中国汉族人群近日钟基因与高脂血症的关联

Association of Polymorphisms of Circadian Gene,Clock and Clif,with Hyperlipidemia in Chinese Han descent

目的针对中国汉族人群,开展Clock、Clif节律基因多态性与高脂血症间关联研究,以进一步探讨近日节律对高脂血症的影响与作用,为基于易感基因的靶向药物治疗提供新思路。方法采用病例-对照关联分析(casecontrol association study),以明确诊断的205例高脂血症患者和281例健康对照者为研究对象,研究节律基因相关的基因位点与高脂血症易感性、疾病严重程度等临床表型之间的关系并阐明其机制。根据选取的节律基因位点Clock(rs3840267,rs3749474,rs10529257)和Clif(rs2289709),确定相关位点的基因型,采用遗传统计学分析确定基因型与临床表型之间的关联性。结果通过Clock、Clif基因多态性与高脂血症的病例-对照分析,发现Clock rs10529257等位基因显著增加了高脂血症的患病风险(8.51%vs 13.95%,Palleo=0.003,ORalleo=0.529,95%CI=0.346,0.809);Clock rs3840267、rs3749474和Clif rs2289709在病例组和对照组中无显著差异(P>0.05)。通过高脂血症分型后病例-对照分析,发现Clock rs10529257在Ⅳ型高脂蛋白血症亚型病例组和对照组之间有显著差异(9.72%vs 13.95%,Palleo-IV=0.043,ORalleo-IV=0.525,95%CI=0.278,0.991);Clif rs2289709在Ⅱb型高脂蛋白血症亚型病例组和对照组之间亦有显著差异(19.23%vs 8.72%,Palleo-IIb=4.738×10-4,ORalleo-IIb=2.959,95%CI=1.645,5.322)。通过病例组中总胆固醇、甘油三酯、低密度脂蛋白胆固醇水平与两个阳性位点Clock rs10529257、Clif rs2289709不同基因型比较发现,Clock rs10529257中-/A杂合子携带者与A/A纯合子基因型携带者的甘油三酯水平存在显著差异[(1.27±0.69)vs(1.76±1.22),P=0.01];Clif rs2289709中A/G杂合子携带者与G/G纯合子基因型携带者的甘油三酯、低密度脂蛋白分别存在显著差异[(2.31±1.81)vs(1.11±0.32),P=2.33×10-8;(2.83±0.98)vs(1.63±0.69),P=5.83×10-15)。结论本研究结果发现,节律基因Clock、Clif可能为中国汉族人群高脂血症疾病的相关基因。

The Clock gene is a central component of an endogenous circadian rhythm and Clif is a newly discovered circadian gene. Both of them not only maintain the circadian rhythm of ceils but also regulate lipid and glucose metabolism in peripheral organs. The purpose of this study was to determine to whether genetic variations （single nucleotide poly- morphisms - SNPs） in the Clock and/or Clif genes were associated with hyperlipidemia in Chinese Han descent. Methods The Clock variants （rs3840267, rs3749474, rs1052925）, and the Clif variant （rs2289709） were analyzed in 205 patients with hyperlipidemia and 281 healthy controls by sequence-specific primer -polymerase chain reaction （SSP-PCR）. Results The Clock variant （rs1052925） shows （showed） significant association to hyperlipidemia （Palleo = 0. 003, ORalleo= 0. 529）. We also found correlations between the Clock （rs1052925）, the Clif （rs2289709） and types of hyperlipidemia （Palleo =0. 043, ORalleo=0. 525 ; Palleo llb =4. 738× 10^-4 , ORalleo llb = 2. 959）. In addition, the Clock （rs1052925）, the level of triglycerides in carriers of A/- heterozygote, was significantly different from carriers of A/A heterozygote （1. 271±0.69 vs. 1.76±1.22; P=0.01）. The Clif （rs2289709）, the level of triglycerides and LDL cholesterol in carriers of G/ A heterozygote was significantly different from carriers of G/G heterozygote （2.31±1.81 vs. 1.11±0.32; P= 2.33×10^-8 ; 2.83±0.98 vs. 1. 630±0.69; P=5.83× 10^-1 , respectively）. Conclusion Our findings indicate that Clock /Clif genetic variations might be associated with hyperlipidemia.