原发性高尿酸血症相关基因和环境因素及与代谢性疾病关系的研究
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摘要
尿酸是人体内嘌呤代谢的终产物,大部分嘌呤在肝脏通过肝原酶、尿酸酶氧化代谢后变成尿酸,再由肾脏和肠道排出。正常情况下,体内的尿酸处于平衡状态,但如果体内尿酸生成过多或排泄减少,导致体内尿酸潴留过多,血中尿酸值升高,尿酸代谢失去平衡就会引起高尿酸血症。原发性高尿酸血症为细胞外液的尿酸盐呈超饱和状态,是以体内嘌呤代谢紊乱、尿酸增高为特征的疾病,可引起痛风和尿酸性肾病。到目前为止,原发性高尿酸血症的确切发生机制未完全清楚,现场和遗传流行病学研究证实与环境和遗传因素相关,是由基因和环境综合作用所致。从遗传学角度来讲高尿酸血症并不符合经典的孟德尔单基因遗传规律,属多基因遗传病或人类复杂疾病,其主要遗传机制有两个方面:一方面主要与常染色体显性遗传导致尿酸清除率过低,尿酸排泄减少有关,约占原发性高尿酸血症的90%。报道的与之相关基因主要包括:尿酸转运蛋白基因,Leptin基因、ApoE基因、尿调素(UMOD)基因等。另外与嘌呤代谢过程中某些酶基因突变、酶活性改变导致尿酸生成过多有关,报道的主要有磷酸核糖焦磷酸合成酶(PRPP)活性增加、次黄嘌呤-鸟嘌呤磷核糖转移酶(HGPRT)部分缺陷、亚甲基四氢叶酸还原酶(MTHFR)缺陷、β3-肾上腺素受体(β3-AR)缺陷、血管紧张素转换酶基因(ACE)、血管紧张素原基因(AGT)等等改变,导致血尿酸升高,约占原发性高尿酸血症的10%。环境因素主要涉及到生活方式、饮食习惯、文化与职业等方面,如活动较少、高嘌呤、高蛋白、高热量饮食及酗酒等都为原发性高尿酸血症的诱发因素。近年来随着人们生活水平的提高和饮食结构的改变,原发性高尿酸血症的发病率明显增高,且与肥胖、糖尿病(DM)、血脂异常、高血压、心血管疾病及胰岛素抵抗(IR)、代谢综合症等代谢性疾病密切相关。
新疆为多民族聚居区,汉族和维吾尔族为主要的两个民族,有着不同的遗传背景,而且生活方式和饮食习惯也不同,因此为了了解新疆乌鲁木齐市汉族和维吾尔族的尿酸水平和原发性高尿酸血症的患病现况以及相关环境危险因素,本研究在现况调查的基础上,应用分子生物学技术研究高尿酸血症相关基因多态性在原发性高尿酸血症发病机制中的作用,并分析原发性高尿酸血症与代谢性疾病之间的关系。
研究目的
1了解新疆乌鲁木齐市汉族和维吾尔族居民尿酸水平和原发性高尿酸血症的患病现况。
2分析原发性高尿酸血症相关基因单核苷酸多态性。
3揭示原发性高尿酸血症的相关环境和遗传因素。
4探讨原发性高尿酸血症与其它代谢性疾病的关系。
研究内容与方法
本研究首先对新疆乌鲁木齐市汉族和维吾尔族健康人群进行了现况调查,了解被调查人群的尿酸水平和原发性高尿酸血症的患病现况,同时利用等位基因特异性多重PCR技术(Multi-ARMS PCR)、聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)等技术研究尿酸清除率过低导致尿酸排泄减少相关基因多态性,如ApoE基因、Leptin基因;以及利用基因芯片方法研究嘌呤代谢过程中某些酶基因突变如:亚甲基四氢叶酸还原酶(MTHFR)缺陷、β3-肾上腺素受体基因(β3-AR)缺陷、血管紧张素转换酶基因(ACE)、血管紧张素原基因(AGT)变异导致尿酸生成过多相关基因多态性。并且对两个民族被调查人群进行面对面的问卷调查,了解两个民族生活方式、饮食习惯、现患疾病和家族史等可能与原发性高尿酸血症相关环境的因素,并分析高尿酸血症与相关代谢性疾病之间的关系。探索原发性高尿酸血症相关的基因和环境因素及与代谢性疾病之间的关系。揭示遗传和环境因素在新疆维、汉两个民族原发性高尿酸血症发生发展中的作用。
结果
1汉族和维吾尔族血尿酸水平及原发性高尿酸血症患病现况
(1)汉族血尿酸水平高于维吾尔族,男性高于女性,差异有统计学意义(P＜0.05)。(2)原发性高尿酸血症汉族男女平均患病年龄分别为38.01岁和42.07岁,维吾尔族男性为44.92岁,女性为50.00岁。汉族原发性高尿酸血症检出率高于维吾尔族,男性均高于女性,差异有统计学意义(P＜0.05)。(3)汉族和维吾尔族不同年龄段尿酸值差异有统计学意义(P＜0.05)。趋势性检验发现汉族男性血尿酸水平随年龄增长而变化趋势不明显,而维吾尔族男性和两个民族女性随着年龄的增长,尿酸水平逐渐升高(P＜0.05)。(4)趋势性检验发现汉族男性随着年龄的增长原发性高尿酸血症的检出率有降低的趋势(P＜0.05)。维吾尔族男性的检出率变化趋势不明显,各年龄段差异无统计学意义(P＞0.05)。而汉族和维吾尔族女性随着年龄的增高,原发性高尿酸血症的检出率增高,各年龄段之间差异均有统计学意义(P＜0.05)。
2原发性高尿酸血症相关基因单核苷酸多态性(SNP)
2.1尿酸排泄减少型原发性高尿酸血症相关基因SNP
2.1.1载脂蛋白E基因(ApoE)SNP与原发性高尿酸血症相关性
(1)两个民族比较,汉族和维吾尔族ApoE基因型分布差异有统计学意义(P＜0.05),ApoE 3/3为占主导的基因型,汉族E 2/2基因频率高于E 4/4,而维吾尔族正好相反。(2)新疆汉族和维吾尔族ApoEε2、ε3、ε4的等位基因频率均以ε3最常见,ε4及ε2等位发生频率较低,同一般人群中ApoE的分布特点相符。与正常组相比高尿酸组ε2等位基因频率降低,而ε4等位基因频率升高,提示ε4等位基因可能是新疆汉族和维吾尔族原发性高尿酸血症的遗传易感基因。(3)汉族和维吾尔族ApoE各等位基因的携带者SAU和生化指标变化不同,表现出民族之间的差异。(4)除HDL-C外,两个民族ApoE各等位基因携带者,高尿酸组SUA和其它的各生化指标均高于正常组,但是尿酸和血脂代谢仍然有一定的差别。(5)新疆汉族ApoEε4基因型出现频率接近亚洲人,而维吾尔族接近欧美人。汉族和维吾尔族研究人群ε2等位基因频率均高于ε4,而且ε2等位基因频率高于国内其它研究结果。
2.1.2 Leptin基因G2548A多态性与原发性高尿酸血症相关性
(1)汉族所有检测人群Leptin基因2548 G→A变异,AA、AG、GG等位基因频率分别为0.541、0.374和0.085,维吾尔族分别为0.497、0.415和0.088。(2)汉族和维吾尔族Leptin基因G2548A变异高尿酸组AA等位基因频率均高于正常组,AG和GG等位基因频率均低于正常组。(3)汉族AA加AG基因型患原发性高尿酸血症的风险是GG基因型的0.625倍(OR=0.625;95%CI=0.285～1.368),维吾尔族AA加AG基因型患原发性高尿酸血症的风险是GG基因型的0.478倍(OR=0.478;95%I=0.103～2.213)。(4)高尿酸组与正常组相比,汉族AA+AG基因型,除了血清Leptin以及BUN以外的各项指标,高尿酸组均大于正常组(P＜0.05),而GG基因型,除了尿酸之间差异有统计学意义外,其它各项指标差异无统计学意义(P＞0.05)。维吾尔族AA+AG基因型除了血清Leptin与血糖以外的各项指标,高尿酸组均大于正常组(P＜0.05),推测A等位基因可能与高尿酸血症的发生以及各种脂代谢紊乱相关联。
2.2尿酸生成增多型原发性高尿酸血症相关基因SNP
