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

Exploration of associations between the FTO rs9939609 genotype, fasting and postprandial appetite-related hormones and perceived appetite in healthy men and women

Background: The fat mass and obesity-associated gene (FTO) rs9939609 A-allele has been associated with obesity risk. Although the exact mechanisms involved remain unknown, the FTO rs9939609 A-allele has been associated with an impaired postprandial suppression of appetite. Objectives: To explore the influence of FTO rs9939609 genotype on fasting and postprandial appetite-related hormones and perceived appetite in a heterogeneous sample of men and women. Design: 112 healthy men and women aged 18-50-years-old completed three laboratory visits for the assessment of FTO rs9939609 genotype, body composition, aerobic fitness, resting metabolic rate, visceral adipose tissue, liver fat, fasting leptin, and fasting and postprandial acylated ghrelin, total PYY, insulin, glucose and perceived appetite. Participants wore accelerometers for seven consecutive days for the assessment of physical activity and sedentary behaviour. Multivariable general linear models quantified differences between FTO rs9939609 groups for fasting and postprandial appetite outcomes, with and without the addition of a priori selected physiological and behavioural covariates. Sex-specific univariable Pearson's correlation coefficients were quantified between the appetite-related outcomes and individual characteristics. Results: 95% confidence intervals for mean differences between FTO rs9939609 groups overlapped zero in unadjusted and adjusted general linear models for all fasting (P ≥ 0.28) and postprandial (P ≥ 0.19) appetite-related outcomes. Eta2 values for explained variance attributable to FTO rs9939609 were <5% for all outcomes. An exploratory correlation matrix indicated that associations between fasting and postprandial acylated ghrelin, total PYY and general or abdominal adiposity were also small (r = −0.23 to 0.15, P ≥ 0.09). Fasting leptin, glucose and insulin and postprandial insulin concentrations were associated with adiposity outcomes (r = 0.29 to 0.81, P ≤ 0.033). Conclusions: Associations between the FTO rs9939609 genotype and fasting or postprandial appetite-related outcomes were weak in healthy men and women

True interindividual variability exists in postprandial appetite responses in healthy men but is not moderated by the FTO genotype

Background: After meal ingestion, a series of coordinated hormone responses occur concomitantly with changes in perceived appetite. It is not known whether interindividual variability in appetite exists in response to a meal. Objectives: This study aimed to 1) assess the reproducibility of appetite responses to a meal; 2) quantify individual differences in responses; and 3) explore any moderating influence of the fat mass and obesity associated (FTO) gene. Methods: Using a replicated crossover design, 18 healthy men (mean ± SD 28.5 ± 9.8 years, 27.0 ± 5.0 kg·m-2 ) recruited according to FTO genotype (9 AA, 9 TT) completed two identical control and two identical standardized meal conditions (5025 kJ) in randomized sequences. Perceived appetite and plasma acylated ghrelin, total peptide YY (PYY), insulin and glucose concentrations were measured before and after interventions as primary outcomes. Interindividual differences were explored using Pearson’s product-moment correlations between the first and second replicate of the control-adjusted meal response. Within-participant covariate-adjusted linear mixed models were used to quantify participant by-condition and genotype-by-condition interactions. Results: The meal suppressed acylated ghrelin and appetite perceptions (standardized effect sizes (ES): 0.18-4.26) and elevated total PYY, insulin and glucose (ES: 1.96-21.60). For all variables, SD of change scores was greater in the meal versus control conditions. Moderate-to-large positive correlations were observed between the two replicates of control-adjusted meal responses for all variables (r=0.44-0.86, P≤0.070). Participant-by-condition interactions were present for all variables (P≤0.056). FTO genotype-by-condition interactions were not significant (P≥0.19) and treatment effect differences between genotype groups were small (ES≤0.27) for all appetite parameters. Conclusions: Reproducibility of postprandial appetite responses is generally good. True interindividual variability is present beyond any random within-subject variation in healthy men but is not moderated by the FTO genotype. These findings highlight the 3 importance of exploring individual differences in appetite for the prevention and/or treatment of obesity. Clinical trial registry number: NCT03771690 (ClinicalTrials.gov)

Genetic analysis of common variants of MMPs and their involvement in Rheumatoid Arthritis in the East Midlands, UK

Introduction: Rheumatoid arthritis (RA) affects around 1% of population and causes irreversible synovial joint damage and bone erosion. Matrix metalloproteinases (MMPs) play a role in pathologic processes; however their involvement in RA is not clear. This study investigated the association of MMP2, MMP7 and MMP9 with RA. Methods: DNA samples from European (103 controls, 125 patients) and South Asian (91 controls, 115 patients) populations were genotyped for MMP7 (rs11568818), MMP9 (rs17576) and MMP2 (rs2241145). Diplotype and triplotypes analyses were performed. Results: An individual is twice as likely to develop RA if they have an AG genotype at both the MMP9 and MMP7 loci in European (OR 2.2, CI 1.03-4.70) or South Asian population (OR 2.28, CI 1.00-5.20). A CG genotype at the MMP2 locus and AG at MMP9- 836 gives protection within a European population (OR 0.34, CI 0.17-0.70). Heterozygous genotype combination on all three loci in South Asians increases risk of RA by three times (OR 3.27, CI 1.04-10.20). South Asians showed a significant doubling of RA risk with a total genetic risk score of three or more. Conclusion: Our results show that polymorphisms at these three MMP loci impact RA susceptibility and have a synergetic effect

Exploration of associations between the FTO rs9939609 genotype, fasting and postprandial appetite-related hormones and perceived appetite in healthy men and women

Background: The fat mass and obesity-associated gene (FTO) rs9939609 A-allele has been associated with obesity risk. Although the exact mechanisms involved remain unknown, the FTO rs9939609 A-allele has been associated with an impaired postprandial suppression of appetite. Objectives: To explore the influence of FTO rs9939609 genotype on fasting and postprandial appetite-related hormones and perceived appetite in a heterogeneous sample of men and women. Design: 112 healthy men and women aged 18-50-years-old completed three laboratory visits for the assessment of FTO rs9939609 genotype, body composition, aerobic fitness, resting metabolic rate, visceral adipose tissue, liver fat, fasting leptin, and fasting and postprandial acylated ghrelin, total PYY, insulin, glucose and perceived appetite. Participants wore accelerometers for seven consecutive days for the assessment of physical activity and sedentary behaviour. Multivariable general linear models quantified differences between FTO rs9939609 groups for fasting and postprandial appetite outcomes, with and without the addition of a priori selected physiological and behavioural covariates. Sex-specific univariable Pearson’s correlation coefficients were quantified between the appetite-related outcomes and individual characteristics. Results: 95% confidence intervals for mean differences between FTO rs9939609 groups overlapped zero in unadjusted and adjusted general linear models for all fasting (P≥0.28) and postprandial (P≥0.19) appetite-related outcomes. Eta2 values for explained variance attributable to FTO rs9939609 were <5% for all outcomes. An exploratory correlation matrix indicated that associations between fasting and postprandial acylated ghrelin, total PYY and general or abdominal adiposity were also small (r = -0.23 to 0.15, P≥0.09). Fasting leptin, glucose and insulin and postprandial insulin concentrations were associated with adiposity outcomes (r = 0.29 to 0.81, P≤0.033). Conclusions: Associations between the FTO rs9939609 genotype and fasting or postprandial appetite-related outcomes were weak in healthy men and women