GENETIC SUSCEPTIBILITY OF TRANSCRIPTION FACTOR 7-LIKE 2 GENE VARIANT AND RISK OF TYPE 2 DIABETES IN ASIAN INDIANS

Background: The variants of transcription factor 7-like 2 (TCF7L2) gene have been shown to be associated with type 2 diabetes mellitus (T2DM) and its related complications. Objectives: We aimed to explore the possible association of rs7903146 (C/T) variant in TCF7L2 with the risk of T2DM in the North Indian population. Methods: The present case–control study included a total of 638 human subjects (318 T2DM subjects and 320 healthy controls). Various anthropometric, biochemical, and genetic parameters were studies in all the subjects. Genotyping of TCF7L2 gene was carried out using allele-specific polymerase chain reaction method. Results: The results of this study indicate significantly higher values of body mass index, waist circumference, waist-to-hip ratio, and body fat (%) in T2DM subjects than controls (p≤0.001). Dyslipidemia represented by higher levels of triglycerides and reduced values of high-density lipoprotein was more predominant in diabetic subjects compared to healthy subjects. The frequency of risk genotype (TT) frequency was significantly higher in T2DM subjects (16.4%) compared to controls (11.6%). The “T” allele was more dominant in diabetic subjects than controls. Logistic regression analysis of the data revealed a significant association of TT genotype with 2-fold (odds ratio with 95% of confidence interval; 2.09 [1.29–3.42] p=0.003) and CT genotype with 1.7-fold (1.73 [1.23–2.44] p=0.002) increased risk of developing T2DM. Conclusions: The present study demonstrated a significant association of rs7903146 (C/T) variant in TCF7L2 with the augmented risk of T2DM in North Indian population

Genetic variation of MHC Class I polymorphic Alu insertions (POALINs) in three subpopulations of the East Midlands, UK.

Background: Alu elements are highly researched due to their useful nature as markers in the study of human population genetics. Recently discovered Major Histocompatibility Complex (MHC) polymorphic Alu insertions (POALINs) have not been examined extensively for genetic variation and their HLA associations. Aims: The aim of this study is to assess the genetic variation between three populations using five recently discovered POALINs. Methods and Subjects: The study examined 190 healthy, unrelated subjects from three different populations in the East Midlands (UK) for the presence or absence of five Alu elements (AluHG, AluMICB, AluHJ, AluTF and AluHF) via the polymerase chain reaction followed by gel electrophoresis. Data were analysed for genetic variation and phylogenetic analyses. Results: All Alus were polymorphic in study populations. Appreciable allele frequency variation was observed at number of loci. The British population was significantly different from both the Punjabi Jat Sikh and Gujarati Patel populations, though showing a closer genetic relationship to the Punjabi Jat Sikh population than the Gujarati Patel population (Nei’s DA = 0.0031 and 0.0064 respectively). Conclusions: MHC POALINs are useful markers in the investigation of genetic variation and the assessment of population relationships and may have bearing on disease associations due to their linkage disequilibrium with HLA loci; this warrants further studies

Metabolic syndrome and risk of major coronary events among the urban diabetic patients: North Indian Diabetes and Cardiovascular Disease Study-NIDCVD-2

Objective: The present study aimed at estimating the prevalence of metabolic syndrome (MetS) and prospectively, evaluating cardiovascular events among Asian Indians type 2 diabetic subjects. Methods: The sample comprised 1522 type 2 diabetic mellitus (T2DM) subjects aged 25-91. years, who participated in the North Indian Diabetes and Cardiovascular Disease Study (NIDCVD). The participants were screened for hypertension, dyslipidemia, obesity and cardiovascular events. Anthropometric, clinical and biochemical measurements were done in all subjects. The prevalence of MetS was estimated in all the subjects according to the harmonized criteria of 2009. Results: The prevalence of MetS among urban Indian diabetic subjects was 71.9% and was significantly higher in females (86%) as compared to males (57.9%). To determine the independent predictors of the MetS in diabetic sample, binary logistic regression analyses were performed using demographic and biochemical parameters. Significant differences in the indices of generalized and abdominal obesity and lipids (total cholesterol, high density lipoprotein) were observed (p <. 0.01) in male:female and MetS and non-MetS comparisons. Regression analysis for prediction of CAD showed that family history, age, body mass index (BMI), SBP, physical inactivity and hypertension independently and significantly predicted the disease outcome. Binary logistic regression analysis revealed that MetS may be an independent risk/predictor of CAD (odd ratio (OR) = 3.44, CI 1.31-9.01, p = 0.012) along with higher age groups, BMI and hypertension in Indian population. Conclusion: The study demonstrated that the high prevalence of MetS and its different components were positively associated with a higher risk of CAD in north Indian diabetic subjects. Nevertheless, MetS is a major health problem in India, comprehensive population studies are warranted for estimation of incidence and prevalence, and education should be provided on its prevention and control to reduce the diabetes-related morbidity and mortality

