DIABETICMedicine DOI: 10.1111/dme.12588
Editor’s Selection: This Month’s Highlighted Article Hunting for genes in Type 2 diabetes Diabet. Med. 31, 1279 (2014) The first association study carried out between diabetes and variation of DNA was on the insulin gene in 1982. The rationale for picking the insulin gene as a candidate was simple as it was the first relevant hormonal/metabolic gene to be cloned. In one of the early studies, the distribution of insulin genotypes was compared among 56 blood donors and 47 people with Type 2 diabetes and 37 people with Type 1 diabetes [1]. Despite the small numbers studied, it was an inspired choice, as the association between Type 1 diabetes and the insulin gene has stood the test of time, whereas the association with Type 2 diabetes proved to be a false-positive. The hunt for Type 2 diabetes genes has seen many phases beginning with candidate gene studies in which, in the early days, the choice of which gene to study was more like the chances of winning the lottery; the early wins being IRS1, PPARG, KCNJ11 and CAPN10. Family studies (particularly affected sib pairs) were the next flavour of the month and, despite the many putative chromosomal regions identified, the only truly positive result was the identification of TCF7L2, which was identified in a founder population. The game changer came with the mapping of the human genome and microarray-based technology, which enabled between 500 000 and 1 000 000 genetic markers to be studied in large numbers of people, initially in the tens of thousands and subsequently 100 000 and more. In 2008, the field exploded with the arrival of genome-wide association studies, which allowed hypothesis-free testing of the human genome, and within 3 years with the discovery of 60 or more loci robustly associated with Type 2 diabetes, the candidacy of many of which was based on their functional relationship to the b cell. However, the majority of these genetic markers lie outside the body of the genes and, furthermore, because of linkage disequilibrium, the precise genes cannot always be identified with accuracy. The additional and more recent approach is exome (a coding region of the genes) and whole-genome sequencing that is now possible for < $1000 per genome. This allows the hunt for low-frequency variants of more powerful effect than genome-wide association study loci and, importantly, these are likely to have functional consequences. In 2014, by a combination of all methods, >80 genes have been identified, but together they only explain < 15% of the genetic component of Type 2 diabetes.
ª 2014 The Author. Diabetic Medicine ª 2014 Diabetes UK
Cover image: Computer art simulation of the use of microarrays used for genotyping. Credit: Pasieka/Science Photo Library. This week’s Editor’s choice is a paper by Ling and colleagues (page 1350) who use 22 tag SNPs in 11 286 people to show an association between Type 2 diabetes and variation in SLC6A20.
Has this long journey been worthwhile? We have not identified single risk markers that can be used to predict disease, as most genetic markers only increase risk of diabetes by ~2%. In the future, we may see the advent of genetic risk scores, based on genotyping, that integrate information across the whole genome as against using a selective marker set. As of 2014 the ‘at risk’ individual is still best identified by enquiry into positive family history, high risk ethnic group and/or social deprivation, previous history of gestational diabetes and obesity. However, what we are learning by gene hunting is to identify biochemical pathways which, when perturbed, confer protection or increased risk of disease, and some of these are being used to develop novel therapeutic agents for diabetes. G. A. Hitman Editor-in-Chief Diabetic Medicine
Reference 1 Owerbach D, Nerup J. Restriction fragment length polymorphism of the insulin gene in diabetes mellitus. Diabetes 1982; 31: 275–277.
1279
Editor’s Selection: This Month’s Highlighted Article Hunting for genes in Type 2 diabetes Diabet. Med. 31, 1279 (2014) The first association study carried out between diabetes and variation of DNA was on the insulin gene in 1982. The rationale for picking the insulin gene as a candidate was simple as it was the first relevant hormonal/metabolic gene to be cloned. In one of the early studies, the distribution of insulin genotypes was compared among 56 blood donors and 47 people with Type 2 diabetes and 37 people with Type 1 diabetes [1]. Despite the small numbers studied, it was an inspired choice, as the association between Type 1 diabetes and the insulin gene has stood the test of time, whereas the association with Type 2 diabetes proved to be a false-positive. The hunt for Type 2 diabetes genes has seen many phases beginning with candidate gene studies in which, in the early days, the choice of which gene to study was more like the chances of winning the lottery; the early wins being IRS1, PPARG, KCNJ11 and CAPN10. Family studies (particularly affected sib pairs) were the next flavour of the month and, despite the many putative chromosomal regions identified, the only truly positive result was the identification of TCF7L2, which was identified in a founder population. The game changer came with the mapping of the human genome and microarray-based technology, which enabled between 500 000 and 1 000 000 genetic markers to be studied in large numbers of people, initially in the tens of thousands and subsequently 100 000 and more. In 2008, the field exploded with the arrival of genome-wide association studies, which allowed hypothesis-free testing of the human genome, and within 3 years with the discovery of 60 or more loci robustly associated with Type 2 diabetes, the candidacy of many of which was based on their functional relationship to the b cell. However, the majority of these genetic markers lie outside the body of the genes and, furthermore, because of linkage disequilibrium, the precise genes cannot always be identified with accuracy. The additional and more recent approach is exome (a coding region of the genes) and whole-genome sequencing that is now possible for < $1000 per genome. This allows the hunt for low-frequency variants of more powerful effect than genome-wide association study loci and, importantly, these are likely to have functional consequences. In 2014, by a combination of all methods, >80 genes have been identified, but together they only explain < 15% of the genetic component of Type 2 diabetes.
ª 2014 The Author. Diabetic Medicine ª 2014 Diabetes UK
Cover image: Computer art simulation of the use of microarrays used for genotyping. Credit: Pasieka/Science Photo Library. This week’s Editor’s choice is a paper by Ling and colleagues (page 1350) who use 22 tag SNPs in 11 286 people to show an association between Type 2 diabetes and variation in SLC6A20.
Has this long journey been worthwhile? We have not identified single risk markers that can be used to predict disease, as most genetic markers only increase risk of diabetes by ~2%. In the future, we may see the advent of genetic risk scores, based on genotyping, that integrate information across the whole genome as against using a selective marker set. As of 2014 the ‘at risk’ individual is still best identified by enquiry into positive family history, high risk ethnic group and/or social deprivation, previous history of gestational diabetes and obesity. However, what we are learning by gene hunting is to identify biochemical pathways which, when perturbed, confer protection or increased risk of disease, and some of these are being used to develop novel therapeutic agents for diabetes. G. A. Hitman Editor-in-Chief Diabetic Medicine
Reference 1 Owerbach D, Nerup J. Restriction fragment length polymorphism of the insulin gene in diabetes mellitus. Diabetes 1982; 31: 275–277.
1279
