title: Pancreatic beta-cell function and type 2 diabetes risk: quantify the causal effect using a Mendelian randomization approach based on meta-analyses.
abstract: 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.
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Song
authors.forename: Edwina
authors.initials: E
authors.lastname: Yeung
authors.forename: Aiyi
authors.initials: A
authors.lastname: Liu
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Vanderweele
authors.forename: Liwei
authors.initials: L
authors.lastname: Chen
authors.forename: Chen
authors.initials: C
authors.lastname: Lu
authors.forename: Chunling
authors.initials: C
authors.lastname: Liu
authors.forename: Enrique F
authors.initials: EF
authors.lastname: Schisterman
authors.forename: Yi
authors.initials: Y
authors.lastname: Ning
authors.forename: Cuilin
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044382:Population Groups / Q000235:genetics; D012306:Risk; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics
chemical_list: D007328:Insulin; D058118:Transcription Factor 7-Like 2 Protein