HealthDay News — Clusters of type 2 diabetes (T2D) loci and traits have been identified, according to a study published online Sept. 21 in PLOS Medicine.
Miriam S. Udler, M.D., Ph.D., from Massachusetts General Hospital in Boston, and colleagues categorized genetic loci into groups representing likely disease mechanistic pathways. In total, 94 independent T2D genetic loci and 47 diabetes-related traits were investigated.
The researchers identified five robust clusters of T2D loci and traits, each with distinct tissue-specific enhancer enrichment. In two clusters, there were variant-trait associations suggestive of reduced beta cell function but differing based on high versus low proinsulin levels.
Features of insulin resistance were seen in the three other clusters: obesity-mediated (high body mass index [BMI] and waist circumference), “lipodystrophy-like” fat distribution (low BMI, adiponectin, and high-density lipoprotein cholesterol and high triglycerides), and disrupted liver lipid metabolism (low triglycerides). There was an association between increased cluster genetic risk scores and distinct clinical outcomes, including increased blood pressure, coronary artery disease, and stroke.
When assessing the potential clinical impact of these clusters in four other cohorts, the researchers found that individuals with T2D in the top genetic risk score decile for each cluster reproducibly exhibited the predicted cluster-associated phenotypes. Approximately 30 percent of all individuals were assigned to just one cluster top decile.
“Our approach identifies salient T2D genetically anchored and physiologically informed pathways, and supports the use of genetics to deconstruct T2D heterogeneity,” the authors write.