Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans

Jacob M. Keaton, Chuan Gao, Meijian Guan, Jacklyn N. Hellwege, Nicholette D. Palmer, Jim Pankow, Myriam Fornage, James G. Wilson, Adolfo Correa, Laura J. Rasmussen-Torvik, Jerome I. Rotter, Yii Der I. Chen, Kent D. Taylor, Stephen S. Rich, Lynne E. Wagenknecht, Barry I. Freedman, Maggie C.Y. Ng, Donald W. Bowden

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P < 5 × 10 −8 ) interaction with MTNR1B and joint effects were detected for CMIP intronic SNP rs17197883 (P interaction = 1.43 × 10 −8 ; P joint = 4.70 × 10 −8 ). CMIP variants have been nominally associated with T2D, fasting glucose, and adiponectin in individuals of East Asian ancestry, with high-density lipoprotein, and with waist-to-hip ratio adjusted for body mass index in Europeans. These data support the hypothesis that additional genetic factors contributing to T2D risk, including insulin sensitivity loci, can be identified through interactions with insulin secretion loci.

Original languageEnglish (US)
Pages (from-to)559-570
Number of pages12
JournalGenetic epidemiology
Volume42
Issue number6
DOIs
StatePublished - Sep 1 2018

Fingerprint

African Americans
Type 2 Diabetes Mellitus
Genome
Insulin
Genes
Insulin Resistance
Joints
Single Nucleotide Polymorphism
Glucose
Genetic Loci
Waist-Hip Ratio
Adiponectin
Human Genome
HDL Lipoproteins
Fasting
Body Mass Index
Logistic Models
Genotype

Keywords

  • gene–gene interactions
  • insulin resistance
  • insulin sensitivity

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

Cite this

Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans. / Keaton, Jacob M.; Gao, Chuan; Guan, Meijian; Hellwege, Jacklyn N.; Palmer, Nicholette D.; Pankow, Jim; Fornage, Myriam; Wilson, James G.; Correa, Adolfo; Rasmussen-Torvik, Laura J.; Rotter, Jerome I.; Chen, Yii Der I.; Taylor, Kent D.; Rich, Stephen S.; Wagenknecht, Lynne E.; Freedman, Barry I.; Ng, Maggie C.Y.; Bowden, Donald W.

In: Genetic epidemiology, Vol. 42, No. 6, 01.09.2018, p. 559-570.

Research output: Contribution to journalArticle

Keaton, JM, Gao, C, Guan, M, Hellwege, JN, Palmer, ND, Pankow, J, Fornage, M, Wilson, JG, Correa, A, Rasmussen-Torvik, LJ, Rotter, JI, Chen, YDI, Taylor, KD, Rich, SS, Wagenknecht, LE, Freedman, BI, Ng, MCY & Bowden, DW 2018, 'Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans', Genetic epidemiology, vol. 42, no. 6, pp. 559-570. https://doi.org/10.1002/gepi.22126
Keaton, Jacob M. ; Gao, Chuan ; Guan, Meijian ; Hellwege, Jacklyn N. ; Palmer, Nicholette D. ; Pankow, Jim ; Fornage, Myriam ; Wilson, James G. ; Correa, Adolfo ; Rasmussen-Torvik, Laura J. ; Rotter, Jerome I. ; Chen, Yii Der I. ; Taylor, Kent D. ; Rich, Stephen S. ; Wagenknecht, Lynne E. ; Freedman, Barry I. ; Ng, Maggie C.Y. ; Bowden, Donald W. / Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans. In: Genetic epidemiology. 2018 ; Vol. 42, No. 6. pp. 559-570.
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