A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans.

CONTEXT: Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent. OBJECTIVES AND METHODS: To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration. RESULTS: Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10-32; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10-78; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument. CONCLUSION: Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.

Nationwide estimation of daily ambient PM2.5 from 2008 to 2020 at 1 km2 in India using an ensemble approach.

High-resolution assessment of historical levels is essential for assessing the health effects of ambient air pollution in the large Indian population. The diversity of geography, weather patterns, and progressive urbanization, combined with a sparse ground monitoring network makes it challenging to accurately capture the spatiotemporal patterns of ambient fine particulate matter (PM2.5) pollution in India. We developed a model for daily average ambient PM2.5 between 2008 and 2020 based on monitoring data, meteorology, land use, satellite observations, and emissions inventories. Daily average predictions at each 1 km × 1 km grid from each learner were ensembled using a Gaussian process regression with anisotropic smoothing over spatial coordinates, and regression calibration was used to account for exposure error. Cross-validating by leaving monitors out, the ensemble model had an R2 of 0.86 at the daily level in the validation data and outperformed each component learner (by 5-18%). Annual average levels in different zones ranged between 39.7 µg/m3 (interquartile range: 29.8-46.8) in 2008 and 30.4 µg/m3 (interquartile range: 22.7-37.2) in 2020, with a cross-validated (CV)-R2 of 0.94 at the annual level. Overall mean absolute daily errors (MAE) across the 13 years were between 14.4 and 25.4 µg/m3. We obtained high spatial accuracy with spatial R2 greater than 90% and spatial MAE ranging between 7.3-16.5 µg/m3 with relatively better performance in urban areas at low and moderate elevation. We have developed an important validated resource for studying PM2.5 at a very fine spatiotemporal resolution, which allows us to study the health effects of PM2.5 across India and to identify areas with exceedingly high levels.

Impact of maternal pre-pregnancy body mass index on maternal, fetal and neonatal adverse outcomes in the worldwide populations: A systematic review and meta-analysis.

OBJECTIVE: Systematic review and meta-analysis conducted to investigate the effect of stratified pre-pregnancy maternal body mass index on twenty maternal and fetal/neonatal adverse outcomes. METHODS: PubMed, Google Scholar, Medline, Embase, Web of Science databases were searched from inception till July 11, 2020. Cohort studies were included. The pooled odds ratio with 95% confidence interval was reported considering the random effect and the quality effect model. The sub-group analysis and meta-regression were conducted for BMI cut-offs, geographical region, source of BMI, and sample size. RESULTS: Overall, 86 studies representing 20,328,777 pregnant women were included in this meta-analysis. Our study reveals that overweight and obese mothers are at increased odds of cesarean delivery, elective cesarean delivery, emergency cesarean delivery, gestational diabetes, gestational hypertension, induction of labor, postpartum hemorrhage, pre-eclampsia, pre-term premature rupture of membrane, and the fetuses/neonates of overweight and obese mothers are at increased risk of admission in the newborn intensive care unit, APGAR scores less than 7 at 5 min, large for gestational age, macrosomia, extreme pre-term birth in pregnant mothers compared with standard BMI mothers. However, the underweight mothers showed increased odds for small for gestational age infant and pre-term birth, whereas obese mothers were at higher risk for post-term birth and stillbirths. The subgroup and meta-regression analyses have shown the impact of BMI cut-offs, geographical region, source of BMI, and sample size on several maternal, fetal/neonatal adverse outcomes. CONCLUSION: The meta-analysis confirmed the association of elevated pre-pregnancy maternal BMI with higher odds of adverse maternal and fetal/neonatal outcomes.

Epigenetic age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations: the population based cross-sectional RODAM study.

BACKGROUND: African populations are experiencing health transitions due to rapid urbanization and international migration. However, the role of biological aging in this emerging burden of cardiometabolic diseases (CMD) among migrant and non-migrant Africans is unknown. We aimed to examine differences in epigenetic age acceleration (EAA) as measured by four clocks (Horvath, Hannum, PhenoAge and GrimAge) and their associations with cardiometabolic factors among migrant Ghanaians in Europe and non-migrant Ghanaians. METHODS: Genome-wide DNA methylation (DNAm) data of 712 Ghanaians from cross-sectional RODAM study were used to quantify EAA. We assessed correlation of DNAmAge measures with chronological age, and then performed linear regressions to determine associations of body mass index (BMI), fasting blood glucose (FBG), blood pressure, alcohol consumption, smoking, physical activity, and one-carbon metabolism nutrients with EAA among migrant and non-migrants. We replicated our findings among 172 rural-urban sibling pairs from India migration study and among 120 native South Africans from PURE-SA-NW study. FINDINGS: We found that Ghanaian migrants have lower EAA than non-migrants. Within migrants, higher FBG was positively associated with EAA measures. Within non-migrants, higher BMI, and Vitamin B9 (folate) intake were negatively associated with EAA measures. Our findings on FBG, BMI and folate were replicated in the independent cohorts. INTERPRETATION: Our study shows that migration is negatively associated with EAA among Ghanaians. Moreover, cardiometabolic factors are differentially associated with EAA within migrant and non-migrant subgroups. Our results call for context-based interventions for CMD among transitioning populations that account for effects of biological aging. FUNDING: European Commission.

Building capacity for air pollution epidemiology in India.

