Novel genomic variants related to visceral adiposity index (VAI) and body adiposity index (BAI) in Indian sib-pairs.

BACKGROUND: Obesity is among the leading public health threats globally. Over the last few years, visceral adiposity index (VAI), and body adiposity index (BAI), derived from anthropometric, and biochemical measures, have gained importance as a measure of obesity. However, unlike other common indices like body mass index, and waist circumference, the genetic predisposition of VAI, and BAI under-examined. METHODS: 2265 sib-pairs from Indian Migration Study were used for examining the association of genetic variants from the Cardio-Metabochip array with VAI, and BAI. Mixed linear regression models were run, and all inferences were based on the within-sib component of the Fulker's association models. Gene-environment/lifestyle interaction analyses were also undertaken. RESULTS: rs6659428 at LOC400796 | SEC16B (ß = 0.26, SE = 0.05), and rs7611535 at DRD3 | LOC645180 (ß = 0.18, SE = 0.04) were associated with VAI at suggestive significance value of <8.21 × 10-6. For BAI, rs73300702 at JAZF1-AS1 (ß = 0.27, SE = 0.06), was the top hit at p value < 8.21 × 10-6. Further, rs6659428 showed marginal effect modification with rural/urban location (ß = 0.26, SE = 0.13, p value = 0.047), and rs73300702 with physical activity (ß = -0.29,SE = 0.14, p value = 0.034). CONCLUSION: We report three novel genetic loci for VAI, and BAI in Indians that are important indicators of adiposity. These findings need to be replicated and validated with larger samples from different ethnicities. Further, functional studies for understanding the biological mechanisms of these adiposity indices need to be undertaken to understand the underlying pathophysiology.

Genetic architecture of adiposity measures among Asians: Findings from GWAS.

Adiposity has gradually become a global public threat over the years with drastic increase in the attributable deaths and disability adjusted life years (DALYs). Given an increased metabolic risk among Asians as compared to Europeans for any given body mass index (BMI) and considering the differences in genetic architecture between them, the present review aims to summarize the findings from genome-wide scans for various adiposity indices and related anthropometric measures from Asian populations. The search for related studies, published till February 2022, were made on PubMed and GWAS Catalog using search strategy built with relevant keywords joined by Boolean operators. It was recorded that out of a total of 47 identified studies, maximum studies are from Korean population (n = 14), followed by Chinese (n = 7), and Japanese (n = 6). Nearly 200 loci have been identified for BMI, 660 for height, 16 for weight, 28 for circumferences (waist and hip), 32 for ratios (waist hip ratio [WHR] and thoracic hip ratio [THR]), 5 for body fat, 16 for obesity, and 28 for adiposity-related blood markers among Asians. It was observed that though, most of the loci were unique for each trait, there were 3 loci in common to BMI and WHR. Apart from validation of variants identified in European setting, there were many novel loci discovered in Asian populations. Notably, 125 novel loci form Asian studies have been reported for BMI, 47 for height, 5 for waist circumference, and 2 for adiponectin level to the existing knowledge of the genetic framework of adiposity and related measures. It is necessary to examine more advanced adiposity measures, specifically of relevance to abdominal adiposity, a major risk factor for cardiometabolic disorders among Asians. Moreover, in spite of being one continent, there is diversity among different ethnicities across Asia in terms of lifestyle, climate, geography, genetic structure and consequently the phenotypic manifestations. Hence, it is also important to consider ethnic specific studies for identifying and validating reliable genetic variants of adiposity measures among Asians.

Effect of supplemental nutrition in pregnancy on offspring's risk of cardiovascular disease in young adulthood: Long-term follow-up of a cluster trial from India.

