Pancreatic beta-cell function and type 2 diabetes risk: Quantify the causal effect using a Mendelian randomization approach based on meta-analyses

Yiqing Song, Edwina Yeung, Aiyi Liu, Tyler J. Vanderweele, Liwei Chen, Chen Lu, Chunling Liu, Enrique F. Schisterman, Yi Ning, Cuilin Zhang

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14 Citations (Scopus)


The objective of the study is to quantify the causal effect of β-cell function on type 2 diabetes by minimizing residual confounding and reverse causation. We employed a Mendelian randomization (MR) approach using TCF7L2 variant rs7903146 as an instrument for lifelong levels of β-cell function. We first conducted two sets of meta-analyses to quantify the association of the TCF7L2 variant with the risk of type 2 diabetes among 55 436 cases and 106 020 controls from 66 studies by calculating pooled odds ratio (OR) and to quantify the associations with multiple direct or indirect measures of β-cell function among 35 052 non-diabetic individuals from 31 studies by calculating pooled mean difference. We further applied the method of MR to obtain the causal estimates for the effect of β-cell function on type 2 diabetes risk based on findings from the meta-analyses. The OR [95% confidence interval (CI)] was 0.87 (0.81-0.93) for each five unit increment in homeostasis model assessment of insulin secretion (HOMA-%B) (P = 3.0 × 10-5). In addition, for measures based on intravenous glucose tolerance test, ORs (95% CI) associated with type 2 diabetes risk were 0.24 (0.08-0.74) (P = 0.01) and 0.14 (0.04-0.48) (P = 0.002) for per 1 standard deviation increment in insulin sensitivity index and disposition index, respectively. Findings from the present study lend support to a causal role of pancreatic β-cell function itself in the etiology of type 2 diabetes.
Original languageEnglish
Article numberdds339
Pages (from-to)5010-5018
Number of pages9
JournalHuman Molecular Genetics
Issue number22
Publication statusPublished - 1 Nov 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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