Distinct Genetic Backgrounds in Quantitative Traits Preceding Type 2 Diabetes: One Reason for Missing Heritability

Genome-wide association studies (GWAS) have identified variants associated with type 2 diabetes (T2D), but less than five percent of the genetic variance associated with T2D is accounted for in GWAS studies performed using T2D as endpoint. These findings suggest relevance of assessing preceding quantitative traits (QTs) or sub-phenotypes and their respective markers for contributing to the appearance of glycemic thresholds defining T2D. The QTs first appear in gestation and childhood when birth weight and childhood weight gain have an influence on T2D. Changes in fetal growth are associated with metabolic programming for T2D in adulthood. Subsequently gains in body fat leading to obesity, ectopic lipid deposition in liver and muscle, dyslipidemia and hypertension express in the β-cells, hypothalamus, adipocytes, myocytes, liver and kidney, and are associated with worsening insulin resistance and β-cell failure preceding overt T2D. Obesity, an increasingly common trait is associated with gene variants that regulate energy balance but have no association with T2D with few exceptions. For instance, FTO gene variants are associated with early onset of obesity and have also been associated with T2D and hypertension suggesting pleiotropism. Non-alcoholic fatty liver disease (NAFLD) has an independent genetic background and is considered as a new addition to the metabolic syndrome. Association of NAFLD with dyslipidemia, cardiovascular disease and hepatic insulin resistance contributes to progression to T2D. The classic dyslipidemia encountered in insulin resistant states consisting of increased triglyceride, low high-density lipoprotein cholesterol (HDL-C) and molding of triglyceride-containing lipoproteins to form atherogenic LDL particles and dysfunctional HDL particles, has strong environmental and genetic association. In addition evidence is accumulating to show that the abnormal lipoproteins have a direct effect on β-cells leading to failure and possible acceleration of diabetes onset. Consequently known variants affecting either the dyslipidemia or β-cell function have a compound effect on T2D. Like other preceding traits the genetic background for commonly encountered hypertension is independent of diabetes although it remains a predictive trait. However, increasing evidence supports a role for the renin-angiotensin system in causing oxidative stress and insulin resistance. Finally when glucose intolerance has progressed to overt T2D, reversibility is usually no longer possible; therefore recognition of preceding pre-diabetic glycemic thresholds and both their genetic and environmental associations may facilitate and serve as signals for prevention. Thus a better understanding of the sequential expression of the respective QTs and genetic variation affecting their metabolic effects leading to T2D could initiate more effective prevention strategies.