based on intention-to-treat principle and adjusted for age, sex and baseline values. RESULTS: There were 1846 participants in the control and 1838 in the intervention group. Between baseline and 12 months, mean weight of participants in the intervention group reduced by 1.8 kg compared with 0.4 kg in the control group (adjusted mean difference -1.10 kg (95% CI -1.70 to -1.06), p<0.001). The adjusted mean difference for waist circumference was -1.9 cm (95% CI -2.5; to 1.3), p<0.001). No overall difference was observed for blood pressure or HbA1c. People who attended multiple intervention sessions had a dose-dependent effect on waist circumference, blood pressure and HbA1c, but not on weight. CONCLUSION: An intensive family-based lifestyle intervention adopting low-resource strategies led to effective reduction in weight and waist circumference at 12 months, which has potential long-term benefits for preventing T2D. A higher number of attended sessions increased the effect on waist circumference, blood pressure and HbA1c. TRIAL REGISTRATION NUMBER: EudraCT: 2016-001350-18; ClinicalTrials.gov: NCT02949739.
Subject(s)
Diabetes Mellitus, Type 2 , Adult , Asian People , Diabetes Mellitus, Type 2/prevention & control , Female , Follow-Up Studies , Humans , Life Style , Male , Weight LossABSTRACT
BACKGROUND: The prevalence of obesity and its related chronic diseases have been increasing especially in Asian countries. Obesity-related genetic variants have been identified, but these explain little of the variation in BMI. Recent studies reported associations between DNA methylation and obesity, mostly in non-Asian populations. METHODS: We performed an epigenome-wide association study (EWAS) on general adiposity (body mass index, BMI) and abdominal adiposity (waist circumference, WC) in 409 multi-ethnic Asian individuals and replicated BMI and waist-associated DNA methylation CpGs identified in other populations. The cross-lagged panel model and Mendelian randomization were used to assess the temporal relationship between methylation and BMI. The temporal relationship between the identified CpGs and inflammation and metabolic markers was also examined. RESULTS: EWAS identified 116 DNA methylation CpGs independently associated with BMI and eight independently associated with WC at false discovery rate PFDR < 0.05 in 409 Asian samples. We replicated 110 BMI-associated CpGs previously reported in Europeans and identified six novel BMI-associated CpGs and two novel WC-associated CpGs. We observed high consistency in association direction of effect compared to studies in other populations. Causal relationship analyses indicated that BMI was more likely to be the cause of DNA methylation alteration, rather than the consequence. The causal analyses using BMI-associated methylation risk score also suggested that higher levels of the inflammation marker IL-6 were likely the consequence of methylation change. CONCLUSION: Our study provides evidence of an association between obesity and DNA methylation in multi-ethnic Asians and suggests that obesity can drive methylation change. The results also suggested possible causal influence that obesity-related methylation changes might have on inflammation and lipoprotein levels.
Subject(s)
Asian People/genetics , Body Mass Index , Genome-Wide Association Study/methods , Waist Circumference/genetics , Analysis of Variance , Asian People/ethnology , Biomarkers/analysis , DNA Methylation/genetics , DNA Methylation/physiology , Genome-Wide Association Study/statistics & numerical data , Humans , Obesity/geneticsABSTRACT
BACKGROUND: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. METHODS: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. RESULTS: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10- 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). CONCLUSIONS: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.
Subject(s)
Apolipoprotein C-III/genetics , Coronary Artery Disease/genetics , Genetic Variation , Aged , Alleles , Coronary Artery Disease/ethnology , Europe/epidemiology , Female , Genetic Association Studies , Genotype , Heterozygote , Humans , India/epidemiology , Male , Mendelian Randomization Analysis , Middle Aged , Mutation , Risk , Sequence Analysis, DNA , Triglycerides/bloodABSTRACT
OBJECTIVES: The clinical impact of SARS-CoV-2 has varied across countries with varying cardiovascular manifestations. We review the cardiac presentations, in-hospital outcomes and development of cardiovascular complications in the initial cohort of SARS-CoV-2 positive patients at Imperial College Healthcare National Health Service Trust, UK. METHODS: We retrospectively analysed 498 COVID-19 positive adult admissions to our institute from 7 March to 7 April 2020. Patient data were collected for baseline demographics, comorbidities and in-hospital outcomes, especially relating to cardiovascular intervention. RESULTS: Mean age was 67.4±16.1 years and 62.2% (n=310) were male. 64.1% (n=319) of our cohort had underlying cardiovascular disease (CVD) with 53.4% (n=266) having hypertension. 43.2%(n=215) developed acute myocardial injury. Mortality was significantly increased in those patients with myocardial injury (47.4% vs 18.4%, p<0.001). Only four COVID-19 patients had invasive coronary angiography, two underwent percutaneous coronary intervention and one required a permanent pacemaker implantation. 7.0% (n=35) of patients had an inpatient echocardiogram. Acute myocardial injury (OR 2.39, 95% CI 1.31 to 4.40, p=0.005) and history of hypertension (OR 1.88, 95% CI 1.01 to 3.55, p=0.049) approximately doubled the odds of in-hospital mortality in patients admitted with COVID-19 after other variables had been controlled for. CONCLUSION: Hypertension, pre-existing CVD and acute myocardial injury were associated with increased in-hospital mortality in our cohort of COVID-19 patients. However, only a low number of patients required invasive cardiac intervention.
