Role of PON1 L55M Gene Polymorphism in Parkinson's Disease among North Indian Population.

BACKGROUND AND OBJECTIVES: The role of various genetic markers including alpha synuclein, Parkin, etc., is known in the pathogenesis of Parkinson's disease (PD). Novel genetic markers including paraoxonase 1 (PON1) have also been linked to PD pathogenesis in recent studies. The PON1 L55M allele carriers may have defective clearance of environmental toxins and may result in increased susceptibility to PD. Hence, we studied the role of PON1 L55M polymorphism in PD among a North Indian population. MATERIALS AND METHOD: Seventy-four PD patients and 74 age- and sex-matched controls were recruited in this hospital-based case-control study. Baseline characteristics were recorded using structured questionnaire. DNA was extracted from 3-4 ml of venous blood, followed by PCR and restriction digestion. PON1 L55M genotypes were visualized as bands: LL (177 bp), LM (177, 140 bp) and MM (140,44 bp) on 3% agarose gel. Mann-Whitney U test and Chi-squared test were used for comparing two groups of skewed and categorical variables, respectively. Measures of strength of association were calculated by binary regression analysis. P value < 0.05 was considered as significant. RESULTS: Parkinson's disease patients had significantly higher exposure to pesticides (12.2%; P (organophosphate exposure) < 0.001) and well water drinking (28.4%; P = 0.006) compared to controls. Frequency distribution of LL, LM, MM genotypes was 67.5% (50/74), 28.4% (21/74), and 4.1% (3/74), respectively, for cases and 72.6% (54/74), 26% (19/74) and 1.4% (1/74), respectively, for controls. PON1 L55M genotype distribution between Parkinson's disease cases and controls was not significant (P = 0.53). PON1 L55M polymorphism was not associated with PD after adjusting for confounders by binary regression analysis. CONCLUSION: There was no significant association between PON1 L55M polymorphism and PD. Larger population-based studies would be required from India before drawing any definite conclusions.

STENOSIS: Long-term single versus dual antiplatelet therapy in patients with ischaemic stroke due to intracranial atherosclerotic disease - a randomised trial.

Rationale: Intracranial atherosclerotic disease (ICAD) is a pathological process that causes progressive stenosis and cerebral hypoperfusion, leading to stroke occurrence and recurrence around the world. The exact duration of dual antiplatelet therapy (DAPT) for ICAD is unclear in view of long-term risk of bleeding complications. Aim: The current study aims to study the efficacy and safety of long-term DAPT (up to 12 months) in patients with ICAD. Sample size: Using 80% power and an alpha error of 5 %, presuming a 10%-15% drop-out rate, a total of 2200 patients will be recruited for the study. Methodology: This is a prospective, randomised, double-blind, placebo controlled trial. Study outcomes: The primary outcomes include recurrent ischaemic stroke (IS) or transient ischaemic attack and any intracranial haemorrhage (ICH), major or minor systemic bleeding at the end of 12 months. Secondary outcomes include composite of any stroke, myocardial infarction or death at the end of 12 months. The safety outcomes include any ICH, major or minor bleeding as defined using GUSTO (Global Use of Streptokinase and tPA for occluded Coronary Arteries) classification at the end of 12 months and 1 month after completion of the drug treatment phase. Discussion: The study will provide level I evidence on the duration of DAPT among patients with IS due to ICAD of more than or equal to 50%.

RE-OPEN: Randomised trial of biosimilar TNK versus TPA during endovascular therapy for acute ischaemic stroke due to large vessel occlusions.

Rationale: Rapid and timely treatment with intravenous thrombolysis and endovascular treatment (EVT) in patients with acute ischaemic stroke (AIS) and large vessel occlusion (LVO) significantly improves patient outcomes. Bridging therapy is the current standard of care in these patients. However, an incompletely answered question is whether one thrombolytic agent is better than another during bridging therapy. Aim: The current study aims to understand if one thrombolytic agent is superior to the other during bridging therapy in the treatment of AIS and LVO. Sample size estimates: Using 80% power and an alpha error of 5 %, presuming a 10% drop out rate, a total of 372 patients will be recruited for the study. Methods and design: This study is a prospective, randomised, multicentre, open-label trial with blinded outcome analysis design. Study outcomes: The primary outcomes include proportion of patients who will be independent at 3 months (modified Rankin score (mRS) ≤2 as good outcome) and proportion of patients who achieve recanalisation modified thrombolysis in cerebral infarction grade 2b/3 at first angiography run at the end of EVT. Secondary outcomes include proportion of patients with early neurological improvement, rate of symptomatic intracerebral haemorrhage (ICH), rate of any ICH, rate of any systemic major or minor bleeding and duration of hospital stay. Safety outcomes include any intracranial bleeding or symptomatic ICH. Discussion: This trial is envisioned to confirm the theoretical advantages and increase the strength and quality of evidence for use of tenecteplase (TNK) in practice. Also, it will help to generate data on the efficacy and safety of biosimilar TNK. Trial registration number: CTRI/2022/01/039473.

Trends in hypertension prevalence, awareness, treatment, and control: an 8-year follow-up study from rural North India.