(1)原发性高尿酸血症组和正常组MTHFR基因C/C、C/T、T/T基因型频率总体分布的差异无统计学意义,但原发性高尿酸血症组T等位基因的分布频率高于正常组(P＜0.05),并使患病的危险性增加为C等位基因患病危险性的1.617倍。(2)各基因型尿酸的水平的方差分析显示,C/C、C/T、T/T基因型的尿酸依次升高,分别为392.77μmol/L、411.28μmol/L和458.69μmol/L,其中T/T基因型与C/C基因型尿酸水平差异有统计学意义(P＜0.05)。其余各变量WHR、SBP、DBP、TC、LDL-C、VLDL-C也有依次升高的趋势,而BUN、CREA以及HDL-C有依次降低的趋势,但是统计学检验各基因型之间差异无统计学意义(P＞0.05)。结果提示,MTHFR基因T等位基因可能是男性原发性高尿酸血症的危险因素。(3)β3-AR基因64位点T/A多态性基因型和等位基因型在原发性高尿酸血症组和正常组的分布差异无统计学意义(P＞0.05)。(4)本研究中未能发现原发性高尿酸血症与ACE基因I/D多态性和AGT基因T704C多态性存在关联。
3原发性高尿酸血症相关基因与环境因素及与代谢性疾病关系
(1)Logistic回归分析发现推测爱吃精瘦肉和爱喝乳制品者为高尿酸血症的保护因素;汉族罹患原发性高尿酸血症的危险是维吾尔族的2.697倍,而高甘油三脂血症、胰岛素抵抗指数、高胆固醇血症、腰臀比、Leptin浓度、职业(商业)、高血压、喜欢喝肉汤鸡汤等可能是原发性高尿酸血症的危险因素。(2)相关性分析发现汉族人群与SUA相关的生化指标主要有FINS,DBP、SBP、BMI、WHR、SCR、BUN、TG、HDL-C、LDL-C和VLDC-C。维吾尔族SUA主要与AGE、DBP、SBP、BMI、WHR、SCR、TG、TC、HDL、LDL-C和VLDC-C相关(P＜0.05)。(3)汉族高尿酸组各项指标除了HDL-C低于正常组,FBS两组相近外,其它指标均高于正常组;而维吾尔族各项指标除了HDL-C外,高尿酸组SUA、SBP、DBP、Serum leptin、BMI、WHR、FINS、SCR、TG、VLDL-C均高于正常组(P＜0.05)。同时也各生化指标在两个民族之间变化也有各自的特点。(4)随着尿酸水平的升高,汉族除了血清Leptin和FBS,维吾尔族除了Leptin和FBS、BUN没有表现出明显的规律,HDL-C随着尿酸的升高而降低,其它指标均随着尿酸的升高而升高,各尿酸水平组之间差异有统计学意义(P＜0.05)。(5)原发性高尿酸血症组与正常组相比,汉族肥胖、高甘油三脂血症、高甘油合并高胆固醇血症、低高密度脂蛋白血症及代谢综合症检出率均升高(P＜0.05),罹患上述疾病的危险分别是正常组的2.362、3.812、3.163、0.924和4.971倍。而维吾尔族肥胖、高血压、高甘油三脂血症、高胆固醇血症、高甘油合并高胆固醇血症、代谢综合症检出率均升高(P＜0.05),罹患上述疾病的危险分别是正常组的3.626、2.593、1.905、3.403、4.016、2.575倍。代谢综合征、高甘油三脂血症、高甘油合并高胆固醇血症对汉族高尿酸血症的影响较大。高胆固醇血症肥胖、高甘油三脂血症对维吾尔族高尿酸血症的影响较大。
结论
原发性高尿酸血症在新疆表现出民族和性别之间的差异,汉族血尿酸平均水平和高尿酸血症的检出率高于维吾尔族,男性高于女性。Logistic回归分析发现喜欢吃精瘦肉类和乳制品为高尿酸血症的保护因素,而患有高甘油三脂血症、胰岛素抵抗、高胆固醇血症、从事商业工作、高血压、喜欢喝肉汤鸡汤者以腰臀比较大、血清Leptin浓度较高可能是原发性高尿酸血症的危险因素。基因多态性研究发现ApoEε4等位基因、Leptin基因A等位基因、MTHFR基因T等位基因可能是原发性高尿酸血症的危险因素,尚不能说明β3-AR基因、ACE基因I/D多态性和AGT基因T704C多态性与高尿酸血症之间存在关联。同时高尿酸血症与BMI、肥胖、高血压、高甘油三脂血症、低高密度脂蛋白血症、代谢综合症等代谢性疾病相关,并且是代谢综合症的一个的组成成分。综上所述,原发性高尿酸血症是一种复杂性疾病,由基因和环境因素所致,而且与代谢性疾病密切相关。
Uric acid an end product of purine metabolism, is degraded in most mammals by the hepatic enayme and urate oxidase (uricase), to allantion which freely in the urine. Usually, the pool size of urate for an adult male is about 1,200 mg, and 700 mg urate is produced daily. The production is balanced by the excretion of urate into urine (500 mg) and intestine (200 mg). The hyperuricemia occurs if this balance is disturbed, Some human subjects have various abnormalities in urate metabolism. According to the mechanisms, hyperuricemia is classified into two different types, overproduction and underexcretion. Overproduction is caused by some enzymatic abnormalities, such as PRPP synthetase superactivity, HPRT deficiency et al .Study show that it still can be caused by genetic defects, such as the superactivity of Angiotensin Converting Enzyme Gene (ACE), angiotensin-coverting enzyme gene (AGT),Beta 3-adrenergic receptor gene, Methylenetetrahydrofolate reductase, MTHFR (C677T) gene defects. Underexcretion of urate is caused by renal insufficiency and genetic defects, for example. The Human Urate Transporter gene, ApoE gene, Leptin gene were cinsidered the correlation with hyperyricemia.
Many studies showed that primary hyperuricemia was a complx genetic traits caused by mutiple genetic and environmental components. The correlated environmental factors include diet, life style, culture, occupation and economy level et al. A number of studies have shown that serum uric acid (SUA) plays a role in the development of cardiovascular morbidity in the general population, as well as in patients with hypertension, type II diabetes, and cardiac or vascular diseases.
