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Diabetes. 2014 Sep;63(9):3149-58. doi: 10.2337/db13-1800. Epub 2014 Apr 10.

Pleiotropic Effects of Lipid Genes on Plasma Glucose, HbA1c, and HOMA-IR Levels.

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  • 1Department of Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.
  • 2Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • 3Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • 4Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • 5Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • 6Department of Genetics, University of Pennsylvania, School of Medicine, Philadelphia, PA Department of Medical Genetics, Biomedical Genetics, University Medical Center, Utrecht, the Netherlands Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 7Department of Epidemiology, Genetic Epidemiology and Bioinformatics Unit, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • 8Department of Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands m.h.hofker@umcg.nl fjingyuan@gmail.com.
  • 9Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands m.h.hofker@umcg.nl fjingyuan@gmail.com.

Abstract

Dyslipidemia is strongly associated with raised plasma glucose levels and insulin resistance (IR), and genome-wide association studies have identified 95 loci that explain a substantial proportion of the variance in blood lipids. However, the loci's effects on glucose-related traits are largely unknown. We have studied these lipid loci and tested their association collectively and individually with fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and IR in two independent cohorts: 10,995 subjects from LifeLines Cohort Study and 2,438 subjects from Prevention of Renal and Vascular Endstage Disease (PREVEND) study. In contrast to the positive relationship between dyslipidemia and glucose traits, the genetic predisposition to dyslipidemia showed a pleiotropic lowering effect on glucose traits. Specifically, the genetic risk score related to higher triglyceride level was correlated with lower levels of FPG (P = 9.6 × 10(-10) and P = 0.03 in LifeLines and PREVEND, respectively), HbA1c (P = 4.2 × 10(-7) in LifeLines), and HOMA of estimated IR (P = 6.2 × 10(-4) in PREVEND), after adjusting for blood lipid levels. At the single nucleotide polymorphism level, 15 lipid loci showed a pleiotropic association with glucose traits (P < 0.01), of which eight (CETP, MLXIPL, PLTP, GCKR, APOB, APOE-C1-C2, CYP7A1, and TIMD4) had opposite allelic directions of effect on dyslipidemia and glucose levels. Our findings suggest a complex genetic regulation and metabolic interplay between lipids and glucose.

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

PMID:
24722249
[PubMed - in process]
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