Subject(s)
COVID-19/epidemiology , Cardiovascular Diseases/epidemiology , Pandemics , Aged , Comorbidity , Female , Hospital Mortality/trends , Humans , Incidence , London , Male , RNA, Viral/analysis , Retrospective Studies , SARS-CoV-2/genetics , Survival Rate/trendsABSTRACT
BACKGROUND: South Asia has become a major epicentre of the COVID-19 pandemic. Understanding South Asians' awareness, attitudes and experiences of early measures for the prevention of COVID-19 is key to improving the effectiveness and mitigating the social and economic impacts of pandemic responses at a critical time for the Region. METHODS: We assessed the knowledge, behaviours, health and socio-economic circumstances of 29,809 adult men and women, at 93 locations across four South Asian countries. Data were collected during the national lockdowns implemented from March to July 2020, and compared with data collected prior to the pandemic as part of an ongoing prospective surveillance initiative. RESULTS: Participants were 61% female, mean age 45.1 years. Almost half had one or more chronic disease, including diabetes (16%), hypertension (23%) or obesity (16%). Knowledge of the primary COVID-19 symptoms and transmission routes was high, but access to hygiene and personal protection resources was low (running water 63%, hand sanitisers 53%, paper tissues 48%). Key preventive measures were not widely adopted. Knowledge, access to, and uptake of COVID-19 prevention measures were low amongst people from disadvantaged socio-economic groups. Fifteen percent of people receiving treatment for chronic diseases reported loss of access to long-term medications; 40% reported symptoms suggestive of anxiety or depression. The prevalence of unemployment rose from 9.3% to 39.4% (P < 0.001), and household income fell by 52% (P < 0.001) during the lockdown. Younger people and those from less affluent socio-economic groups were most severely impacted. Sedentary time increased by 32% and inadequate fruit and vegetable intake increased by 10% (P < 0.001 for both), while tobacco and alcohol consumption dropped by 41% and 80%, respectively (P < 0.001), during the lockdown. CONCLUSIONS: Our results identified important knowledge, access and uptake barriers to the prevention of COVID-19 in South Asia, and demonstrated major adverse impacts of the pandemic on chronic disease treatment, mental health, health-related behaviours, employment and household finances. We found important sociodemographic differences for impact, suggesting a widening of existing inequalities. Our findings underscore the need for immediate large-scale action to close gaps in knowledge and access to essential resources for prevention, along with measures to safeguard economic production and mitigate socio-economic impacts on the young and the poor.
ABSTRACT
BACKGROUND: The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. RESULTS: We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10-10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations. CONCLUSION: Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.
Subject(s)
DNA Methylation/genetics , Epigenesis, Genetic , Genome-Wide Association Study , Lipid Metabolism/genetics , Metabolome/genetics , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Germany , Humans , Male , Middle Aged , Myocardial Infarction/genetics , Myocardial Infarction/physiopathology , Obesity/genetics , Obesity/physiopathologyABSTRACT
DNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart. Using the Illumina HumanMethylation450 BeadChip, DNA methylation was measured in blood samples from 5606 Melbourne Collaborative Cohort Study (MCCS) participants. For 1088 of them, these measures were repeated using blood samples collected a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models. Independent data from the London Life Sciences Prospective Population (LOLIPOP) (N = 4042) and Cooperative Health Research in the Augsburg Region (KORA) (N = 1662) cohorts were used to replicate associations discovered in the MCCS. Cross-sectional analyses identified 1414 CpGs associated with alcohol intake at P < 10-7 , 1243 of which had not been reported previously. Of these novel associations, 1078 were replicated (P < .05) using LOLIPOP and KORA data. Using the MCCS data, we also replicated 403 of 518 previously reported associations. Interaction analyses suggested that associations were stronger for women, non-smokers, and participants genetically predisposed to consume less alcohol. Of the 1414 CpGs, 530 were differentially methylated (P < .05) in former compared with current drinkers. Longitudinal associations between the change in alcohol intake and the change in methylation were observed for 513 of the 1414 cross-sectional associations. Our study indicates that alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with alcohol consumption changes in adulthood.