Many ethnicities were lived in XingJiang, and the Han and Uygur ethnicity were the main in all population,they came from different genetic background ,different life mode and diet habit. In the present study, we investigated uria acid level and the prevalence of primary hyperuricemia in Han and Uygur ethenicity. Furthermore used PCR and gene chip technic to clarify the relationship between gene polymorphism and primary hyperuricemia in Han and Uygur ethnicity.Finaly via Logistic regression to found the related factors that related genetical and environment and to determine wither primary hyperuricemia corrected with other metabolic diseases.
Objectives:
1. Rreveal the uric acid level of Han and Uygur ethnicity and find the prevalence and the rule of primary hyperuricemia of two ethnicities in Xinjiang.
2. Analyze the correlation of gene SNP and primary hyperuricemia in Han and Uygur ethnicity in Xinjiang.
3. Found the correlated factors of genic and environment with primary hyperuricemia between Han and Uygur ethnicity in Xinjiang
4. Reveal the relationship of primary hyperuricemia and Metabolic Diseases.
Contents and Methods
In the present study, we first investigated uria acid level and the prevalence of primary hyperuricemia in Han and Uygur ethenicity. Furthermore used the Multiplex Amplification Refractory Mutation System Polymerase Chain Reaction (Multi-ARMS PCR), Restriction Fragment Length Polymorphism Polymerase Chain Reaction (PCR-RFLP) and gene chip technic to clarify the relationship between gene polymorphism and primary hyperuricemia in Han and Uygur ethnicity. A questionnaire including family history of disease, lifestyle-related variables and other factors which may be corrected with primary hyperuricemia was used to every participants.The questionnaires were discussed during physical examinations. Finaly via Logistic regression to found the related factors that related genetical and environment and to determine wither primary hyperuricemia corrected with other metabolic diseases. Analysis the correlated Genic and Environment Factors of primary Hyperuricemia and relationship with Metabolic Diseases.
Results:
1 Uric Acid Level and Prevalence of Primary hyperuricemia in Hanand Uygur Ethnicity
(1)Han ethnicity SUA level was was higher than Uygur ethnicity and man was higher than womanin (P<0.05). (2)The average age of primary hyperuricemia occered of
Han was 38.01 in man and 42.07 in woman, Uygur ethnicity was 44.92 in man and 50.00 in woman. The prevalence of primary hyperuricemia Han ethnicity was Han ethnicity was higher than Uygur ethnicity (P<0.05) and man was higher than womanin (P<0.05). (3)The uric acid level were increased accompanying the age growing in two ethnicities. Between different age groups, uric acid level were different in two ethnicities (P<0.05).These differnences show statistically significant (P<0.05). But the increase trend in man was not bigger than in woman. (4)Accompany with ages growing, the prevalence of primary hyperuricemia of Han and Uygur ethnicity were increased (P<0.05). But except man in Han ethnicity was decreased, man in Uygur ethnicity did not show rule , the woman in two ethnicities,were increased, they all show statistically significant (P<0.05).
