Pleiotropic effects of lipid genes on plasma glucose, HbA1c and HOMA-IR levels

  1. Jingyuan Fu3,$
  1. 1University of Groningen, University Medical Center Groningen, Department of Molecular Genetics, Groningen, the Netherlands
  2. 2Department 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
  3. 3University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
  4. 4University of Groningen, University Medical Center Groningen, The LifeLines Cohort Study, Groningen, The Netherlands
  5. 5University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Division of Nephrology, the Netherlands
  6. 6University of Groningen, University Medical Center Groningen, Department of Endocrinology, Groningen, the Netherlands
  7. 7 University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
  8. 8Department of Genetics, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA
  9. 9Department of Medical Genetics, Biomedical Genetics, University Medical Center, Utrecht, the Netherlands
  10. 10Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
  11. 11University of Groningen, University Medical Center Groningen, Department of Epidemiology, Genetic Epidemiology & Bioinformatics Unit, Groningen, the Netherlands
  1. $Corresponding author: Marten H. Hofker, E-mail: M.H.Hofker{at}umcg.nl and Jingyuan Fu, E-mail: fjingyuan{at}gmail.com

Abstract

Dyslipidemia is strongly associated with raised plasma glucose levels and insulin resistance, 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 insulin resistance in two independent cohorts: 10,995 subjects from LifeLines and 2,438 subjects from PREVEND. 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=9.6x10-10 and P=0.03 in Lifelines and PREVEND, respectively), HbA1c (P=4.2x10-7 in LifeLines) and HOMA-IR (P=6.2x10-4 in PREVEND), after adjusting for blood lipid levels. At the single SNP 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.

Footnotes

  • These authors contributed equally

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  1. Diabetes
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