BACKGROUND: Undernutrition during intrauterine life and early childhood is hypothesised to increase the risk of cardiovascular disease (Developmental Origins of Health and Disease Hypothesis), but experimental evidence from humans is limited. This hypothesis has major implications for control of the cardiovascular disease epidemic in South Asia (home to a quarter of world's population), where a quarter of newborns have low birth weight. We investigated whether, in an area with prevalent undernutrition, supplemental nutrition offered to pregnant women and their offspring below the age of 6 years was associated with a lower risk of cardiovascular disease in the offspring when they were young adults. METHODS AND FINDINGS: The Hyderabad Nutrition Trial was a community-based nonrandomised controlled intervention trial conducted in 29 villages near Hyderabad, India (1987-1990). Protein-calorie food supplement was offered daily to pregnant and lactating women (2.09 MJ energy and 20-25 g protein) and their offspring (1.25 MJ energy and 8-10 g protein) until the age of six years in the 15 intervention villages, but not in the 14 control villages. A total of 1,826 participants (949 from the intervention villages and 877 from the control villages, representing 70% of the cohort) at a mean age of 21.6 years (62% males) were examined between 2009 and 2012. The mean body mass index (BMI) of the participants was 20 kg/m2 and the mean systolic blood pressure was 115 mm Hg. The age, sex, socioeconomic position, and urbanisation-adjusted effects of intervention (beta coefficients and 95% confidence intervals) on outcomes were as follows: carotid intima-media thickness, 0.01 mm (-0.01 to 0.03), p = 0.36; arterial stiffness (augmentation index), -1.1% (-2.5 to 0.3), p = 0.097; systolic blood pressure, 0.5 mm Hg (-0.6 to 1.6), p = 0.36; BMI, -0.13 kg/m2 (-0.75 to 0.09), p = 0.093; low-density lipoprotein (LDL) cholesterol, 0.06 mmol/L (-0.07 to 0.2), p = 0.37; and fasting insulin (log), -0.06 mU/L (-0.19 to 0.07), p = 0.43. The limitations of this study include nonrandomised allocation of intervention and lack of data on compliance, and potential for selection bias due to incomplete follow-up. CONCLUSIONS: Our results showed that in an area with prevalent undernutrition, protein-calorie food supplements offered to pregnant women and their offspring below the age of 6 years were not associated with lower levels of cardiovascular risk factors among offspring when they were young adults. Our findings, coupled with evidence from other intervention studies to date, suggest that policy makers should attach limited value to cardiovascular health benefits of maternal and child protein-calorie food supplementation programmes.

Role of CYP1B1, p.E229K and p.R368H mutations among 120 families with sporadic juvenile onset open-angle glaucoma.

BACKGROUND: To determine the frequency of CYP1B1 p.E229K and p.R368H, gene mutations in a cohort of sporadic juvenile onset open-angle glaucoma (JOAG) patients and to evaluate their genotype/phenotype correlation. METHODS: Unrelated JOAG patients whose first-degree relatives had been examined and found to be unaffected were included in the study. The patients and their parents were screened for p.E229K and p.R368H mutations. The phenotypic characteristics were compared between probands carrying the mutations and those who did not carry these mutations. RESULTS: Out of 120 JOAG patients included in the study, the p.E229K mutation was seen in 9 probands (7.5%) and p.R368H in 7 (5.8%). The average age of onset of the disease (p = 0.3) and the highest untreated IOP (p = 0.4) among those carrying mutations was not significantly different from those who did not have these mutations. The proportion of probands with angle dysgenesis among those with p.E229K and p.R368H mutations was 70% (11 out of 16) in comparison to 65% (67 out of 104) of those who did not harbour these mutations (p = 0.56). Similarly, the probands with moderate to high myopia among those with p.E229K and p.R368H mutations was 20% (3 out of 16) in comparison to 18% (18 out of 104) of those who did not harbour these mutations (p = 0.59). CONCLUSION: The frequency of p.E229K and p.R368H mutations of the CYP1B1 gene is low even among sporadic JOAG patients. Moreover, there is no clinical correlation between the presence of these mutations and disease severity.

Chronic Obstructive Pulmonary Disease and its Non-Smoking Risk Factors in India.