2 The Gene Single Nucleotide Polymorphism (SNP) of Primary Hyperuricemia in Han and Uygur Ethnicity
2.1 Underexcretical Primary Hyperuricemia Related Gene SNP Aanalysis
2.1.1 Relationship between Apolipopritein E gene SNP and Primary Hyperuricemia
(1)The distribution of Apolipoprotein E gene type in Han and Uygur ethnicity were significant differences (P<.05). Among the six genotypes of Apolipopretein E gene, E3/3 was the most common one in two ethnicities. E2/2 gene frequency were larger than E4/4 in Han ethnicity, but E4/4>E2/2 in Urger ethnicity. (2)The allele gene frequency ofε2,ε3,ε4 in Han were 0.224, 0.688 and 0.067 and 0.245, 0.615, 0.14 in Uygur ethnicity. Theε3 allele gene was the most one in two ethnicities, same as the common people in world. Compared with normal group,ε2 allele gene frequency was decreased andε4 was increased in primary hyperuricemia group of two ethnicities. (3) The SUA and other biochemical criterion in Apolipoprotein E allele genes showed different rule in two ethnicities.(4) The serum of uric acid and plasma lipid parameters in hyperueicmia group were higher than the normal group in Han and Uygur ethnicity in different allele gene (P<0.05).but still showed difference in two ethnicities.(5) hyperuricemia groupε4 allele frequency in Han ethnicity was similar to Asian, but in Uygur ethnicity was closed to people Europe and American.
2.1.2 Relationship between Leptin Gene G2548A Polymorphism and Primary Hyperuricemia
(1) The AA,AG,GG allele frequency of Leptin gene G 2548A in Han were 0.541, 0.374 and 0.085,in Uygur ethnicity were 0.497, 0.415 and 0.088.(2) The AA allele frequency of leptin G2548A was significantly higher and AG,GG were lower in hyperuricemia group than the normal group (P<0.05). (3) The relative risk of primary hyperuricemia of AA+AG gene type was 0.625 times (OR=0.625; 95%CI=0.285-1.368) to GG gene type in Han and 0.478 times (OR=0.478, 95%CI=0.103-2.213) in Uygur ethnicity, but not insignificence between primary hyperuricemia and normal groups in two etnicities (P>0.05). (4) In Han ethnicity, the AA+Ag gene type, Compared to normol group, hyperuricemic group uric acid and other plasma lipid parameters except the BUN were higher than the normal group in Han ethnicity ,were stastisignificence (P<0.05), but in GG gene type only the SUA was higher than normal, was stastisignificence (P<0.05) In Uygur ethnicity, Compared to normol group, the AA+Ag gene type hyperuricemicl group uric acid and other plasma lipid parameters except the seurm leptin and FBS level, were higher than the normal group, and have stastisignificence (P<0.05).
2.2 Overproductical Primary hyperuricemia Related Gene SNP Analysis
(1)The frequency of MTHFR T allele amone the cases was significantly higher than the controls (P<0.05), the odds ratios for primary hyperuricemia was 1.617. UA, TG concentrations and body mass index were remarkabley higher in subjects with TT gene type than in subjects with CC gene type (P<0.05). (2)The SUA, BMI and TG level in MTHFR gene type C/C, C/T, T/T were increased, T/T and C/C gene type was significantly (P<0.05), other plasma lipid parameters, for example, WHR, SBP, DBP, TC, LDL-C, VLDL-C were increased two, and BUN, SCR, HDL-C decreased, but between the different gene types were insignificantly(P>0.05).(3)The frequency ofβ3-AR T964A gene type and allele between the cases and the controls was insignificantly(P>0.05), wen can not sayβ3-AR Trp64Arg mution was the risk of primary hyperuricemia.The large samples andprospective study to find the relationship of this mution and primary hyperuricemia.(4)The frequency of ACE I/D and AGT T704C gene type and allele between the cases and the controls was insignificantly (P>0.05) too.
