Li Naishi, van der Sijde Marijke R, Bakker Stephan J L, Dullaart Robin P F, van der Harst Pim, Gansevoort Ron T, Elbers Clara C, Wijmenga Cisca, Snieder Harold, Hofker Marten H, Fu Jingyuan
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.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Diabetes. 2014 Sep;63(9):3149-58. doi: 10.2337/db13-1800. Epub 2014 Apr 10.
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.
血脂异常与血浆葡萄糖水平升高及胰岛素抵抗（IR）密切相关，全基因组关联研究已确定了95个基因位点，这些位点可解释血脂变异的很大一部分。然而，这些基因位点对与葡萄糖相关性状的影响在很大程度上尚不清楚。我们研究了这些血脂基因位点，并在两个独立队列中集体和单独测试了它们与空腹血糖（FPG）、糖化血红蛋白（HbA1c）及IR的关联：来自生命线队列研究的10995名受试者和来自预防肾和血管终末期疾病（PREVEND）研究的2438名受试者。与血脂异常和葡萄糖性状之间的正相关关系相反，血脂异常的遗传易感性对葡萄糖性状显示出多效性降低作用。具体而言，在调整血脂水平后，与较高甘油三酯水平相关的遗传风险评分与较低的FPG水平（在生命线队列和PREVEND队列中分别为P = 9.6×10⁻¹⁰和P = 0.03）、HbA1c水平（在生命线队列中为P = 4.2×10⁻⁷）及估计IR的稳态模型评估（HOMA）（在PREVEND队列中为P = 6.2×10⁻⁴）相关。在单核苷酸多态性水平上，15个血脂基因位点显示出与葡萄糖性状的多效性关联（P < 0.01），其中8个（CETP、MLXIPL、PLTP、GCKR、APOB、APOE - C1 - C2、CYP7A1和TIMD4）对血脂异常和葡萄糖水平具有相反的等位基因效应方向。我们的研究结果提示脂质与葡萄糖之间存在复杂的遗传调控和代谢相互作用。