The rising prevalence of the chronic obstructive pulmonary disease (COPD) is generally attributed to smoking, since the role of other risk factors among non-smokers are not well established especially in low and middle income countries like India. This is also reflected by the limited literature available on non-smoking related COPD risk factors like indoor and outdoor air pollution. The present review is an attempt to assess the influence of non-smoking risk factors on COPD and its measures in Indian subcontinent. The most noteworthy factors among non-smokers appear to be the use of biomass fuel for cooking and heating purposes. We observed that the studies undertaken to evaluate the role of such risk factors are inconclusive due to weak methodologies and small sample sizes, may be due to limited financial resources. The present review suggests the need of a nationally representative study to estimate the effect of each of the potential modifiable risk factor (other than smoking) for framing impactful public health policies to prevent and manage COPD at community and population level in India.

Association of Low Birth Weight with the Risk of Childhood Stunting in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis.

BACKGROUND: Stunting is an important predictor of growth and development of children under 5 years of age, and it remains the significant problem in LMIC. However, LBW emerges as risk factor, but its association with LMIC needs attention. OBJECTIVE: This systematic review and meta-analysis aimed to investigate the association of low birth weight with the risk of childhood stunting among the age group of 0-5 years in LMICs. METHODS: PubMed, Google Scholar, MEDLINE, Embase, and Web of Science databases were searched from January 1, 2010 untill December 20, 2021. Cross-sectional, cohort, and case-control study designs were included in the meta-analyses. The pooled odds ratio with a 95% confidence interval was reported considering the random-effects and the quality-effects models. The subgroup analysis and meta-regression were conducted for study design, geographical location, and sample size. RESULTS: Low birth weight was associated with >2-fold increased risk of childhood stunting (pooled OR: 2.32; 95% CI, 2.05-2.62). Asian studies have shown relatively higher risk than African studies in stratified analyses. The cohort studies predicted a higher risk of childhood stunting, followed by case-control and cross-sectional study designs, and the sample size stratification showed that studies with sample size <1,000 predicted much higher risk than relatively to the studies with sample size >1,000. The meta-regression was performed in all three subgroups, but none of the models appeared significant. CONCLUSION: This meta-analysis confirmed the association of low birth weight with the higher risk of childhood stunting among the 0-5 years' age group and suggests a moderately higher risk in Asia as compared to Africa.

Longitudinal associations between ambient PM2.5 exposure and lipid levels in two Indian cities.

Background: Exposure to ambient PM2.5 is known to affect lipid metabolism through systemic inflammation and oxidative stress. Evidence from developing countries, such as India with high levels of ambient PM2.5 and distinct lipid profiles, is sparse. Methods: Longitudinal nonlinear mixed-effects analysis was conducted on >10,000 participants of Centre for cArdiometabolic Risk Reduction in South Asia (CARRS) cohort in Chennai and Delhi, India. We examined associations between 1-month and 1-year average ambient PM2.5 exposure derived from the spatiotemporal model and lipid levels (total cholesterol [TC], triglycerides [TRIG], high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]) measured longitudinally, adjusting for residential and neighborhood-level confounders. Results: The mean annual exposure in Chennai and Delhi was 40 and 102 µg/m3 respectively. Elevated ambient PM2.5 levels were associated with an increase in LDL-C and TC at levels up to 100 µg/m3 in both cities and beyond 125 µg/m3 in Delhi. TRIG levels in Chennai increased until 40 µg/m3 for both short- and long-term exposures, then stabilized or declined, while in Delhi, there was a consistent rise with increasing annual exposures. HDL-C showed an increase in both cities against monthly average exposure. HDL-C decreased slightly in Chennai with an increase in long-term exposure, whereas it decreased beyond 130 µg/m3 in Delhi. Conclusion: These findings demonstrate diverse associations between a wide range of ambient PM2.5 and lipid levels in an understudied South Asian population. Further research is needed to establish causality and develop targeted interventions to mitigate the impact of air pollution on lipid metabolism and cardiovascular health.