3 Primary Hyperuricemia Correlated Genic and Environment Factors and Relationship with Metabolic Diseases
(1) Multivariate logistic regression analyses for influence of primary hyperuricemia shown nationality ,FINS, Hypertriglyceridemia, Hypercholesterolemia, BMI, serum Leptin, hypercholesterolemia, hypertriglyceridemia, low HDL cholesterol, diabetes, hypertension occupation(commerce) ,like drinking broth and chicken soup may be the risk factors of primary hyperuricemia. Like eating muscle,drinking milk may be the protective facyors of primary hyperuricemia,Han has 2.697- fold in increased risk of primary hyperuricemia than Uygur. (2)Univariate regression analyses found that the relationship with uric acid were FINS, DBP, SBP, BMI, WHR, CREA, BUN, TG, HDL-C, LDL-C and VLDC-C in Han people. AGE, DBP, SBP, BMI, WHR, SCR, TG, TC, HDL, LDL-C and VLDC-C in Uygur (P<0.05). (3) Compared with normal group, except LDL-C, other biochemical criterion were higher than normal groupof Han people,but only SUA、SBP、DBP、BMI、WHR、FINS、SCR、TG、VLDL-C, have stastisignificence (P<0.05).In Uygur,except HDL-C,other biochemical criterion SUA、SBP、DBP、Serum leptin、BMI、WHR、FINS、CREA、TG、VLDL-C were higher than mormal group, have stastisignificence (P<0.05); Between normal groups in two ethnicities, the SUA、BMI、WHR、FINS、Serum leptin level in Uygur were higher than Han people(P<0.05); between hyperuricamia groups in two ethnicities, the BMI、Serum leptin level in Uygur were higher than Han people, but SCR、HDL-C level were lower than Han people (P<0.05). (4) From low to the high uric level group, except the Leptin and FBS , HDL-C has the decresed trend ,other biochemical criterions were increased in Han and Uygur ethnicity (P<0.05). The prevalence of obesity, Hypertension, Diabetes mellitus, hypertriglyceridemia, hypercholesterolemia, hypertriglyceridemia combination hypercholesterolemia and metabolic syndyome have the increasing trend when SUA level increasing, but only the prevalence of obesity, hypertriglyceridemia has significantly (P<0.05) in Han people,however in the Uygur ethnic,except the Diabetes mellitus,other diseases were significantly (P<0.05) too in different uria acid level groups. (5) Compared with normal group, the primary hyperuricemia group, the prevalence of obesity, hypertriglyceridemia, hypertriglyceridemia combination hypercholesterolemia and metabolic syndyome in Han people had the increasing trend (P<0.05). The Odds ratios of obesity, hypertriglyceridemia, hypertriglyceridemia combination hypercholesterolemia and metabolic syndyome in the presence of primary hyperuricemia were 2.362-times, 3.812-times, 3.163-times, 0.924-times and 4.971-times to SUA normal group. In about Uygur people, the prevalence of obesity, Hypertension, hypertriglyceridemia, hypercholesterolemia, hypertriglyceridemia combination hypercholesterolemia and metabolic syndyome in Han people had the increasing trend (P<0.05). The Odds ratios of these diseses were 3.626-times, 2.593-times, 1.905-times, 3.403-times, 4.016-times and 2.575-times to normal group.
Conclusion
The uric acid level and prevalence of primary hyperuricemia were different in Han and Uygur ethnicity and sexes. Han were higher than Uygur ethnicity, man was higher than woman. Logistic regression analyses found tha tnationality, FINS, Hypertriglyceridemia, Hypercholesterolemia,BMI,serum Leptin, hypercholesterolemia, hypertriglyceridemia, low HDL cholesterol, diabetes, hypertension occupation (commerce), like drinking broth and chicken soup may be the risk factors ,and eating muscle, drinking milk, may be the protect factors of primar y hyperuricemia. Related Gene SNP Analysis found theε4 allele gene of ApoE gene , A allele of leptin G2548A and MTHFR T allele may be a genetic factor that may contribute to individual susceptibility for primary hyperuricemia. In the main while,Hyperuricemia were corrected with obesity, hypertriglyceridemia, hypertriglyceridemia combination hypercholesterolemia and metabolic syndyome et al matsbilc diseases. It is suggested that primary hyperuricemia was a component of metabolic syndrome and often accompanied by obesity, hypertension, hyperlipidemia, glucose intolerance, and cardiovascular risk factor clustering.In conclusion, primary hyperuricemia was a complx genic traits caused by mutiple genetic and environmental components. And corrected with matablic diseases.
