Statistical Genetics of Outcomes and Drug Response in Patients with Type 2 Diabetes.

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

In projects led by collaborators, we have completed the following projects. Diabetes Complications in Individuals of African Ancestry: Led by collaborators at Vanderbilt, we examined why people of African ancestry experience higher rates of diabetes complications. We focused on glucose-6-phosphate dehydrogenase (G6PD) deficiency, common in some African populations, which lowers HbA1c levels by shortening red blood cell lifespan. We identified a specific variant associated with G6PD deficiency that increased the risk of diabetic retinopathy and other complications. Despite lower HbA1c levels, individuals with this variant had higher glucose levels and a higher risk of complications. Our findings suggest that adjusting diabetes management based on glucose levels or genotype-adjusted HbA1c could reduce these risks. Led by Dr. John House, the group has two major subprojects. The first project involves the Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohort and an emerging phenotype in diabetes care and management - hemoglobin glycation index (HGI). HGI captures unexplained variation between point and mean-based measurements of glucose control in diabetics and has been associated with many comorbidities in individuals with diabetes. John has found sex-based genetic associations with HGI (a first), and demonstrated these are different than associations of either fasting plasma glucose or HbA1c levels. John's second project is leading the genetic mapping of resistant hypertension (RHTN) in a meta analysis in The International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). RHTN is defined as blood pressure that remains above 140/90 mmHg despite optimal use of three antihypertensive medications of different classes, including a diuretic1. Such patients are more likely to have a secondary cause and to suffer end-organ damage. John has conducted GWAS for RHTN in ACCORD, and the meta analysis from other participants. This manuscript is nearing completion with unique replicated associations in another independent cohort (TopMED). Additionally, we work with consortia that rely on trials and cohorts with similar outcomes for meta-analyses and replication efforts.