MTHFR C677T polymorphism, folate, vitamin B12 and homocysteine in recurrent pregnancy losses: a case control study among North Indian women.

AIM: The present study attempts to understand the role of methylenetetrahydrofolate reductase C677T (MTHFR C677T) in recurrent pregnancy losses in North Indian women because of hyperhomocysteinemia in light of serum folate and vitamin B12. METHODS: One hundred and seven women with three or more consecutive unexplained recurrent pregnancy losses and 343 women with two or more successful and uncomplicated pregnancies were recruited. Plasma homocysteine, serum folate and vitamin B12 were analyzed using chemiluminescence. MTHFR C677T detection was completed in all subjects. RESULTS: MTHFR genotypic distribution among cases and controls showed no significant difference (P=0.409). However, MTHFR C677T polymorphism was found to be significantly associated with increased homocysteine in the case group (P=0.031). Hyperhomocysteinemia and vitamin B12 deficiency were found to be significant risk factors for recurrent pregnancy loss (RPL) (OR=7.02 and 16.39, respectively). Folate deficiency was more common in controls (63.47%) as compared to the case group (2.56%). CONCLUSION: Low vitamin B12 increases homocysteine, specifically among T allele carrying case mothers, suggesting T allele is detrimental with B12 deficiency. The study emphasizes the importance of vitamin B12 in the prevention of RPL in North Indian women.

Lung Function and Respiratory Morbidity Among Informal Workers Exposed to Cement Dust: A Comparative Cross-Sectional Study.

Background: Cement dust is a significant source of occupational exposure affecting lung function and respiratory health. A higher burden of respiratory morbidity is known among factory workers involved in cement production. Globally or from India, there are no estimates of this burden from informal workers exposed to cement dust. Objective: To assess difference in lung function and respiratory symptoms among informal workers exposed to cement and those unexposed, using a comparative community based cross-sectional study from purposively selected areas in Delhi, India. Methods: Using a portable spirometer we measured lung function and collected respiratory symptoms from conveniently sampled informal workers (n = 100) exposed to cement dust, 50 indoor informal workers (tailors), and 50 outdoor (vegetable) vendors. Regression analyses were performed to compare respiratory symptom score and lung function parameters, adjusted for age, body mass index, smoking, socioeconomic status, and years of occupational exposure. Findings: Exposed workers had significantly lower lung function (PEF = -750 ml/s and -810 ml/s and FEV1/FVC (%) = -3.87 and -2.11) compared to indoor and outdoor groups, with three times higher chronic respiratory symptoms when compared to the unexposed groups. The cement dust exposure was observed to be associated with PEF (mean difference (MD) = -0.75L, 95%CI = -1.36 to -0.15, p = 0.01), %FEV1/FVC (MD = -3.87, 95%CI = -6.77 to -0.96, p = 0.03) and respiratory symptoms (p < 0.001). Conclusion: This study generates evidence regarding the respiratory burden of occupational exposure among vulnerable informal workers. There is an urgent need for policy reforms to safeguard health from occupational exposures, especially among informal workers.

Adverse childhood experiences in mental health of young adults: An exploratory study from Delhi-NCR, India.

