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Testing the Gene or Testing a Variant?

The Case of TCF7L2

¹ Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California
² Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
³ Department of Medicine, University of California, Los Angeles, Los Angeles, California
⁴ Department of Pediatrics, University of California, Los Angeles, Los Angeles, California
⁵ Department of Human Genetics, University of California, Los Angeles, Los Angeles, California

Address correspondence and reprint requests to Mark O. Goodarzi, MD, PhD, Cedars-Sinai Medical Center, Division of Endocrinology, Diabetes and Metabolism, 8700 Beverly Blvd., Becker B-131, Los Angeles, CA 90048. E-mail: mark.goodarzi@cshs.org

Abbreviations: LD, linkage disequilibrium; MAF, minor allele frequency; SNP, single nucleotide polymorphism

The first 20% of the full text of this article appears below.

Given that susceptibility to type 2 diabetes appears in large measure due to genetic makeup, investigators have spent years of effort trying to identify genes that influence type 2 diabetes risk. An important goal of gene identification is to improve our understanding of the pathophysiology of diabetes, leading to new measures of diagnosis, prevention, and treatment. A diabetes gene is considered identified when variants in that gene (more specifically, variation in DNA sequence between individuals) are found to be associated with type 2 diabetes and/or its pathophysiologic abnormalities such as insulin resistance or secretion.

TCF7L2 (transcription factor 7-like 2) was identified as a gene for type 2 diabetes in 2006 (1). Notably, its effect on diabetes (relative risk 1.5–1.6) is substantially larger than previously established diabetes genes (e.g., peroxisome proliferator–activated receptor [PPARG] and ß-cell inwardly rectifying K⁺ channel KIR6.2 [KCNJ11], relative risk 1.2 each). Most studies of TCF7L2 have focused on the genetic variants that were implicated in the original report (1), largely ignoring the remainder of the gene. In this issue of Diabetes, investigators took the alternative approach of examining variants across the entire gene, which allowed them to discover a completely novel variant in TCF7L2 that affects diabetes risk (2). We believe this approach to genetic association studies is of great merit, as described below.

In the report that first identified TCF7L2 as a diabetes gene, a microsatellite (DG10S478) was highly associated with type 2 diabetes (in three Caucasian cohorts), as were five single nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD). Of those five SNPs, two (rs12255372 and rs7903146) were identified as most strongly associated with type 2 diabetes; subsequent reports . . . [Full Text of this Article]

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