“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

DNA methylation markers for oral pre-cancer progression: A critical review.

Although oral cancers are generally preceded by a well-established pre-cancerous stage, there is a lack of well-defined clinical and morphological criteria to detect and signal progression from pre-cancer to malignant tumours. We conducted a critical review to summarize the evidence regarding aberrant DNA methylation patterns as a potential diagnostic biomarker predicting progression. We identified all relevant human studies published in English prior to 30th April 2015 that examined DNA methylation (%) in oral pre-cancer by searching PubMed, Web-of-Science and Embase databases using combined key-searches. Twenty-one studies (18-cross-sectional; 3-longitudinal) were eligible for inclusion in the review, with sample sizes ranging from 4 to 156 affected cases. Eligible studies examined promoter region hyper-methylation of tumour suppressor genes in pathways including cell-cycle-control (n=15), DNA-repair (n=7), cell-cycle-signalling (n=4) and apoptosis (n=3). Hyper-methylated loci reported in three or more studies included p16, p14, MGMT and DAPK. Two longitudinal studies reported greater p16 hyper-methylation in pre-cancerous lesions transformed to malignancy compared to lesions that regressed (57-63.6% versus 8-32.1%; p<0.01). The one study that explored epigenome-wide methylation patterns reported three novel hyper-methylated loci (TRHDE; ZNF454; KCNAB3). The majority of reviewed studies were small, cross-sectional studies with poorly defined control groups and lacking validation. Whilst limitations in sample size and study design preclude definitive conclusions, current evidence suggests a potential utility of DNA methylation patterns as a diagnostic biomarker for oral pre-cancer progression. Robust studies such as large epigenome-wide methylation explorations of oral pre-cancer with longitudinal tracking are needed to validate the currently reported signals and identify new risk-loci and the biological pathways of disease progression

Single nucleotide polymorphisms as markers of genetic susceptibility for oral potentially malignant disorders risk: Review of evidence to date

SummaryBackgroundOral cancers are preceded by oral potentially malignant disorders (OPMD). Understanding genetic susceptibility for OPMD risk could provide an opportunity for risk assessment of oral cancer through early disease course. We conducted a review of single nucleotide polymorphism (SNP) studies for OPMD risk.MethodsWe identified all relevant studies examining associations of SNPs with OPMD (leukoplakia, erythroplakia and oral sub-mucous fibrosis) conducted world-wide between January, 2000 and February, 2016 using a combined keyword search on PubMed. Of these, 47 studies that presented results as odds ratios and 95% CI were considered for full review.ResultsThe majority of eligible studies that explored candidate gene associations for OPMD were small (N<200 cases), limiting their scope to provide strong inference for any SNP identified to date in any population. Commonly studied SNPs were genes of carcinogen metabolism (n=18 studies), DNA repair (n=11 studies), cell cycle control (n=8 studies), extra-cellular matrix alteration (n=8 studies) and immune-inflammatory (n=6 studies) pathways. Based on significant associations as reported by two or more studies, suggestive markers included SNPs in GSTM1 (null), CCND1 (G870A), MMP3 (-1171; promotor region), TNFα (-308; rs800629), XPD (codon 751) and Gemin3 (rs197412) as well as in p53 (codon 72) in Indian populations. However, an equal or greater number of studies reported null or mixed associations for SNPs in GSTM1 (null), p53 (codon 72), XPD (codon 751), XRCC (rs25487 C/T), GSTT1 (null) and CYP1A1m1 (MspI site).ConclusionCandidate gene association studies have not yielded consistent data on risk loci for OPMD. High-throughput genotyping approaches for OPMD, with concurrent efforts for oral cancer, could prove useful in identifying robust risk-loci to help understand early disease course susceptibility for oral cancer

Single nucleotide polymorphisms as markers of genetic susceptibility for oral potentially malignant disorders risk: Review of evidence to date.

