Does summation of alleles account for genetic risk and genotype-phenotype association in Type 2 Diabetes Mellitus?

Abstract

Introduction: Type 2 diabetes (T2DM) is a common complex disorder with a high prevalence in the Maltese population. The aim of this study is to further define the genetic interplay between cognate genes from metabolic and inflammatory pathways on the likelihood of developing T2DM in adulthood and to relate the association of certain genetic profiles with defined biological and clinical end points. Method: Four T2DM cohorts, each with 200 cases were recruited. Anthropometric and biochemical parameters, including serum high-sensitivity C-reactive protein (hsCRP) and HOMA-IR levels were determined, and genotyping of 42 cognate genes carried out. Neonatal cord blood samples were used as the control reference population in this study. The gene expression profile of peripheral blood mononuclear cells from T2DM cases was compared to that of healthy non-diabetic controls using an IIlumina HT-12® microarray platform. Results: Ten polymorphisms in metabolic/inflammatory pathways showed significant association with T2DM. Three loci showed significant association with lipid profile, body weight, hsCRP and HOMA-IR levels. hsCRP levels demonstrated a strong positive correlation with body mass index. Genetic score analysis showed that combining multiple genetic markers results in higher relative risks. Transcriptome analysis of peripheral blood mononuclear cells identifies up regulation of diverse mRNAs linked to leukocyte activation, adhesion, migration, inflammation and oxidative damage. Network analysis identified diabetic nephropathy and renal injury as the indirect consequences of the observed gene expression changes in T2DM. Conclusion: A panel of ten candidate genes has consistently demonstrated significant association with type 2 diabetes in the Maltese population. These gene variants serve functional roles in inflammation and adipose tissue function. A recruited cohort of untreated newly-diagnosed T2DM serves to identify and explore genotype-phenotype association. The strong effect sizes of these alleles could be used to develop personal genetic susceptibility profiles for T2DM leading to personalization of care and prevention of chronic complications. Changes in the leukocyte transcriptome, such as overexpression of defensin and versican mRNA in T2DM are potential biomarkers of incipient diabetic nephropathy and microvascular damage. KeyWords: T2DM - type 2 diabetes mellitus hsCRP - high-sensitivity C-Reactive protein HOMA-IR - homeostatic model assessment of insulin resistance mRNA - messenger ribonucleic acid