Air pollution represents a major public health threat in India affecting 19% of the world's population at extreme levels. Despite this, research in India lags behind in large part due to a lack of comprehensive air pollution exposure assessment that can be used in conjunction with health data to investigate health effects. Our vision is to provide a consortium to rapidly expand the evidence base of the multiple effects of ambient air pollution. We intend to leapfrog current limitations of exposure assessment by developing a machine-learned satellite-informed spatiotemporal model to estimate daily levels of ambient fine particulate matter measuring less than 2.5 µm (PM2.5) at a fine spatial scale across all of India. To catalyze health effects research on an unprecedented scale, we will make the output from this model publicly available. In addition, we will also apply these PM2.5 estimates to study the health outcomes of greatest public health importance in India, including cardiovascular diseases, chronic obstructive pulmonary disease, pregnancy (and birth) outcomes, and cognitive development and/or decline. Thus, our efforts will directly generate actionable new evidence on the myriad effects of air pollution on health that can inform policy decisions, while providing a comprehensive and publicly available resource for future studies on both exposure and health effects. In this commentary, we discuss the motivation, rationale, and vision for our consortium and a path forward for reducing the enormous burden of disease from air pollution in India.

Leveraging Existing Cohorts to Study Health Effects of Air Pollution on Cardiometabolic Disorders: India Global Environmental and Occupational Health Hub.

Air pollution is a growing public health concern in developing countries and poses a huge epidemiological burden. Despite the growing awareness of ill effects of air pollution, the evidence linking air pollution and health effects is sparse. This requires environmental exposure scientist and public health researchers to work more cohesively to generate evidence on health impacts of air pollution in developing countries for policy advocacy. In the Global Environmental and Occupational Health (GEOHealth) Program, we aim to build exposure assessment model to estimate ambient air pollution exposure at a very fine resolution which can be linked with health outcomes leveraging well-phenotyped cohorts which have information on geolocation of households of study participants. We aim to address how air pollution interacts with meteorological and weather parameters and other aspects of the urban environment, occupational classification, and socioeconomic status, to affect cardiometabolic risk factors and disease outcomes. This will help us generate evidence for cardiovascular health impacts of ambient air pollution in India needed for necessary policy advocacy. The other exploratory aims are to explore mediatory role of the epigenetic mechanisms (DNA methylation) and vitamin D exposure in determining the association between air pollution exposure and cardiovascular health outcomes. Other components of the GEOHealth program include building capacity and strengthening the skills of public health researchers in India through variety of training programs and international collaborations. This will help generate research capacity to address environmental and occupational health research questions in India. The expertise that we bring together in GEOHealth hub are public health, clinical epidemiology, environmental exposure science, statistical modeling, and policy advocacy.

Association of Long-Term Exposure to Fine Particulate Matter and Cardio-Metabolic Diseases in Low- and Middle-Income Countries: A Systematic Review.

: Background: Numerous epidemiological studies indicated high levels of particulate matter less than2.5 µm diameter (PM2.5) as a major cardiovascular risk factor. Most of the studies have been conducted in high-income countries (HICs), where average levels of PM2.5 are far less compared to low- and middle- income countries (LMICs), and their socio-economic profile, disease burden, and PM speciation/composition are very different. We systematically reviewed the association of long-term exposure to PM2.5 and cardio-metabolic diseases (CMDs) in LMICs. METHODS: Multiple databases were searched for English articles with date limits until March 2018. We included studies investigating the association of long-term exposure to PM2.5 (defined as an annual average/average measure for 3 more days of PM2.5 exposure) and CMDs, such as hospital admissions, prevalence, and deaths due to CMDs, conducted in LMICs as defined by World Bank. We excluded studies which employed exposure proxy measures, studies among specific occupational groups, and specific episodes of air pollution. RESULTS: A total of 5567 unique articles were identified, of which only 17 articles were included for final review, and these studies were from Brazil, Bulgaria, China, India, and Mexico. Outcome assessed were hypertension, type 2 diabetes mellitus and insulin resistance, and cardiovascular disease (CVD)-related emergency room visits/admissions, death, and mortality. Largely a positive association between exposure to PM2.5 and CMDs was found, and CVD mortality with effect estimates ranging from 0.24% to 6.11% increased per 10 µg/m3 in PM2.5. CVD-related hospitalizations and emergency room visits increased by 0.3% to 19.6%. Risk factors like hypertension had an odds ratio of 1.14, and type 2 diabetes mellitus had an odds ratio ranging from 1.14-1.32. Diversity of exposure assessment and health outcomes limited the ability to perform a meta-analysis. CONCLUSION: Limited evidence on the association of long-term exposure to PM2.5 and CMDs in the LMICs context warrants cohort studies to establish the association.

Migration and DNA methylation: a comparison of methylation patterns in type 2 diabetes susceptibility genes between indians and europeans.

BACKGROUND: Type 2 diabetes is a global problem that is increasingly prevalent in low and middle income countries including India, and is partly attributed to increased urbanisation. Genotype clearly plays a role in type 2 diabetes susceptibility. However, the role of DNA methylation and its interaction with genotype and metabolic measures is poorly understood. This study aimed to establish whether methylation patterns of type 2 diabetes genes differ between distinct Indian and European populations and/or change following rural to urban migration in India. METHODS: Quantitative DNA methylation analysis in Indians and Europeans using Sequenom® EpiTYPER® technology was undertaken in three genes: ADCY5, FTO and KCNJ11. Metabolic measures and genotype data were also analysed. RESULTS: Consistent differences in DNA methylation patterns were observed between Indian and European populations in ADCY5, FTO and KCNJ11. Associations were demonstrated between FTO rs9939609 and BMI and between ADCY5rs17295401 and HDL levels in Europeans. However, these observations were not linked to local variation in DNA methylation levels. No differences in methylation patterns were observed in urban-dwelling migrants compared to their non-migrant rural-dwelling siblings in India. CONCLUSIONS: Analysis of DNA methylation at three type 2 diabetes susceptibility loci highlighted geographical and ethnic differences in methylation patterns. These differences may be attributed to genetic and/or region-specific environmental factors.