Hypertension is a major contributor to global CVD burden. LMICs including India is challenged with rising hypertension prevalence, yet limited studies are available on temporal change and incidence among community-cohorts. This study aimed to describe trends in hypertension prevalence, awareness, treatment, and control over 8 years among a rural community-cohort from Haryana, India. The study also lends towards an analysis of incidence. Adults ≥ 30 years (N = 1542) recruited during baseline cross-sectional study between 2011 and 2014 were followed up after a median 8.1 years. At endline, demographic/lifestyle characteristics and blood pressure were re-examined. Overall median SBP significantly increased from 120 mmHg at baseline to 125.5 mmHg at endline (p < 0.001), while hypertension prevalence increased from 34.4% (95% CI 32.0-36.9) to 40.4% (95% CI 37.5-43.4) (p = 0.002). Age-standardized hypertension incidence was 30.2% (95% CI 26.7-35.2) over 8 years. Among hypertensive group, awareness, treatment, and control increased from 9.6, 8.8 and 5.0% to 31.8, 27.3 and 9.6% (p < 0.05), respectively. Increasing trend in SBP and hypertension prevalence was observed as the cohort ages. This increase is supported by the high incidence of hypertension. Nevertheless, our study highlights positive trends in hypertension care cascade but poor control, suggesting that this trend may not be adequately impactful to reduce hypertension burden.

Sex-specific variations in global DNA methylation levels with age: a population-based exploratory study from North India.

Purpose: Aging is one of the most important risk factors for a number of human diseases. Epigenetic alterations, including changes in DNA methylation patterns, have been reported to be one of the hallmarks of aging. Being a malleable process, the role of site-specific DNA methylation in aging is being extensively investigated; however, much less attention has been given to alterations in global DNA methylation with aging at the population level. The present study aims to explore overall and sex-specific variations in global DNA methylation patterns with age. Methods: A total of 1,127 adult individuals (792 females) aged 30-75 years belonging to Haryana, North India, were recruited. Socio-demographic data was collected using a pretested interview schedule. Global DNA methylation analysis, of peripheral blood leucocyte (PBL) DNA, was performed using the ELISA-based colorimetric technique. Results: Though the overall correlation analysis revealed a weak inverse trend between global DNA methylation and age, the adjusted regression model showed no significant association between global DNA methylation and age. In age-stratified analysis, global DNA methylation levels were found to be fairly stable until 60 years of age, followed by a decline in the above-60 age group. Further, no significant difference in DNA patterns methylation pattern was observed between males and females. Conclusion: Overall, the study suggests a lack of association between global DNA methylation and age, especially until 60 years of age, and a similar DNA methylation pattern between males and females with respect to age.

Gender-specific association of blood lipids and reproductive trajectory with cognitive impairment: A community based cross-sectional study from India.

Background: Abnormal blood lipid levels in the general population and adverse reproductive events among women have been associated with cognitive impairment (CI). However, their relationship has not been extensively studied in community settings. Hence, this study aims to explore the association of CI with blood lipid levels in both sexes and reproductive events/trajectory among women. Methods: A cross-sectional study was conducted among a North Indian rural population. A total of 808 adults were recruited through door-to-door household survey. Data on socio-demographic variables, reproductive profile of women, and cognitive impairment status were collected. Fasting blood sample was collected to estimate serum lipid profile. Multivariate logistic regression was performed to test for association. Results: The study demonstrated a lack of association between lipid profile and cognitive impairment among males. Surprisingly, low HDL-C among females was found to be protective against moderate/severe cognitive impairment (value of p = 0.049). Further, menopausal women and those having five or higher live births were found to be at higher risk of CI than pre-menopausal women and those with 1-2 live births, respectively. Conclusion: The present study hints toward a gender-specific association of blood lipid levels with CI. Further, higher live births and menopause appear to be important risk factors for CI among women.

Association of air pollution and homocysteine with global DNA methylation: A population-based study from North India.

BACKGROUND: Anthropogenic air pollution has been implicated in aberrant changes of DNA methylation and homocysteine increase (>15µM/L). Folate (<3 ng/mL) and vitamin B12 (<220 pg/mL) deficiencies also reduce global DNA methylation via homocysteine increase. Although B-vitamin supplements can attenuate epigenetic effects of air pollution but such understanding in population-specific studies are lacking. Hence, the present study aims to understand the role of air pollution, homocysteine, and nutritional deficiencies on methylation. METHODS: We examined cross-sectionally, homocysteine, folate, vitamin B12 (chemiluminescence) and global DNA methylation (colorimetric ELISA Assay) among 274 and 270 individuals from low- and high- polluted areas, respectively, from a single Mendelian population. Global DNA methylation results were obtained on 254 and 258 samples from low- and high- polluted areas, respectively. RESULTS: Significant decline in median global DNA methylation was seen as a result of air pollution [high-0.84 (0.37-1.97) vs. low-0.96 (0.45-2.75), p = 0.01]. High homocysteine in combination with air pollution significantly reduced global DNA methylation [high-0.71 (0.34-1.90) vs. low-0.93 (0.45-3.00), p = 0.003]. Folate deficient individuals in high polluted areas [high-0.70 (0.37-1.29) vs. low-1.21 (0.45-3.65)] showed significantly reduced global methylation levels (p = 0.007). In low polluted areas, despite folate deficiency, if normal vitamin B12 levels were maintained, global DNA methylation levels improved significantly [2.03 (0.60-5.24), p = 0.007]. Conversely, in high polluted areas despite vitamin B12 deficiency, if normal folate status was maintained, global DNA methylation status improved significantly [0.91 (0.36-1.63)] compared to vitamin B12 normal individuals [0.54 (0.26-1.13), p = 0.04]. CONCLUSIONS: High homocysteine may aggravate the effects of air pollution on DNA methylation. Vitamin B12 in low-polluted and folate in high-polluted areas may be strong determinants for changes in DNA methylation levels. The effect of air pollution on methylation levels may be reduced through inclusion of dietary or supplemented B-vitamins. This may serve as public level approach in natural settings to prevent metabolic adversities at community level.