BACKGROUND: Oral cancers are preceded by oral potentially malignant disorders (OPMD). Understanding genetic susceptibility for OPMD risk could provide an opportunity for risk assessment of oral cancer through early disease course. We conducted a review of single nucleotide polymorphism (SNP) studies for OPMD risk. METHODS: We identified all relevant studies examining associations of SNPs with OPMD (leukoplakia, erythroplakia and oral sub-mucous fibrosis) conducted world-wide between January, 2000 and February, 2016 using a combined keyword search on PubMed. Of these, 47 studies that presented results as odds ratios and 95% CI were considered for full review. RESULTS: The majority of eligible studies that explored candidate gene associations for OPMD were small (N<200 cases), limiting their scope to provide strong inference for any SNP identified to date in any population. Commonly studied SNPs were genes of carcinogen metabolism (n=18 studies), DNA repair (n=11 studies), cell cycle control (n=8 studies), extra-cellular matrix alteration (n=8 studies) and immune-inflammatory (n=6 studies) pathways. Based on significant associations as reported by two or more studies, suggestive markers included SNPs in GSTM1 (null), CCND1 (G870A), MMP3 (-1171; promotor region), TNF? (-308; rs800629), XPD (codon 751) and Gemin3 (rs197412) as well as in p53 (codon 72) in Indian populations. However, an equal or greater number of studies reported null or mixed associations for SNPs in GSTM1 (null), p53 (codon 72), XPD (codon 751), XRCC (rs25487 C/T), GSTT1 (null) and CYP1A1m1 (MspI site). CONCLUSION: Candidate gene association studies have not yielded consistent data on risk loci for OPMD. High-throughput genotyping approaches for OPMD, with concurrent efforts for oral cancer, could prove useful in identifying robust risk-loci to help understand early disease course susceptibility for oral cancer

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-?, 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- ? (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

Association of Hip Bone Mineral Density and Body Composition in a Rural Indian Population:The Andhra Pradesh Children and Parents Study (APCAPS)

BACKGROUND: Fat mass is variably associated with bone mass, possibly due to differential mechanical and biological effects of fat mass. We examined the association of fat mass with bone mass in a lean population. OBJECTIVE: To investigate association between hip bone mineral density and fat and lean mass in a cross-sectional study from southern India. DESIGN: The Andhra Pradesh Children and Parents Study is a prospective cohort study in Hyderabad, India. In 2009-2012, the study collected data on anthropometric measures, bone mineral density (BMD), fat mass, and lean mass measured by dual-energy x-ray absorptiometry, and socioeconomic data of the adult participants (n = 1760; mean age = 34.9 years old for women; 2130 and 32.3 for men). RESULTS: The median BMI (kg/m2) was 20.1 kg/m2. Women had relatively higher fat mass as compared to men. In models adjusted for lean mass, there was an association between hip bone mineral density and fat mass in women (β (95% confidence interval): premenopausal 0.025 (0.006 to 0.045); postmenopausal 0.045 (0.014 to 0.076)) but not in men (0.001 (-0.012 to 0.0014)). The association between hip BMD and fat mass was stronger in postmenopausal than premenopausal women. Hip BMD was consistently associated with lean mass, in both men and women. CONCLUSIONS: In this relatively lean population, lean mass was more consistently associated with hip BMD than fat mass. Weight gain through lean mass improvement may be a more reliable public health strategy for strengthening bone health in transitional settings

Socio-economic patterning of cardiometabolic risk factors in rural and peri-urban India: Andhra Pradesh children and parents study (APCAPS).

AIM: To assess the prevalence of cardiometabolic risk factors by socio-economic position (SEP) in rural and peri-urban Indian population. SUBJECTS AND METHODS: Cross-sectional survey of 3,948 adults (1,154 households) from Telangana (2010-2012) was conducted to collect questionnaire-based data, physical measurements and fasting blood samples. We compared the prevalence of risk factors and their clustering by SEP adjusting for age using the Mantel Hansel test. RESULTS: Men and women with no education had higher prevalence of increased waist circumference (men: 8 vs. 6.4 %, P < 0.001; women: 20.9 vs. 12.0 %, P = 0.01), waist-hip ratio (men: 46.5 vs. 25.8 %, P = 0.003; women: 58.8 vs. 29.2 %, P = 0.04) and regular alcohol intake (61.7 vs. 32.5 %, P < 0.001; women: 25.7 vs. 3.8 %, P < 0.001) than educated participants. Unskilled participants had higher prevalence of regular alcohol intake (men: 57.7 vs. 38.7 %, P = 0.001; women: 28.3 vs. 7.3 %, P < 0.001). In contrast, participants with a higher standard of living index had higher prevalence of diabetes (top third vs. bottom third: men 5.2 vs. 3.5 %, P = 0.004; women 5.5 vs. 2.4 %, P = 0.003), hyperinsulinemia (men 29.5 vs. 16.3 %, P = 0.002; women 31.1 vs. 14.3 %, P < 0.001), obesity (men 23.3 vs. 10.6 %, P < 0.001; women 25.9 vs. 12.8 %, P < 0.001), and raised LDL (men 16.8 vs. 11.4 %, P = 0.001; women 21.3 vs. 14.0 %, P < 0.001). CONCLUSIONS: Cardiometabolic risk factors are common in rural India but do not show a consistent association with SEP except for higher prevalence of smoking and regular alcohol intake in lower SEP group. Strategies to address the growing burden of cardiometabolic diseases in urbanizing rural India should be assessed for their potential impact on social inequalities in health

