高甘油三酯与原发性痛风发生的遗传易感性研究

Latest prospective study found that high triglycerides are independent risk factors of male primary gout disease. Clinical practice also found that some gout patients have elevated triglycerides before the advent of hyperuricemia, and the serum uric acid level and gout symptoms of them reduced and abated accordingly after they have took lipid-lowering medications. This clinical phenomenon suggests that there is possible pathway of gout development from high triglycerides to high uric acid to gout. A large number of studies have shown that the onset of gout is the outcome of combined action of genetic and environmental factors, and dyslipidemia is one of the inducing factors, but its causal relationship with hyperlipidemia is unknown so far. To this end, based on the literature review and pilot study, we have proposed the hypothesis of an existing pathway of high triglycerides - high uric acid - gout disease. Exon sequencing, high resolution melting curve analysis and pyrosequencing technology are used to detect the gene polymorphisms of APOC3 and ABCG2 in subjects for performing the case-control study of genetic susceptibility of primary gout with high triglycerides and the secondary multicenter validation of them, and the prospective study of high risk group from medical examination. Our aims are to establish gout disease warning model of molecular genetics and to realize primary prevention of gout, to provide new theory and new ideas for molecular mechanism research of gout pathogenesis by exploring the genetic background and environmental factors of inducing patients with gout from high blood triglycerides and screening the genetic molecular markers and high risk factors of gout development.

最新前瞻性研究发现高甘油三酯是男性原发性痛风发病的独立危险因素。临床实践也发现部分痛风患者在高尿酸血症前确实存在甘油三酯升高，降脂药物治疗时其血尿酸水平也相应降低，痛风症状有所缓解，这提示在痛风发病中可能存在高甘油三酯-高尿酸-痛风的发病路径。大量研究表明痛风发病是遗传与环境因素共同作用的结果，血脂异常是其诱发因素之一，但其与高血脂的因果关系不明。为此，本项目基于文献复习和前期研究，提出存在高甘油三酯-高尿酸-痛风发病途径的假说。拟采用外显子测序、高分辨熔解曲线分析和焦磷酸测序技术，检测APOC3和ABCG2基因多态性，进行高甘油三酯原发性痛风遗传易感性的病例对照研究和二次多中心验证以及体检高危人群的前瞻性研究，探索高甘油三酯血症发展为痛风的遗传背景和诱发环境因素，最终筛选遗传分子标志物和高危风险因子，建立痛风发病的遗传学分子预警模型，为痛风一级预防和发病的分子机制研究提供新理论和新思路。

痛风已经成为继高血压、高血糖、高脂血症之后的第四高，流行病学研究显示其发病率已达10%，它可发展导致肢体残疾，给患者和社会都带来了巨大的心理和经济压力。因而痛风的发病机制研究或可为缓解以及预防痛风的发展发生提供支撑，减轻社会和个人的负担，改善人民生活质量。本研究将痛风的其中一个可能的致病途径进行分子生物学水平的探索，揭示甘油三酯在痛风发病当中的作用及影响。经过前期的队列及人群研究，高尿酸血症的人群发生为痛风的风险较高，而高甘油三酯血症和高尿酸血症之间的关系也在本研究中得到进一步的明确，继甘油三酯是高尿酸血症的一个独立危险因素，而且随着甘油三酯水平的升高，高尿酸血症的发病风险也升高。现已完成对APOC3基因和SLC2A9基因等共计35个SNP的突变检测体系的建立（PCR-HRM体系），完成了637例痛风人群的样本分子分型；成功建立新突变基因鉴定体系；完成了对35个SNP位点的病例对照研究，并在甘肃地区汉族人群中进行了易感基因的验证；完成了对体检高危人群共计3884例的三年期的监测随访研究，明确了甘油三酯与高尿酸血症的关系；成功建立了基于PCR-HRM技术以及结合临床资料进行预警的模型，应用于高甘油三酯血症的高危人群的痛风的早期预警和预防。通过该预警模型进行检测和评价，对高危人群进行干预，可为高尿酸血症的发生以及痛风的发展进行预防。