Paraoxonase 1 gene polymorphisms (Q192R and L55M) are associated with coronary artery disease susceptibility in Asian Indians

Background: Coronary artery disease (CAD) is a complex metabolic disorder in which lifestyle and genetic factors are known to play key roles in pathogenesis. The paraoxonase 1 (PON1) enzyme has a defensive effect against CAD progression, as it safeguards low-density lipoproteins (LDLs) from oxidative modifications. The most extensively studied genetic variants in the PON1 gene are Q192R and L55M, which have been related with LDL antioxidative activity and risk of CAD. Objective: The present case-control study intended to examine the Q192R and L55M polymorphisms and their association with the risk of CAD patients in north Indians. Methods: A total of 872 subjects (412 CAD patients and 460 controls) were recruited from north India. The PON1 gene was amplified and genotypes were studies using PCR-RFLP. χ2 analysis was performed to compare genotype/allele frequencies in patients and controls. Results: The present study indicated abdominal obesity, elevated body mass index, and dyslipidemia with increased levels of total cholesterol and triglycerides as well as reduced high-density lipoprotein cholesterol in CAD subjects compared to healthy controls (p < 0.05). Logistic regression analysis of the data revealed an association of the RR genotype of the Q192R polymorphism with an about 2-fold elevated risk of CAD (OR = 2.23, 95% CI = 1.47–3.37, p = 0.0001). Contrariwise, the L55M polymorphism did not show significant association with CAD (OR = 1.81, 95% CI = 0.66–4.95, p = 0.326). Conclusions: The Q192R polymorphism in the PON1 gene may be a susceptibility gene associated with increased risk of CAD in an Asian Indian population

Prevalence and predictors of age related macular degeneration in the population of Punjab: North Indian age related macular degeneration epidemiology and molecular genetic study (NI-ARMEMS)

Background: Age related macular degeneration (AMD) is an ocular disease that is threatening elderly population of Punjab for vision impairment and blindness. Comprehensive understanding of the susceptible factors still remains to be explored in this region. Objective: To examine the risk variables which are independently associated with the risk of AMD along with the investigation of its prevalence in the population of Punjab. Methods: A case-control study by design involved 416 subjects (cases; 219, controls; 197) of age ranging from 45 to 75 years. Various risk factors were investigated for their role in consenting and confirmed AMD subjects along with controls. Results: In the univariate full factorial regression analysis, advancing age (≥66years), being a woman, diastolic blood pressure (DBP) (>80mmHg), cigarette smoking, alcohol drinking, body mass index (BMI) (23-29.9Kgm-2 and ≥30Kgm-2 ), sedentary life style, total cholesterol (>200mg/dl), low density lipoproteins (>100mg/dl), high density lipoproteins (≥40mg/dl), non-vegetarian diet and positive family history were found to be risky determinants. Multivariable stepwise regression analysis revealed age ≥66 years, DBP > 80mmHg, alcohol drinking and smoking as independent predictors for the risk of AMD. Conclusion: Considerable prevalence of dry AMD (20.5%) is evident in the population of Punjab which is mediated independently by age (≥66 years), DBP (>80 mmHg), alcohol drinking and smoking

ENPP1 K121Q functional variant enhances susceptibility to insulin resistance and dyslipidemia with metabolic syndrome in Asian Indians

