A combined analysis of 48 type 2 diabetes genetic risk variants shows no discriminative value to predict time to first prescription of a glucose lowering drug in Danish patients with screen detected type 2 diabetes

PLoS One. 2014 Aug 26;9(8):e104837. doi: 10.1371/journal.pone.0104837. eCollection 2014.

Abstract

Objective: To investigate the genetic influence of 48 type 2 diabetes susceptibility variants on disease progression measured as risk of early prescription redemption of glucose lowering drugs in screen-detected patients with type 2 diabetes.

Methods: We studied type 2 diabetes progression in 1,480 patients with screen-detected type 2 diabetes from the ADDITION-Denmark study using information of redeemed prescriptions from the Register of Medicinal Products Statistics from 2001-2009 in Denmark. Patients were cluster randomized by general practitioners, who were randomized to treat type 2 diabetes according to either a conventional or a multifactorial intensive treatment algorithm. We investigated the genetic influence on diabetes progression by constructing a genetic risk score (GRS) of all 48 validated type 2 diabetes susceptibility variants, a GRS of 11 variants linked to β-cell function and a GRS of 3 variants linked to insulin sensitivity and assessed the association between number of risk alleles and time from diagnosis until first redeemed prescription of either any glucose lowering drug or an insulin drug.

Results: The GRS linked to insulin sensitivity only nominally increased the risk of an early prescription redemption with an insulin drug by 39% (HR [95% C.I.] = 1.39 [1.09-1.77], p = 0.009] in patients randomized to the intensive treatment group. Furthermore, the strongest univariate predictors of diabetes progression for the intensive treatment group (measured as time to first insulin) were younger age (HR [95% C.I.] = 0.96 [0.93-0.99]), increased BMI (1.05 [1.01-1.09]), increased HbA1c (1.50 [1.36-.66]), increased TG (1.24 [1.11-1.39]) and reduced fasting serum HDL (0.37 [0.17-0.80]) at baseline. Similar results were obtained for the conventional treatment group.

Conclusion: Higher levels of HbA1c, fasting circulating levels of triglyceride, lower HDL, larger BMI and younger age are significant determinants of early pharmacological intervention in type 2 diabetes. However, known common type 2 diabetes-associated gene variants do not appear to significantly affect disease progression.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Denmark / epidemiology
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Progression
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Resistance / genetics
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Risk Factors

Substances

  • Hypoglycemic Agents

Grants and funding

The study was supported by grants from The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCamp; http://www.lucamp.org) and The Novo Nordisk Foundation Center for Basic Metabolic Research, which is an independent Research Center at the University of Copenhagen and is partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://metabol.ku.dk/). The ADDITION study in Denmark was supported by the National Health Services in the counties of Copenhagen, Aarhus, Ringkøbing, Ribe and South Jutland, together with the Danish Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment, the Diabetes Fund of the National Board of Health, the Danish Medical Research Council, the Aarhus University Research Foundation and the Novo Nordisk Foundation. The ADDITION trial has been given unrestricted grants from Novo Nordisk A/S, Novo Nordisk Scandinavia AB, ASTRA Denmark, Pfizer Denmark, GlaxoSmithKline Pharma Denmark, SERVIER Denmark A/S and HemoCue Denmark A/S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.