BACKGROUND: Despite the growing realization regarding the importance of adverse childhood experiences (ACEs) in adult health outcomes, this area of research has received little scientific attention in low- and middle-income countries, including India. AIMS: To understand the overall and domain-specific association of exposure to ACEs with current depression, anxiety, stress, and well-being among young adults of Delhi-NCR. METHODS: This cross-sectional study was carried out among 1,812 young adults (aged 18-25 years) of both sexes (68.7% females). Fieldwork was conducted on the campuses of the University of Delhi, Delhi, and Amity University, Noida, India. ACEs, depression, anxiety, stress, and well-being were screened using the Adverse Childhood Experiences International Questionnaire, Beck Depression Inventory-II, Beck Anxiety Inventory, Perceived Stress Scale, and WHO-5 Well-Being Index, respectively. RESULTS: Exposure to ACEs was found to increase the odds of moderate/severe depression, moderate/severe anxiety, and high stress and decreased the odds of good well-being in a dose-response manner. Being bullied, followed by emotional abuse, was associated with the highest odds of current moderate/severe depression, moderate/severe anxiety, and high stress and the lowest odds of good well-being. Further, while several domains of household dysfunction showed poor association with studied mental health outcomes, domains of abuse and violence were more consistently associated. CONCLUSIONS: The present study revealed the detrimental impact of ACEs on mental health outcomes among young adults of Delhi-NCR, India, and underscored the relevance of ACEs in the Indian context. Considering the lack of trauma awareness in Indian societies, there is an urgent need to create widespread awareness regarding ACEs and associated health implications.

Genetic associations of TMEM154, PRC1 and ZFAND6 loci with type 2 diabetes in an endogamous business community of North India.

BACKGROUND: More than 250 loci have been identified by genome-wide scans for type 2 diabetes in different populations. South Asians have a very different manifestation of the diseases and hence role of these loci need to be investigated among Indians with huge burden of cardio-metabolic disorders. Thus the present study aims to validate the recently identified GWAS loci in an endogamous caste population in North India. METHODS: 219 T2D cases and 184 controls were recruited from hospitals and genotyped for 15 GWAS loci of T2D. Regression models adjusted for covariates were run to examine the association for T2D and fasting glucose levels. RESULTS: We validated three variants for T2D namely, rs11634397 at ZFAND6 (OR = 3.05, 95%CI = 1.02-9.19, p = 0.047) and rs8042680 at PRC1 (OR = 3.67, 95%CI = 1.13-11.93, p = 0.031) showing higher risk and rs6813195 at TMEM154 (OR = 0.28, 95%CI = 0.09-0.90, p = 0.033) showing protective effect. The combined risk of 9 directionally consistent variants was also found to be significantly associated with T2D (OR = 1.91, 95%CI = 1.18-3.08, p = 0.008). One variant rs10842994 at KLHDC5 was validated for 9.15mg/dl decreased fasting glucose levels (SE = -17.25-1.05, p = 0.027). CONCLUSION: We confirm the role of ZFAND6, PRC1 and TMEM154 in the pathophysiology of type 2 diabetes among Indians. More efforts are needed with larger sample sizes to validate the diabetes GWAS loci in South Asian populations for wider applicability.

Evaluation of genetic variants related to lipid levels among the North Indian population.

Background: A heavy burden of cardiometabolic conditions on low- and middle-income countries like India that are rapidly undergoing urbanization remains unaddressed. Indians are known to have high levels of triglycerides and low levels of HDL-C along with moderately higher levels of LDL-C. The genome-wide findings from Western populations need to be validated in an Indian context for a better understanding of the underlying etiology of dyslipidemia in India. Objective: We aim to validate 12 genetic variants associated with lipid levels among rural and urban Indian populations and derive unweighted and weighted genetic risk scores (uGRS and wGRS) for lipid levels among the Indian population. Methods: Assuming an additive model of inheritance, linear regression models adjusted for all the possible covariates were run to examine the association between 12 genetic variants and total cholesterol, triglycerides, HDL-C, LDL-C, and VLDL-C among 2,117 rural and urban Indian participants. The combined effect of validated loci was estimated by allelic risk scores, unweighted and weighted by their effect sizes. Results: The wGRS for triglycerides and VLDL-C was derived based on five associated variants (rs174546 at FADS1, rs17482753 at LPL, rs2293889 at TRPS1, rs4148005 at ABCA8, and rs4420638 at APOC1), which was associated with 36.31 mg/dL of elevated triglyceride and VLDL-C levels (ß = 0.95, SE = 0.16, p < 0.001). Similarly, every unit of combined risk score (rs2293889 at TRPS1 and rs4147536 at ADH1B) was associated with 40.62 mg/dL of higher total cholesterol (ß = 1.01, SE = 0.23, p < 0.001) and 33.97 mg/dL of higher LDL-C (ß = 1.03, SE = 0.19, p < 0.001) based on its wGRS (rs2293889 at TRPS1, rs4147536 at ADH1B, rs4420638 at APOC1, and rs660240 at CELSR2). The wGRS derived from five associated variants (rs174546 at FADS1, rs17482753 at LPL, rs4148005 at ABCA8, rs4420638 at APOC1, and rs7832643 at PLEC) was associated with 10.64 mg/dL of lower HDL-C (ß = -0.87, SE = 0.14, p < 0.001). Conclusion: We confirm the role of eight genome-wide association study (GWAS) loci related to different lipid levels in the Indian population and demonstrate the combined effect of variants for lipid traits among Indians by deriving the polygenic risk scores. Similar studies among different populations are required to validate the GWAS loci and effect modification of these loci by lifestyle and environmental factors related to urbanization.