Methylenetetrahydrofolate reductase gene polymorphism, global DNA methylation and blood pressure: a population based study from North India.

BACKGROUND: Hypertension is a complex disorder affected by gene-environment interactions. Methylenetetrahydrofolate reductase (MTHFR) gene is one of the genes in One Carbon Metabolic (OCM) pathway that affects both blood pressure and epigenetic phenomenon. MTHFR C677T gene polymorphism leads to reduced methylation capacity via increased homocysteine concentrations. Global DNA methylation (5mC%) also gets affected in conditions such as hypertension. However, no study is found to understand hypertension in terms of both genetics and epigenetics. The present study aims to understand the relation between methylation, MTHFR C677T gene polymorphism and hypertension. It also tries to understand relation (if any) between methylation and anti-hypertensive drugs. METHODS: This is a cross-sectional study where data were collected from a total of 1634 individuals of either sex in age group 35-65 years. Hypertensives (SBP ≥ 140 mm Hg and DBP ≥ 90 mm Hg) (on treatment/not on treatment) and absolute controls were 236 (cases) and 307 (controls), respectively. All the samples were subjected to MTHFR C677T gene polymorphism screening (PCR-RFLP) and global DNA methylation assay (ELISA based colorimetric assay). Results of both the analyses were obtained on 218 cases, 263 controls. RESULTS: Median 5mC% was relatively lower among cases (p > 0.05) compared to controls, despite controlling for confounders (age, sex, smoking, alcohol, diet) (r2-0.92, p-0.08). Cases not on medication had significantly reduced 5mC% compared to controls (p < 0.05), despite adjusting for confounders (r2-0.857, p-0.01). Among cases (irrespective of treatment), there was a significant variation in 5mC% across the three genotypes i.e. CC, CT and TT, with no such variation among controls. Cases (not on medication) with TT genotype had significantly lower methylation levels compared to the TT genotype controls and cases (on medication) (p < 0.01). CONCLUSION: Global DNA hypomethylation seems to be associated with hypertension and antihypertensive drugs seem to improve methylation. Hypertensive individuals with TT genotype but not on medication are more likely to be prone to global DNA hypomethylation. Important precursors in OCM pathway include micronutrients such as vitamin B-12, B-9 and B-6; their nutritional interventions (either dietary or supplement) may serve as strategies to prevent hypertension at population level. However, more epidemiological-longitudinal studies are needed for further validation.

Differential risk factors and morbidity/mortality pattern in type 2 diabetes: A study among two Mendelian populations with different ancestry (India).

BACKGROUND AND AIMS: Association studies of type 2 diabetes mellitus (T2DM) with risk factors have shown variable results. Moreover, population-specific comparative investigations are negligible. Therefore, the present study aimed to evaluate the association of dyslipidemia and obesity with impaired fasting glucose (IFG) and T2DM among two ethnically, geographically and culturally different populations in India. METHODS: This was a cross-sectional study among Jats and Meiteis, each inhabiting a separate geographical region. A total of 2371 individuals, age ≥30 years were recruited through household survey. Obesity variables were captured using anthropometric measurements while fasting blood (2.5 mL) was drawn to measure lipid and glucose levels using enzymatic assay by spectrophotometer. Participants were categorized under normal, IFG and T2DM groups, indicative of diabetes progression stages. Statistical analysis was performed using SPSS 16.0 version. RESULTS: Significant differential distribution of lipid and obesity variables among IFG and T2DM in both populations were observed. Odds ratio revealed high TC and all obesity variables except BMI posed significant increased risk for T2DM among Jats. Abnormal TG, VLDL, WC, and WHtR posed significant increased risk for T2DM among Meiteis. Age-cohort wise prevalence of T2DM showed increasing trend at ≥60 years among Jats and decreasing trend at ≥60 years among Meiteis, suggesting a potential higher morbidity in the former and mortality in latter because of T2DM. CONCLUSIONS: The present study observed a differential association of risk factors for T2DM among Jats and Meiteis. This study emphasize the need to implement community-specific intervention programs for prevention, treatment and management of T2DM.