Pleiotropic effects of lipid genes on plasma glucose, HbA1c, and HOMA-IR levels.
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.
Department 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.
Naishi
N
Li
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Marijke R
MR
van der Sijde
Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Stephan J L
SJ
Bakker
Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Robin P F
RP
Dullaart
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Pim
P
van der Harst
Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Ron T
RT
Gansevoort
Department 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.
Clara C
CC
Elbers
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Cisca
C
Wijmenga
Department of Epidemiology, Genetic Epidemiology and Bioinformatics Unit, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Harold
H
Snieder
Department of Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands m.h.hofker@umcg.nl fjingyuan@gmail.com.
Marten H
MH
Hofker
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands m.h.hofker@umcg.nl fjingyuan@gmail.com.
Jingyuan
J
Fu
D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D050171:Dyslipidemias / Q000235:genetics; D005215:Fasting / Q000097:blood; D020022:Genetic Predisposition to Disease; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D008055:Lipids / Q000097:blood / Q000235:genetics*; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D008055:Lipids; D014280:Triglycerides