Time intervals and patient-level factors in oral cancer diagnostic pathways: An application of the WHO framework in India.

BACKGROUND: Oral cancer, a leading cancer-site in India, is often detected at advanced stages. We evaluated the time intervals from first symptom to help-seeking and diagnosis among oral cancer patients. METHODOLOGY: In this cross-sectional study, we recruited 226 consecutive oral cancer patients (mean age ( ± SD) 51.9 years ( ± 10.9); 81.9% men; 70.3% advanced stage) registered for diagnosis and treatment, between 2019 and 2021 at a cancer care centre in South India. We used WHO framework and previously standardized tools to record time intervals (appraisal, help-seeking and diagnostic) and baseline characteristics. We utilized multivariable logistic regression models to test the associations between 'prolonged (i.e., over 1 month) time intervals') and patient-level factors to estimate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Over a half of patients presented with prolonged appraisal (60%) and help-seeking intervals (57%), and a third (34%) reported prolonged diagnostic interval. Patients with no formal education, no routine healthcare visits, no self-reported risk factors, and those who did not perceive initial symptoms to be serious were 2-4 times more likely to have prolonged appraisal and help-seeking than the rest. High travel costs and self-decision for visiting healthcare facility prolonged help-seeking. Diagnostic interval was prolonged only among women OR= 2.7 (95% CI: 1.2-6.1)) and in patients whose first doctor's opinion was 'nothing to worry' OR (=7.3 (95% CI: 2.6-20.5)). 'Correct knowledge of cancer' shortened appraisal and help-seeking intervals and 'incorrect knowledge and negative beliefs' prolonged diagnostic interval. CONCLUSION: Our findings highlight that interventions targeting sociocultural and economic determinants, symptom awareness, sensitizing persons at risk (especially women) and primary care providers might reduce overall time to diagnosis. Further, patients without any known risk factors for oral cancer might be at-risk for prolonged appraisal interval. These might help inform 'pull' strategies for cancer control in India and similar settings.

Association of MC4R (rs17782313) gene polymorphism with obesity measures in Western India.

BACKGROUND AND AIMS: The association of melanocortin receptor 4 (MC4R) gene with adiposity measures is widely studied in European populations. Only six studies have investigated the role of MC4R gene with adiposity measures among Indian populations. We have evaluated the role of MC4R (rs17782313) gene polymorphism in influencing adiposity measures in India among children and adults. MATERIALS AND METHODS: The present population based cross sectional study was conducted among 303 individuals (208 children and 95 adults) of age group 10-30 years, belonging to Rajasthan. Somatometric measurements (standing height, weight, and waist and hip girths) and blood samples were taken after obtaining written informed consent. Genotyping of MC4R rs17782313 single nucleotide polymorphism was done using restriction fragment length polymorphism method for polymerase chain reaction amplified fragments. We examined association between rs17782313 and different adiposity measures (height, weight, BMI, WHR, and waist and hip girths) using linear regression models. RESULTS: The MC4R variant (rs17782313) predicted increased body weight (0.15 kg, S.E ± 0.076, P = 0.043) among children. In combined population, the rs17782313 variant was moderately associated with body weight (0.13 kg, S.E ± 0.070, P = 0.057). This variant was not found to be associated with any other adiposity measure. CONCLUSION: Further studies are needed to evaluate the association of MC4R variants through sequencing and functional genomics with different adiposity measures in Indian populations for understanding the genetic underpinnings of adiposity in India.

