Chapter I. Pathogenesis and Function

Genetics of Type 2 Diabetes: It Matters From Which Parent We Inherit the Risk

Valeriya Lyssenko^1,2, Leif Groop², Rashmi B. Prasad²

Manuscript submitted October 5, 2015; resubmitted December 3, 2015; accepted December 7, 2015.

Keywords: type 2 diabetes, risk allele, parent-of-origin, SNP, single nucleotide polymorphism, heritability

Abstract

Type 2 diabetes (T2D) results from a co-occurrence of genes and environmental factors. There are more than 120 genetic loci suggested to be associated with T2D, or with glucose and insulin levels in European and multi-ethnic populations. Risk of T2D is higher in the offspring if the mother rather than the father has T2D. Genetically, this can be associated with a unique parent-of-origin (PoO) transmission of risk alleles, and it relates to genetic programming during the intrauterine period, resulting in the inability to increase insulin secretion in response to increased demands imposed by insulin resistance later in life. Such PoO transmission is seen for variants in the KLF14, KCNQ1, GRB10, TCF7L2, THADA, and PEG3 genes. Here we describe T2D susceptibility genes associated with defects in insulin secretion, and thereby risk of overt T2D. This review emphasizes the need to consider distorted parental transmission of risk alleles by exploring the genetic risk of T2D.

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