Pleiotropic Effects of Lipid Genes on Plasma Glucose, HbA1c, and HOMA-IR Levels
- Naishi Li1,2,
- Marijke R. van der Sijde3,
- LifeLines Cohort Study Group4,*,
- Stephan J.L. Bakker5,
- Robin P.F. Dullaart6,
- Pim van der Harst7,
- Ron T. Gansevoort5,
- Clara C. Elbers8,9,10,
- Cisca Wijmenga3,
- Harold Snieder11,
- Marten H. Hofker1⇑ and
- Jingyuan Fu3⇑
- 1Department of Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- 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
- 3Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- 4The LifeLines Cohort Study, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- 5Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- 6Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- 7Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- 8Department of Genetics, University of Pennsylvania, School of Medicine, Philadelphia, PA
- 9Department of Medical Genetics, Biomedical Genetics, University Medical Center, Utrecht, the Netherlands
- 10Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
- 11Department of Epidemiology, Genetic Epidemiology and Bioinformatics Unit, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Corresponding authors: Marten H. Hofker, , and Jingyuan Fu, .
N.L., M.R.v.d.S., H.S., M.H.H., and J.F. contributed equally to this study.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1800/-/DC1.
*A list of the members of the LifeLines Cohort Study Group can be found in the APPENDIX.
- Received November 25, 2013.
- Accepted April 4, 2014.
- © 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.