The mutational spectrum of Myocilin gene among familial versus sporadic cases of Juvenile onset open angle glaucoma.

PURPOSE: Juvenile onset primary open angle glaucoma (JOAG) is a rare disorder associated with high IOP and progressive optic neuropathy in patients diagnosed before the age of 40 years. While in some populations it has primarily an autosomal dominant pattern of inheritance, in others it occurs in a primarily sporadic form. The main aim of the study was to assess the relative prevalence of Myocilin (MYOC) mutations in familial versus sporadic cases of JOAG. METHODS: We screened 92 unrelated (sporadic) JOAG patients, and 22 affected families (70 affected members and 36 unaffected) for variations in the MYOC gene. We also analyzed the clinical features associated with these variations. RESULTS: Three coding sequence variants were identified as mutations causing JOAG. Four families segregated distinct mutations at Gly367Arg, and two families at Gln337Arg, while only two sporadic JOAG cases harbored MYOC mutations (Gly367Arg and Gln48His). The frequency of MYOC mutations in familial cases (27%) was significantly higher than in sporadic JOAG cases (2%); p = 0.001. A 90% penetrance for the Gly367Arg variant was seen by the age of 40 years in our patients. Characteristic allele signatures, indicative of specific founder effects, were not observed for the Gly367Arg mutation that was looked for in 12 patients among 2 geographically close families, which harbored this mutation. CONCLUSION: Our data demonstrated that genetic screening for MYOC mutations should be focused toward cases with familial rather than sporadically occurring JOAG.

LDL-R AvaII and NcoI polymorphisms: an indirect risk factor for coronary heart disease among a Mendelian population of Delhi, India.

AvaII and NcoI polymorphisms in the low-density lipoprotein receptor (LDL-R) gene are reported to alter cholesterol levels. Although found to be highly polymorphic worldwide, these mutations have not been validated in any Indian population. This case-control association study was conducted in an endogamous business community of Delhi. Blood samples from 100 cases and 100 age- and sex-matched controls belonging to the same ethnic group were subjected to biochemical and molecular analyses. Medical history and anthropometric measurements were taken from all the enrolled subjects. Linkage disequilibrium between the two polymorphisms was found to be significant (P = 0.0016). Significant variability was observed for the AvaII polymorphism among cases concerning waist-hip ratio, serum triglyceride, and low-density lipoprotein, which in turn was found to be associated with coronary heart disease.

Causal relationships between lipid and glycemic levels in an Indian population: A bidirectional Mendelian randomization approach.

BACKGROUND: Dyslipidemia and abnormal glycemic traits are leading causes of morbidity and mortality. Although the association between the two traits is well established, there still exists a gap in the evidence for the direction of causality. OBJECTIVE: This study aimed to examine the direction of the causal relationship between lipids and glycemic traits in an Indian population using bidirectional Mendelian randomization (BMR). METHODS: The BMR analysis was conducted on 4900 individuals (2450 sib-pairs) from the Indian Migration Study. Instrument variables were generated for each lipid and glycemic trait (fasting insulin, fasting glucose, HOMA-IR, HOMA-ß, LDL-cholesterol, HDL-cholesterol, total cholesterol and triglycerides) to examine the causal relationship by applying two-stage least squares (2SLS) regression in both directions. RESULTS: Lipid and glycemic traits were found to be associated observationally, however, results from 2SLS showed that only triglycerides, defined by weighted genetic risk score (wGRS) of 3 SNPs (rs662799 at APOAV, rs780094 at GCKR and rs4420638 at APOE/C1/C4), were observed to be causally effecting 1.15% variation in HOMA-IR (SE = 0.22, P = 0.010), 1.53% in HOMA- ß (SE = 0.21, P = 0.001) and 1.18% in fasting insulin (SE = 0.23, P = 0.009). No evidence for a causal effect was observed in the reverse direction or between any other lipid and glycemic traits. CONCLUSION: The study findings suggest that triglycerides may causally impact various glycemic traits. However, the findings need to be replicated in larger studies.

