Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile

Aims: Change in weight, HbA1c, lipids, blood pressure and cardiometabolic events over time is variable in individuals with type 2 diabetes. We hypothesised that people with a genetic predisposition to a more favourable adiposity distribution could have a less severe clinical course/progression. Methods: We involved people with type 2 diabetes from two UK-based cohorts: 11,914 individuals with GP follow-up data from the UK Biobank and 723 from Salford. We generated a ‘favourable adiposity’ genetic score and conducted cross-sectional and longitudinal studies to test its association with weight, BMI, lipids, blood pressure, medication use and risk of myocardial infarction and stroke using 15 follow-up time points with 1-year intervals. Results: The ‘favourable adiposity’ genetic score was cross-sectionally associated with higher weight (effect size per 1 standard deviation higher genetic score: 0.91 kg [0.59,1.23]) and BMI (0.30 kg/m2 [0.19,0.40]), but higher high-density lipoprotein (0.02 mmol/L [0.01,0.02]) and lower triglycerides (−0.04 mmol/L [−0.07, −0.02]) in the UK Biobank at baseline, and this pattern of association was consistent across follow-up. There was a trend for participants with higher ‘favourable adiposity’ genetic score to have lower risk of myocardial infarction and/or stroke (odds ratio 0.79 [0.62, 1.00]) compared to those with lower score. A one standard deviation higher score was associated with lower odds of using lipid-lowering (0.91 [0.86, 0.97]) and anti-hypertensive medication (0.95 [0.91, 0.99]). Conclusions: In individuals with type 2 diabetes, having more ‘favourable adiposity’ alleles is associated with a marginally better lipid profile long-term and having lower odds of requiring lipid-lowering or anti-hypertensive medication in spite of relatively higher adiposity

Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile.

This is the final version. Available from Wiley via the DOI in this record.DATA AVAILABILITY STATEMENT We used patient-level data which was fully anonymised prior to analysis. Any requests for access to the Salford data should be made to Dr Adrian Heald.AIMS: Change in weight, HbA1c , lipids, blood pressure and cardiometabolic events over time is variable in individuals with type 2 diabetes. We hypothesised that people with a genetic predisposition to a more favourable adiposity distribution could have a less severe clinical course/progression. METHODS: We involved people with type 2 diabetes from two UK-based cohorts: 11,914 individuals with GP follow-up data from the UK Biobank and 723 from Salford. We generated a 'favourable adiposity' genetic score and conducted cross-sectional and longitudinal studies to test its association with weight, BMI, lipids, blood pressure, medication use and risk of myocardial infarction and stroke using 15 follow-up time points with 1-year intervals. RESULTS: The 'favourable adiposity' genetic score was cross-sectionally associated with higher weight (effect size per 1 standard deviation higher genetic score: 0.91 kg [0.59,1.23]) and BMI (0.30 kg/m2 [0.19,0.40]), but higher high-density lipoprotein (0.02 mmol/L [0.01,0.02]) and lower triglycerides (-0.04 mmol/L [-0.07, -0.02]) in the UK Biobank at baseline, and this pattern of association was consistent across follow-up. There was a trend for participants with higher 'favourable adiposity' genetic score to have lower risk of myocardial infarction and/or stroke (odds ratio 0.79 [0.62, 1.00]) compared to those with lower score. A one standard deviation higher score was associated with lower odds of using lipid-lowering (0.91 [0.86, 0.97]) and anti-hypertensive medication (0.95 [0.91, 0.99]). CONCLUSIONS: In individuals with type 2 diabetes, having more 'favourable adiposity' alleles is associated with a marginally better lipid profile long-term and having lower odds of requiring lipid-lowering or anti-hypertensive medication in spite of relatively higher adiposity.Diabetes UKEuropean Research CouncilMedical Research CouncilResearch Englan

Juvenile idiopathic arthritis genetics - what's new? What's next?

Studies have established the magnitude of the genetic basis of juvenile idiopathic arthritis (JIA). JIA is a complex genetic condition and the genes that influence susceptibility are actively being sought. A candidate gene approach is being used by several groups. MHC-, cytokine- and T-cell-related genes have all been positively associated with JIA. Here we review some of the latest genetic data, and discuss ways in which JIA genetic research might procee

Glucocorticoid receptor gamma expression is not regulated by genotype, or glucocorticoid

OBJECTIVE: To measure glucocorticoid receptor gamma (GRgamma) expression in transformed lymphocytes from individuals of known GR gene haplotype. Recently, a glucocorticoid receptor haplotype (GAT) has been described that associates with increased sensitivity to dexamethasone. As there is strong linkage disequilibrium across the gene, this haplotype is likely to extend through exon 3, altered splicing of which generates the GRgamma isoform, a splice variant with impaired transactivation activity. Therefore we proposed that the GR haplotype affects glucocorticoid sensitivity either by influencing GRgamma expression basally, or in response to Gc exposure. DESIGN: We have measured expression of GRgamma, using a validated RT-PCR assay in human B lymphoblast cells of known haplotype under basal conditions, and after dexamethasone treatment. PATIENTS: The A549 human lung cell line and normal volunteers, five with the GAT GR haplotype and three with the CGA haplotype. MEASUREMENTS: Relative expression of GRgamma compared to total GR mRNA. RESULTS: GRgamma made up 5-6% of all the GR transcripts. There was no effect of carriage of the GR gene GAT haplotype on this expression. There was no effect of dexamethasone on relative expression of GRgamma. CONCLUSIONS: We propose that the GRgamma isoform is a product of constitutive splicing, that it does not explain the GR haplotype association with altered glucocorticoid sensitivity, and is unlikely to play an important physiological role in affecting glucocorticoid sensitivity. As glucocorticoids do not affect GRgamma expression, relative to total GR, this splice variant is unlikely to influence glucocorticoid treatment response