P2Y14基因与广西家族遗传性痛风发病的相关性研究

As a disease with long history, gout is casting more and more intensive pressure on the health and quality of life in pace with the improvement of living level of residents, especially in some impoverished areas of Guangxi, China, where the residents are suffering serious, disabling and familial gout attacks. As an acute arthritis inflammation caused by hyperuricaemia, the mechanism of gout attack remains uncertain. P2Y14 receptor plays a proved important role in the development of many diseases (including some metabolic diseases) by way of its inflammation effect. However, rare researches focus on the relationship between the P2Y14 receptor and gout, especially this purinergic receptor’s contribution to the process from hyperuricaemia to gout attack. Our previous research on some inherited gout families (in those families, more than two members had suffered gout attacks) in some areas of Guangxi found that the expression levels of P2Y14 gene in the patients who suffered gout attack decreased dramatically, compared with the healthy family members. Meanwhile, the differential expression model of P2Y14 gene was not relative with the nationality of family, gender and age of family member. This finding gives an important clue to reveal the mechanism of gout attack. Based on the work above, this study tries to verify the relationship between the expression and regulation of P2Y14 gene and gout attack by employing the inherited gout families of Guangxi and animal models of acute gout, which will give valuable guidelines for the early alert and individual diagnosis of gout.

痛风作为一种古老疾病，随居民生活水平提高，发病率呈明显上升趋势，给居民生活健康及生活质量的负担日益加重。在广西部分贫困地区，因病致贫、致残及家族遗传性发病现象较为突出。作为由高尿酸血症引起的急性关节炎症反应，其确切的发病机理尚不明确。P2Y14受体在多种疾病(含代谢性疾病)的发病过程尤其是炎症反应中起重要作用，但其在高尿酸血症发展为痛风的疾病进程中的作用未见相关报道。我们的前期研究发现，在聚集性发病的家族中，痛风患者P2Y14基因表达量明显低于其家族内健康成员，且跟民族、性别、年龄等未存在明显关联，这为揭示痛风的发病机制提供了重要线索。本研究拟在此基础上，以家族遗传性人群及相应动物模型为载体，系统研究P2Y14基因及其相关调控因素与痛风发病的相关性，以期为痛风的早期预警及个体化诊疗提供基础数据。

2014年广西农村居民患“怪病”事件引起新闻媒体关注，项目研究团队在广西部分贫困地区人群调查发现痛风患病率逐年上升，存在比较特异的危险因素，痛风家族遗传性发病现象较为突出，痛风患者P2Y14基因表达量明显低于家族内健康成员。针对以上情况，项目组扩大人群调查，通过开展广西农村地区痛风与膳食以及相关慢性疾病的关系，P2Y14基因在痛风遗传家族和非遗传家族的表达差异，痛风靶向代谢组学相关标志物筛选等三个方面的研究。发现无痛风石组膳食模式与对照相比，痛风前、痛风后蔬菜水果膳食模式相对于饮酒或高蛋白膳食模式均是保护因素，OR 值分别为 0.6（95%CI，0.4～0.9）和 0.6（95%CI，0.4～0.9）。痛风组患者血脂异常检出率为57.5%，混合型血脂异常检出率为38.3%；超重、肥胖、高尿酸是血脂异常的主要影响因素(OR值分别为2.923、5.479、2.157)。痛风组代谢综合征患病率为33. 25%，显著高于健康对照组，超重和(或)肥胖、高舒张压和甘油三酯升高为痛风的独立危险因素。痛风非遗传家族和遗传家族病例中P2Y14基因表达存在差异，痛风遗传家族病例中表达量更低。通过靶向代谢组学检测发现痛风病例的烟酸和烟酰胺代谢、氧化磷酸化、柠檬酸（TCA）循环、精氨酸生物合成、胰高血糖素信号通路、丙氨酸代谢、天冬氨酸和谷氨酸代谢、丙酮酸代谢、癌症中枢碳代谢、氨基酸的生物合成、肾细胞癌 等10条代谢途径显著富集（P<0.05）。通过以上研究较好的发现了痛风前后膳食模式的变化及与相关慢性病的关系，揭示了痛风遗传家族生物标志物P2Y14基因表达特征，发现了部分痛风特异代谢通路，为有针对开展痛风的预防控制和深入开展痛风特异基因表达与代谢组学基础研究打下了基础。