新疆为多民族聚居区,汉族和维吾尔族为主要的两个民族,有着不同的遗传背景,而且生活方式和饮食习惯也不同,因此为了了解新疆乌鲁木齐市汉族和维吾尔族的尿酸水平和原发性高尿酸血症的患病现况以及相关环境危险因素,本研究在现况调查的基础上,应用分子生物学技术研究高尿酸血症相关基因多态性在原发性高尿酸血症发病机制中的作用,并分析原发性高尿酸血症与代谢性疾病之间的关系。
研究目的
1了解新疆乌鲁木齐市汉族和维吾尔族居民尿酸水平和原发性高尿酸血症的患病现况。
2分析原发性高尿酸血症相关基因单核苷酸多态性。
3揭示原发性高尿酸血症的相关环境和遗传因素。
4探讨原发性高尿酸血症与其它代谢性疾病的关系。
研究内容与方法
本研究首先对新疆乌鲁木齐市汉族和维吾尔族健康人群进行了现况调查,了解被调查人群的尿酸水平和原发性高尿酸血症的患病现况,同时利用等位基因特异性多重PCR技术(Multi-ARMS PCR)、聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)等技术研究尿酸清除率过低导致尿酸排泄减少相关基因多态性,如ApoE基因、Leptin基因;以及利用基因芯片方法研究嘌呤代谢过程中某些酶基因突变如:亚甲基四氢叶酸还原酶(MTHFR)缺陷、β3-肾上腺素受体基因(β3-AR)缺陷、血管紧张素转换酶基因(ACE)、血管紧张素原基因(AGT)变异导致尿酸生成过多相关基因多态性。并且对两个民族被调查人群进行面对面的问卷调查,了解两个民族生活方式、饮食习惯、现患疾病和家族史等可能与原发性高尿酸血症相关环境的因素,并分析高尿酸血症与相关代谢性疾病之间的关系。探索原发性高尿酸血症相关的基因和环境因素及与代谢性疾病之间的关系。揭示遗传和环境因素在新疆维、汉两个民族原发性高尿酸血症发生发展中的作用。
结果
1汉族和维吾尔族血尿酸水平及原发性高尿酸血症患病现况
(1)汉族血尿酸水平高于维吾尔族,男性高于女性,差异有统计学意义(P＜0.05)。(2)原发性高尿酸血症汉族男女平均患病年龄分别为38.01岁和42.07岁,维吾尔族男性为44.92岁,女性为50.00岁。汉族原发性高尿酸血症检出率高于维吾尔族,男性均高于女性,差异有统计学意义(P＜0.05)。(3)汉族和维吾尔族不同年龄段尿酸值差异有统计学意义(P＜0.05)。趋势性检验发现汉族男性血尿酸水平随年龄增长而变化趋势不明显,而维吾尔族男性和两个民族女性随着年龄的增长,尿酸水平逐渐升高(P＜0.05)。(4)趋势性检验发现汉族男性随着年龄的增长原发性高尿酸血症的检出率有降低的趋势(P＜0.05)。维吾尔族男性的检出率变化趋势不明显,各年龄段差异无统计学意义(P＞0.05)。而汉族和维吾尔族女性随着年龄的增高,原发性高尿酸血症的检出率增高,各年龄段之间差异均有统计学意义(P＜0.05)。
2原发性高尿酸血症相关基因单核苷酸多态性(SNP)
2.1尿酸排泄减少型原发性高尿酸血症相关基因SNP
2.1.1载脂蛋白E基因(ApoE)SNP与原发性高尿酸血症相关性
(1)两个民族比较,汉族和维吾尔族ApoE基因型分布差异有统计学意义(P＜0.05),ApoE 3/3为占主导的基因型,汉族E 2/2基因频率高于E 4/4,而维吾尔族正好相反。(2)新疆汉族和维吾尔族ApoEε2、ε3、ε4的等位基因频率均以ε3最常见,ε4及ε2等位发生频率较低,同一般人群中ApoE的分布特点相符。与正常组相比高尿酸组ε2等位基因频率降低,而ε4等位基因频率升高,提示ε4等位基因可能是新疆汉族和维吾尔族原发性高尿酸血症的遗传易感基因。(3)汉族和维吾尔族ApoE各等位基因的携带者SAU和生化指标变化不同,表现出民族之间的差异。(4)除HDL-C外,两个民族ApoE各等位基因携带者,高尿酸组SUA和其它的各生化指标均高于正常组,但是尿酸和血脂代谢仍然有一定的差别。(5)新疆汉族ApoEε4基因型出现频率接近亚洲人,而维吾尔族接近欧美人。汉族和维吾尔族研究人群ε2等位基因频率均高于ε4,而且ε2等位基因频率高于国内其它研究结果。
2.1.2 Leptin基因G2548A多态性与原发性高尿酸血症相关性
(1)汉族所有检测人群Leptin基因2548 G→A变异,AA、AG、GG等位基因频率分别为0.541、0.374和0.085,维吾尔族分别为0.497、0.415和0.088。(2)汉族和维吾尔族Leptin基因G2548A变异高尿酸组AA等位基因频率均高于正常组,AG和GG等位基因频率均低于正常组。(3)汉族AA加AG基因型患原发性高尿酸血症的风险是GG基因型的0.625倍(OR=0.625;95%CI=0.285～1.368),维吾尔族AA加AG基因型患原发性高尿酸血症的风险是GG基因型的0.478倍(OR=0.478;95%I=0.103～2.213)。(4)高尿酸组与正常组相比,汉族AA+AG基因型,除了血清Leptin以及BUN以外的各项指标,高尿酸组均大于正常组(P＜0.05),而GG基因型,除了尿酸之间差异有统计学意义外,其它各项指标差异无统计学意义(P＞0.05)。维吾尔族AA+AG基因型除了血清Leptin与血糖以外的各项指标,高尿酸组均大于正常组(P＜0.05),推测A等位基因可能与高尿酸血症的发生以及各种脂代谢紊乱相关联。
2.2尿酸生成增多型原发性高尿酸血症相关基因SNP
(1)原发性高尿酸血症组和正常组MTHFR基因C/C、C/T、T/T基因型频率总体分布的差异无统计学意义,但原发性高尿酸血症组T等位基因的分布频率高于正常组(P＜0.05),并使患病的危险性增加为C等位基因患病危险性的1.617倍。(2)各基因型尿酸的水平的方差分析显示,C/C、C/T、T/T基因型的尿酸依次升高,分别为392.77μmol/L、411.28μmol/L和458.69μmol/L,其中T/T基因型与C/C基因型尿酸水平差异有统计学意义(P＜0.05)。其余各变量WHR、SBP、DBP、TC、LDL-C、VLDL-C也有依次升高的趋势,而BUN、CREA以及HDL-C有依次降低的趋势,但是统计学检验各基因型之间差异无统计学意义(P＞0.05)。结果提示,MTHFR基因T等位基因可能是男性原发性高尿酸血症的危险因素。(3)β3-AR基因64位点T/A多态性基因型和等位基因型在原发性高尿酸血症组和正常组的分布差异无统计学意义(P＞0.05)。(4)本研究中未能发现原发性高尿酸血症与ACE基因I/D多态性和AGT基因T704C多态性存在关联。
3原发性高尿酸血症相关基因与环境因素及与代谢性疾病关系
(1)Logistic回归分析发现推测爱吃精瘦肉和爱喝乳制品者为高尿酸血症的保护因素;汉族罹患原发性高尿酸血症的危险是维吾尔族的2.697倍,而高甘油三脂血症、胰岛素抵抗指数、高胆固醇血症、腰臀比、Leptin浓度、职业(商业)、高血压、喜欢喝肉汤鸡汤等可能是原发性高尿酸血症的危险因素。(2)相关性分析发现汉族人群与SUA相关的生化指标主要有FINS,DBP、SBP、BMI、WHR、SCR、BUN、TG、HDL-C、LDL-C和VLDC-C。维吾尔族SUA主要与AGE、DBP、SBP、BMI、WHR、SCR、TG、TC、HDL、LDL-C和VLDC-C相关(P＜0.05)。(3)汉族高尿酸组各项指标除了HDL-C低于正常组,FBS两组相近外,其它指标均高于正常组;而维吾尔族各项指标除了HDL-C外,高尿酸组SUA、SBP、DBP、Serum leptin、BMI、WHR、FINS、SCR、TG、VLDL-C均高于正常组(P＜0.05)。同时也各生化指标在两个民族之间变化也有各自的特点。(4)随着尿酸水平的升高,汉族除了血清Leptin和FBS,维吾尔族除了Leptin和FBS、BUN没有表现出明显的规律,HDL-C随着尿酸的升高而降低,其它指标均随着尿酸的升高而升高,各尿酸水平组之间差异有统计学意义(P＜0.05)。(5)原发性高尿酸血症组与正常组相比,汉族肥胖、高甘油三脂血症、高甘油合并高胆固醇血症、低高密度脂蛋白血症及代谢综合症检出率均升高(P＜0.05),罹患上述疾病的危险分别是正常组的2.362、3.812、3.163、0.924和4.971倍。而维吾尔族肥胖、高血压、高甘油三脂血症、高胆固醇血症、高甘油合并高胆固醇血症、代谢综合症检出率均升高(P＜0.05),罹患上述疾病的危险分别是正常组的3.626、2.593、1.905、3.403、4.016、2.575倍。代谢综合征、高甘油三脂血症、高甘油合并高胆固醇血症对汉族高尿酸血症的影响较大。高胆固醇血症肥胖、高甘油三脂血症对维吾尔族高尿酸血症的影响较大。
结论
