A cautionary tale: the non-causal association between type 2 diabetes risk SNP, rs7756992, and levels of non-coding RNA, CDKAL1-v1

Jonathan M. Locke, Fan Yan Wei, Kazuhito Tomizawa, Michael N. Weedon, Lorna W. Harries

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Aims/hypothesis: Intronic single nucleotide polymorphisms (SNPs) in the CDKAL1 gene are associated with risk of developing type 2 diabetes. A strong correlation between risk alleles and lower levels of the non-coding RNA, CDKAL1-v1, has recently been reported in whole blood extracted from Japanese individuals. We sought to replicate this association in two independent cohorts: one using whole blood from white UK-resident individuals, and one using a collection of human pancreatic islets, a more relevant tissue type to study with respect to the aetiology of diabetes. Methods: Levels of CDKAL1-v1 were measured by real-time PCR using RNA extracted from human whole blood (n = 70) and human pancreatic islets (n = 48). Expression with respect to genotype was then determined. Results: In a simple linear regression model, expression of CDKAL1-v1 was associated with the lead type 2 diabetes-associated SNP, rs7756992, in whole blood and islets. However, these associations were abolished or substantially reduced in multiple regression models taking into account rs9366357 genotype: a moderately linked SNP explaining a much larger amount of the variation in CDKAL1-v1 levels, but not strongly associated with risk of type 2 diabetes. Conclusions/interpretation: Contrary to previous findings, we provide evidence against a role for dysregulated expression of CDKAL1-v1 in mediating the association between intronic SNPs in CDKAL1 and susceptibility to type 2 diabetes. The results of this study illustrate how caution should be exercised when inferring causality from an association between disease-risk genotype and non-coding RNA expression.

Original languageEnglish
Pages (from-to)745-748
Number of pages4
JournalDiabetologia
Volume58
Issue number4
DOIs
Publication statusPublished - Mar 6 2015

Keywords

  • CDKAL1
  • Expression quantitative trait loci
  • Genome-wide association studies
  • Non-coding RNA
  • Type 2 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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