Association of common genetic variants with lipid traits in the Indian population.

Genome-wide association studies (GWAS) have been instrumental in identifying novel genetic variants associated with altered plasma lipid levels. However, these quantitative trait loci have not been tested in the Indian population, where there is a poorly understood and growing burden of cardiometabolic disorders. We present the association of six single nucleotide polymorphisms in 1671 sib pairs (3342 subjects) with four lipid traits: total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). We also investigated the interaction effects of gender, location, fat intake and physical activity. Each copy of the risk allele of rs964184 at APOA1 was associated with 1.06 mmol/l increase in triglycerides (SE = 0.049; p = 0.006), rs3764261 at CETP with 1.02 mmol/l increase in both total cholesterol (SE = 0.042; p = 0.017) and HDL-C (SE = 0.041; p = 0.008), rs646776 at CELSR2-PSRC1-SORT1 with 0.96 mmol/l decrease in cholesterol (SE = 0.043; p = 0.0003) and 0.15 mmol/l decrease in LDL-C levels (SE = 0.043; p = 0.0003) and rs2954029 at TRIB1 with 1.02 mmol/l increase in HDL-C (SE = 0.039; p = 0.047). A combined risk score of APOA1 and CETP loci predicted an increase of 1.25 mmol/l in HDL-C level (SE = 0.312; p = 0.0007). Urban location and sex had strong interaction effects on the genetic association of most of the studied loci with lipid traits. To conclude, we validated four genetic variants (identified by GWAS in western populations) associated with lipid traits in the Indian population. The interaction effects found here may explain the sex-specific differences in lipid levels and their heritability. Urbanization appears to influence the nature of the association with GWAS lipid loci in this population. However, these findings will require replication in other Indian populations

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

Is increasing urbanicity associated with changes in breastfeeding duration in rural India? An analysis of cross-sectional household data from the Andhra Pradesh children and parents study.

OBJECTIVE: To investigate whether village-level urbanicity and lower level socioeconomic factors are associated with breastfeeding practices in transitioning rural communities in India. SETTING: 29 villages in Ranga Reddy district, southern India between 2011 and 2014. PARTICIPANTS: 7848 children under 6 years identified via a cross-sectional household survey conducted as part of the Andhra Pradesh Children and Parents Study. OUTCOME MEASURES: Two key indicators of optimal breastfeeding: termination of exclusive breastfeeding before 6 months and discontinuation of breastfeeding by 24 months. Village urbanicity was classified as low, medium or high according to satellite assessed night-light intensity. RESULTS: Breastfeeding initiation was almost universal, and approximately two in three children were exclusively breastfed to 6 months and a similar proportion breastfed to 24 months. Using multilevel logistic regression, increasing urbanicity was associated with breastfeeding discontinuation before 24 months (medium urbanicity OR 1.45, 95% CI 0.71 to 2.96; high urbanicity OR 2.96, 95% CI 1.45 to 6.05) but not with early (<6 months) termination of exclusive breastfeeding. Increased maternal education was independently associated with both measures of suboptimal breastfeeding, and higher household socioeconomic position was associated with early termination of exclusive breastfeeding. CONCLUSION: In this transitional Indian rural community, early stage urbanicity was associated with a shorter duration of breastfeeding. Closer surveillance of changes in breastfeeding practices alongside appropriate intervention strategies are recommended for emerging economies