eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
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vol. 8

Room for the candidate gene approach in the genome-wide association era: an example from GSTP1 gene polymorphism

Wojciech Mlynarski

Arch Med Sci 2012; 8, 4: 606-607
Online publish date: 2012/09/10
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The evidence for a role of genetic factors in susceptibility to common, multifactorial type 2 diabetes (T2DM) has been known for decades. It has come from twin studies and the analysis of the relative risk in families with affected individuals. After the first successes in monogenic diabetes were published in the early 1990s, the scientists started their effort to identify genes for complex T2DM. They soon realized that this task was much more difficult to achieve than the routine procedure of cloning genes for Mendelian diseases. This was a consequence of the fact that the phenotype of T2DM was, in addition to environmental factors, the result of the complex interaction between tens or even hundreds of variants with very low relative risk located in different genes. In the early years of the research on the genetics of T2DM two approaches were used. First, the researchers looked for an association between frequent polymorphism in the candidate genes and the disease. The candidate genes were selected based on their role in insulin secretion or insulin action. The basic notion of association studies was that susceptibility alleles should be more prevalent in the cases than in the controls. Those early studies suffered from a lack of statistical power, the positive results were difficult to replicate, and soon it became apparent that our knowledge on the best candidates was not excellent. The second approach, linkage analysis, was associated with the idea of positional cloning that worked well for monogenic diseases. In complex traits, however, with the small sizes of the families, a very modest effect of each gene and difficulties to establish the critical interval, this approach brought a lot of disappointments. In fact the list of T2DM genes successfully identified over the decade beginning in the mid 1990s contained just three positions: PPAR-γ (PPARG) and Kir6.2 (KCNJ11) found by the candidate gene approach and TCF7L2 discovered by the positional cloning technique [1]. The recent years have given us a new tool to discover genetic susceptibility to T2DM, e.g. genome-wide association studies (GWAS). This progress was associated with new technologies that were able to generate a lot of genotyping and the advances in our understanding of the organisation and physiology of human DNA. The scientists have also learned their lessons and they understood that large groups of patients and controls are necessary. The GWAS finally produced...

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