"Mendelian Randomization" Approach in Economic Assessment of Health Conditions.

The increased prevalence of non-communicable chronic diseases (NCDs) is reflected in the rising economic burden of health conditions. Observational studies conducted in health economics research are detecting associations of NCDs or related risk factors with economic measures like health insurance, economic inequalities, accessibility of jobs, education, annual income, health expenditure, etc. The inferences of such relationships do not prove causation and are limited to associations which are many times influenced by confounding factors and reverse causation. Mendelian randomization (MR) approach is a useful method for exploring causal relations between modifiable risk factors and measures of health economics. The application of MR in economic assessment of health conditions has been started and is producing fruitful results.

Genetics of nonalcoholic fatty liver disease in Asian populations.

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in the liver without any history of chronic alcohol consumption. It encompasses a wide spectrum of diseases that range from simple steatosis to nonalcoholicsteatohepatitis. NAFLD is strongly associated with obesity, insulin resistance / type-2 diabetes mellitus and the metabolic syndrome. NAFLD is a complex disorder; environmental and genetic factors interact with NAFLD manifestation and determine its progression. In this review, an attempt was made to provide current information on the genetic variants of NAFLD in Asian populations. Literature search was performed by using PubMed, Medline and Google Scholar database. Candidate gene, validation and genomewide association studies (GWASs) were included in this review. A total of 41 studies fulfilled inclusion criteria of which 12 candidate gene studies exclusively focussed on the PNPLA3 gene and 17 other studies on other important candidate genes such as NCANCILP2, PPARG,AGTR1, FABP1, APOC3 etc. reported significant association with NAFLD. Eight validation studies identified associations of variants on PNPLA3, LYPLAL1, TM6SF2, ADIPOR2, STAT3, GCKR, SAMM50 etc. with NAFLD. Thus, so far, four GWASs have been conducted in Asian population that reported PNPLA3, SAMM50, PARVB and GATAD2A genes which were significantly associated with NAFLD. Findings indicate that PNPLA3, APOC3, PPARG, NCAN and GCKR genes emerge out to be the important biological markers associated with NAFLD.

Genetic underpinnings of lung function and COPD.

Spirometry based measurement of lung function is a global initiative for chronic obstructive lung disease (GOLD) standard to diagnose chronic obstructive pulmonary disease (COPD), one of the leading causes of mortality worldwide. The environmental and behavioural risk factors for COPD includes tobacco smoking, air pollutants and biomass fuel exposure, which can induce one or more abnormal lung function patterns. While smoking remains the primary risk factor, only 15-20% smokers develop COPD, indicating that the genetic factors are also likely to play a role. According to the study of Global Burden of Disease 2015, ∼174 million people across the world have COPD. From a comprehensive literature search conducted using the 'PubMed' and 'GWAS Catalogue' databases, and reviewing the literature available, only a limited number of studies were identified which had attempted to investigate the genetics of COPD and lung volumes, implying a huge research gap. With the advent of genomewide association studies several genetic variants linked to lung function and COPD, like HHIP, HTR4, ADAM19 and GSTCD etc., have been found and validated in different population groups, suggesting their potential role in determining lung volume and risk for COPD. This article aims at reviewing the present knowledge of the genetics of lung function and COPD.