Background: Ectonucleotide pyrophosphatase/phosphodiesterase1 (ENPP1/PC-1) is a key modulator of the insulin signaling pathway, and its common variant, K121Q, increases the susceptibility to diabetes and cardiovascular diseases. Objectives: The main objective of the present study was to investigate the association of ENPP1 K121Q polymorphism with the pathophysiology of metabolic syndrome (MetS) in a north Indian population. Methods: A total of 567 participants (303 MetS subjects and 264 healthy controls) were examined for ENPP1 genotypes and various clinical parameters, including body mass index (BMI), waist circumference (WC), systolic and diastolic blood pressures (SBP/DBP), fasting blood glucose (FBG), cholesterol, triglycerides (TG), highdensity lipoprotein, and insulin. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Statistical analysis of the data was done using SPSS. Results: Significant increases in BMI, WC, SBP, DBP, FBG, TG, low-density lipoprotein, insulin, and Homeostasis Model Assessment of insulin resistance (HOMAIR) and of beta-cell function (HOMA-BF) were observed in MetS patients compared to healthy controls. Logistic regression analysis of data demonstrated a nonsignificant association of QQ and KQ+QQ genotypes with increased risk of MetS (OR [95% CI], 1.583 [0.455–5.507], p = 0.470 for QQ genotypes and 1.097 [0.784–1.540], p = 0.587 for KQ+QQ genotypes). Moreover, MetS subjects carrying Q alleles had significantly higher levels of TG, insulin, body fat percentage, and insulin resistance as evident by higher values of HOMAIR. Conclusions: We conclude that ENPP1 K121Q functional variant enhances susceptibility to insulin resistance and dyslipidemia in MetS subjects of an Asian Indian population

The role of TLR4, TNF-α and IL-1β in type 2 diabetes mellitus development within a North Indian Population.

This study investigated the role of IL-1β-511 (rs16944), TLR4-896 (rs4986790) and TNF-α-308 (rs1800629) polymorphisms in type 2 diabetes mellitus (T2DM) among an endogamous Northern Indian population. 414 participants (204 T2DM patients and 210 non-diabetic controls) were genotyped for IL-1β-511, TLR4-896 and TNF-α-308 loci. The C allele of IL-1β-511 was shown to increase T2DM susceptibility by 75% (OR: 1.75 [CI 1.32-2.33]). Having two parents affected by T2DM increased susceptibility by 5.7 times (OR: 5.693 [CI 1.431-22.648]). In this study, we have demonstrated a conclusive association with IL-1β-511 locus and IL1B-511-TLR4-896 diplotype (CC-AA) and T2DM, which warrants further comprehensive analyses in larger cohorts

Global, regional, and national burden of headache disorders, 1990–2023: a systematic analysis for the Global Burden of Disease Study 2023

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 estimates health loss from migraine, tension-type headache, and medication-overuse headache. This study presents updated results on headache-attributed burden from 1990 to 2023, along with clinical and public health implications. Methods: Data on the prevalence, incidence, or remission of migraine, tension-type headache, and medication-overuse headache were extracted from published population-based studies. We used hierarchical Bayesian meta-regression modelling to estimate global, regional, and country-level prevalence of headache disorders. For the first time in GBD 2023, age-specific and sex-specific estimates of time in symptomatic state were applied by meta-analysing individual participant data from 41 653 individuals from the general populations of 18 countries from all parts of the world. Disability weights were applied to calculate years lived with disability (YLDs). Since medication-overuse headache is a sequela of a mistreated primary headache (due to medication overuse), its burden was reattributed to migraine or tension-type headache, informed by a meta-analysis of three longitudinal studies. Findings: In 2023, 2·9 billion individuals (95% uncertainty interval 2·6-3·1) were affected by headache disorders, with a global age-standardised prevalence of 34·6% (31·6-37·5) and a YLD rate of 541·9 (373·4-739·9) per 100 000 population, with 487·5 (323·0-678·8) per 100 000 population attributed to migraine. The prevalence rates of these headache disorders have remained stable over the past three decades. YLD rates due to headache disorders were more than twice as high in females (739·9 [511·2-1011·5] per 100 000) as in males (346·1 [240·4-481·8] per 100 000). Medication-overuse headache contributed 58·9% of the YLD estimates for tension-type headache in males and 56·1% in females, as well as 22·6% of the YLD estimates for migraines in males and 14·1% in females. Interpretation: Headache disorders, in particular migraine, continue to be a major global health challenge, emphasising the need for effective management and prevention strategies. Much headache-attributed burden could be averted or eliminated by avoiding overuse of medication (including over-the-counter medication), underscoring the importance of public education. Funding: Gates Foundation