原发性高尿酸血症在新疆表现出民族和性别之间的差异,汉族血尿酸平均水平和高尿酸血症的检出率高于维吾尔族,男性高于女性。Logistic回归分析发现喜欢吃精瘦肉类和乳制品为高尿酸血症的保护因素,而患有高甘油三脂血症、胰岛素抵抗、高胆固醇血症、从事商业工作、高血压、喜欢喝肉汤鸡汤者以腰臀比较大、血清Leptin浓度较高可能是原发性高尿酸血症的危险因素。基因多态性研究发现ApoEε4等位基因、Leptin基因A等位基因、MTHFR基因T等位基因可能是原发性高尿酸血症的危险因素,尚不能说明β3-AR基因、ACE基因I/D多态性和AGT基因T704C多态性与高尿酸血症之间存在关联。同时高尿酸血症与BMI、肥胖、高血压、高甘油三脂血症、低高密度脂蛋白血症、代谢综合症等代谢性疾病相关,并且是代谢综合症的一个的组成成分。综上所述,原发性高尿酸血症是一种复杂性疾病,由基因和环境因素所致,而且与代谢性疾病密切相关。
Uric acid an end product of purine metabolism, is degraded in most mammals by the hepatic enayme and urate oxidase (uricase), to allantion which freely in the urine. Usually, the pool size of urate for an adult male is about 1,200 mg, and 700 mg urate is produced daily. The production is balanced by the excretion of urate into urine (500 mg) and intestine (200 mg). The hyperuricemia occurs if this balance is disturbed, Some human subjects have various abnormalities in urate metabolism. According to the mechanisms, hyperuricemia is classified into two different types, overproduction and underexcretion. Overproduction is caused by some enzymatic abnormalities, such as PRPP synthetase superactivity, HPRT deficiency et al .Study show that it still can be caused by genetic defects, such as the superactivity of Angiotensin Converting Enzyme Gene (ACE), angiotensin-coverting enzyme gene (AGT),Beta 3-adrenergic receptor gene, Methylenetetrahydrofolate reductase, MTHFR (C677T) gene defects. Underexcretion of urate is caused by renal insufficiency and genetic defects, for example. The Human Urate Transporter gene, ApoE gene, Leptin gene were cinsidered the correlation with hyperyricemia.
Many studies showed that primary hyperuricemia was a complx genetic traits caused by mutiple genetic and environmental components. The correlated environmental factors include diet, life style, culture, occupation and economy level et al. A number of studies have shown that serum uric acid (SUA) plays a role in the development of cardiovascular morbidity in the general population, as well as in patients with hypertension, type II diabetes, and cardiac or vascular diseases.
Many ethnicities were lived in XingJiang, and the Han and Uygur ethnicity were the main in all population,they came from different genetic background ,different life mode and diet habit. In the present study, we investigated uria acid level and the prevalence of primary hyperuricemia in Han and Uygur ethenicity. Furthermore used PCR and gene chip technic to clarify the relationship between gene polymorphism and primary hyperuricemia in Han and Uygur ethnicity.Finaly via Logistic regression to found the related factors that related genetical and environment and to determine wither primary hyperuricemia corrected with other metabolic diseases.
Objectives:
1. Rreveal the uric acid level of Han and Uygur ethnicity and find the prevalence and the rule of primary hyperuricemia of two ethnicities in Xinjiang.
2. Analyze the correlation of gene SNP and primary hyperuricemia in Han and Uygur ethnicity in Xinjiang.
3. Found the correlated factors of genic and environment with primary hyperuricemia between Han and Uygur ethnicity in Xinjiang
4. Reveal the relationship of primary hyperuricemia and Metabolic Diseases.
Contents and Methods
In the present study, we first investigated uria acid level and the prevalence of primary hyperuricemia in Han and Uygur ethenicity. Furthermore used the Multiplex Amplification Refractory Mutation System Polymerase Chain Reaction (Multi-ARMS PCR), Restriction Fragment Length Polymorphism Polymerase Chain Reaction (PCR-RFLP) and gene chip technic to clarify the relationship between gene polymorphism and primary hyperuricemia in Han and Uygur ethnicity. A questionnaire including family history of disease, lifestyle-related variables and other factors which may be corrected with primary hyperuricemia was used to every participants.The questionnaires were discussed during physical examinations. Finaly via Logistic regression to found the related factors that related genetical and environment and to determine wither primary hyperuricemia corrected with other metabolic diseases. Analysis the correlated Genic and Environment Factors of primary Hyperuricemia and relationship with Metabolic Diseases.
