瘦素基因G2548A多态性及环境因素与胆囊胆固醇结石关联性研究

目的评估瘦素基因（LEP）G2548A单核苷酸多态性（SNP）及环境因素与胆囊胆固醇结石发病危险的关联性，同时探究该多态性位点与环境因素对胆囊胆固醇结石的发生是否存在交互作用。方法收集符合条件的胆囊胆固醇结石患者200例进行1∶2匹配的病例对照研究（对照组400例）。应用高分辨率熔解曲线（high-resolution melting, HRM）技术作基因分型检测并对结果进行测序验证，采用多因素分析探索基因多态性及血清瘦素水平与胆囊胆固醇结石的关联性。采用多因子降维法（multifactor dimensionality reduction, MDR）探索基因与环境因素的交互作用对胆囊胆固醇结石发病的影响。结果通过HRM基因分型检测，共得到LEP G2548A位点３种基因型，分别为野生型GG（52例），突变杂合型GA（192例）和突变纯合型AA（356例）。该SNP位点在对照组中的基因型分布均符合Hardy-Weinberg 遗传平衡（P>0.05）。LEP G2548A位点AA基因型携带者血清瘦素水平高于GA/GG基因型携带者，差异有统计学意义（H=6.83, P<0.05）。多因素条件logistic 回归分析结果显示，在调整年龄、性别以及其他影响因素后，胆固醇结石危险因素是：血清高瘦素水平〔标准偏回归系数（β）=0.781，比值比（OR=5.012，95%可信区间（95%CI）：3.248~7.734〕、LEP G2548A突变纯合子AA基因型（β=0.527，OR=2.292，95%CI：1.012~5.193）、胆结石家族史（β=0.267，OR=2.984，95%CI：1.329~6.700）、高收缩压（β=0.239，OR=1.927，95%CI：1.140~3.255）以及吸烟（β=0.236，OR=1.717，95%CI：1.006~2.928）；而保护因素是：饮浓茶习惯（β=-0.477，OR=0.552，95%CI：0.336~0.907）与坚持锻炼（β=-0.252，OR=0.591，95%CI：0.395~0.882）。MDR分析结果显示，饮茶习惯- LEP G2548A多态性-血清瘦素水平组合为最优基因-环境交互作用模型。结论LEP G2548A位点AA基因型可能通过影响血清瘦素水平增加发生胆囊胆固醇结石风险，而携带AA 基因型且有饮淡茶习惯的血清高瘦素水平者对胆囊胆固醇结石可能更加易感。

英文摘要:

Objective To determine the associations of single nucleotide polymorphism (SNP) in leptin (LEP) genes and environmental factors with cholesterol gallstone in southeast Han populations. Methods A 1∶2 matched case-control study was conducted involving 200 patients with cholesterol gallstone. Genotyping of the SNP was examined on the LightCycler480 PCR platform using in-house high resolution melting (HRM) approaches. Detection correctness was validated through direct sequencing. Multifactor dimensionality reduction (MDR) analysis was applied to examine the effects of potential gene-environment interactions. Results Three genotypes of LEP G2548A were obtained by HRM genotyping, including 52 cases of GG wild type, 192 cases of GA mutant heterozygosity and 356 cases of AA mutation homozygous type. The genotype distribution of the SNP locus in the control group was in line with the Hardy-Weinberg genetic balance (P>0.05). The AA genotype carriers of LEP G2548A had significantly higher serum leptin than the GA/GG genotype carriers (H=6.83, P<0.05). The conditional logistic regression revealed that high serum leptin 〔odds ratio (OR)=5.012, 95% confidence interval (CI): 3.248-7.734〕, AA genotype of LEP G2548A site (OR=2.292, 95%CI: 1.012-5.193), family history of gallstones (OR=2.984, 95%CI: 1.329-6.700), high SBP (OR=1.927, 95%CI: 1.140-3.255) and smoking (OR=1.717, 95%CI: 1.006-2.928) were predictors of cholesterol gallstone. However, regular drinking of strong

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