The Hunt for Low-Frequency Alleles Predisposing to Type 2 Diabetes and Related Cardiovascular Risk Factors
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DIABETES + INSULIN RESISTANCE (M RUTTER, SECTION EDITOR)
The Hunt for Low-Frequency Alleles Predisposing to Type 2 Diabetes and Related Cardiovascular Risk Factors Lorena Boquete Vilariño 1 & Timothy M. Frayling 1
Published online: 14 September 2015 # Springer Science+Business Media New York 2015
Abstract Research into the genetic basis of cardiovascularrelated diseases is moving at an extremely fast pace. Developments in technology such as whole-genome sequencing and massive resources of DNA collected from hundreds of thousands of people mean scientists have an unprecedented ability to discover the genetic variation that predisposes to disease. Before 2007, very little was known about the variation in the human DNA sequence and its influence on common diseases. We now know of hundreds of common variants that influence LDL cholesterol levels, type 2 diabetes, hypertension and heart disease to name a few. Attention has now turned to the discovery of the genetic variants that occur in between 1 in 20 and 1 in 1000 individuals. These variants are unlikely to cause disease in the same way that mutations in some genes cause a monogenic disorder with a particular pattern of inheritance. But variants in this frequency range will shed light on biological mechanisms of disease. In this review, we focus on these variants and discuss how a range of study designs have identified low-frequency genetic variants with stronger predisposing effects on type 2 diabetes and related traits than common genetic variants.
Keywords Type 2 diabetes . Genetics . Genetic variants . Single nucleotide polymorphism
This article is part of the Topical Collection on Diabetes + Insulin Resistance * Timothy M. Frayling [email protected] 1
University of Exeter Medical School, University of Exeter, RILD building, Barrack Road, Exeter EX2 5DW, UK
Introduction Diabetes is one of the major risk factors for cardiovascular disease. The obesogenic environment, resulting in a much higher prevalence of obesity today than in previous generations, is the primary cause of the higher prevalence of type 2 diabetes today. However, two individuals with the same BMI can have very different risks of type 2 diabetes [1], and genetic factors affecting insulin secretion, insulin resistance and body fat distribution play a role. Since 2007, genome-wide association studies (GWAS) have identified more than 100 common genetic variants associated with type 2 diabetes and related glycaemic traits [2, 3]. Some of these common variant associations have provided first steps towards an increased biological understanding of diabetes and examples have been discussed in several previous reviews [4–8]. These common variants tend to have relatively small effect sizes on individual risk and cumulatively only explain a small fraction of the heritable component to type 2 diabetes. Here, we review the most recent findings, where studies using whole-genome sequencing, whole exome sequencing, exome-based micro arrays and other approaches have started to uncover variants with l
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