Results:
1 Uric Acid Level and Prevalence of Primary hyperuricemia in Hanand Uygur Ethnicity
(1)Han ethnicity SUA level was was higher than Uygur ethnicity and man was higher than womanin (P<0.05). (2)The average age of primary hyperuricemia occered of
Han was 38.01 in man and 42.07 in woman, Uygur ethnicity was 44.92 in man and 50.00 in woman. The prevalence of primary hyperuricemia Han ethnicity was Han ethnicity was higher than Uygur ethnicity (P<0.05) and man was higher than womanin (P<0.05). (3)The uric acid level were increased accompanying the age growing in two ethnicities. Between different age groups, uric acid level were different in two ethnicities (P<0.05).These differnences show statistically significant (P<0.05). But the increase trend in man was not bigger than in woman. (4)Accompany with ages growing, the prevalence of primary hyperuricemia of Han and Uygur ethnicity were increased (P<0.05). But except man in Han ethnicity was decreased, man in Uygur ethnicity did not show rule , the woman in two ethnicities,were increased, they all show statistically significant (P<0.05).
2 The Gene Single Nucleotide Polymorphism (SNP) of Primary Hyperuricemia in Han and Uygur Ethnicity
2.1 Underexcretical Primary Hyperuricemia Related Gene SNP Aanalysis
2.1.1 Relationship between Apolipopritein E gene SNP and Primary Hyperuricemia
(1)The distribution of Apolipoprotein E gene type in Han and Uygur ethnicity were significant differences (P<.05). Among the six genotypes of Apolipopretein E gene, E3/3 was the most common one in two ethnicities. E2/2 gene frequency were larger than E4/4 in Han ethnicity, but E4/4>E2/2 in Urger ethnicity. (2)The allele gene frequency ofε2,ε3,ε4 in Han were 0.224, 0.688 and 0.067 and 0.245, 0.615, 0.14 in Uygur ethnicity. Theε3 allele gene was the most one in two ethnicities, same as the common people in world. Compared with normal group,ε2 allele gene frequency was decreased andε4 was increased in primary hyperuricemia group of two ethnicities. (3) The SUA and other biochemical criterion in Apolipoprotein E allele genes showed different rule in two ethnicities.(4) The serum of uric acid and plasma lipid parameters in hyperueicmia group were higher than the normal group in Han and Uygur ethnicity in different allele gene (P<0.05).but still showed difference in two ethnicities.(5) hyperuricemia groupε4 allele frequency in Han ethnicity was similar to Asian, but in Uygur ethnicity was closed to people Europe and American.
2.1.2 Relationship between Leptin Gene G2548A Polymorphism and Primary Hyperuricemia
(1) The AA,AG,GG allele frequency of Leptin gene G 2548A in Han were 0.541, 0.374 and 0.085,in Uygur ethnicity were 0.497, 0.415 and 0.088.(2) The AA allele frequency of leptin G2548A was significantly higher and AG,GG were lower in hyperuricemia group than the normal group (P<0.05). (3) The relative risk of primary hyperuricemia of AA+AG gene type was 0.625 times (OR=0.625; 95%CI=0.285-1.368) to GG gene type in Han and 0.478 times (OR=0.478, 95%CI=0.103-2.213) in Uygur ethnicity, but not insignificence between primary hyperuricemia and normal groups in two etnicities (P>0.05). (4) In Han ethnicity, the AA+Ag gene type, Compared to normol group, hyperuricemic group uric acid and other plasma lipid parameters except the BUN were higher than the normal group in Han ethnicity ,were stastisignificence (P<0.05), but in GG gene type only the SUA was higher than normal, was stastisignificence (P<0.05) In Uygur ethnicity, Compared to normol group, the AA+Ag gene type hyperuricemicl group uric acid and other plasma lipid parameters except the seurm leptin and FBS level, were higher than the normal group, and have stastisignificence (P<0.05).
2.2 Overproductical Primary hyperuricemia Related Gene SNP Analysis
(1)The frequency of MTHFR T allele amone the cases was significantly higher than the controls (P<0.05), the odds ratios for primary hyperuricemia was 1.617. UA, TG concentrations and body mass index were remarkabley higher in subjects with TT gene type than in subjects with CC gene type (P<0.05). (2)The SUA, BMI and TG level in MTHFR gene type C/C, C/T, T/T were increased, T/T and C/C gene type was significantly (P<0.05), other plasma lipid parameters, for example, WHR, SBP, DBP, TC, LDL-C, VLDL-C were increased two, and BUN, SCR, HDL-C decreased, but between the different gene types were insignificantly(P>0.05).(3)The frequency ofβ3-AR T964A gene type and allele between the cases and the controls was insignificantly(P>0.05), wen can not sayβ3-AR Trp64Arg mution was the risk of primary hyperuricemia.The large samples andprospective study to find the relationship of this mution and primary hyperuricemia.(4)The frequency of ACE I/D and AGT T704C gene type and allele between the cases and the controls was insignificantly (P>0.05) too.
3 Primary Hyperuricemia Correlated Genic and Environment Factors and Relationship with Metabolic Diseases
(1) Multivariate logistic regression analyses for influence of primary hyperuricemia shown nationality ,FINS, Hypertriglyceridemia, Hypercholesterolemia, BMI, serum Leptin, hypercholesterolemia, hypertriglyceridemia, low HDL cholesterol, diabetes, hypertension occupation(commerce) ,like drinking broth and chicken soup may be the risk factors of primary hyperuricemia. Like eating muscle,drinking milk may be the protective facyors of primary hyperuricemia,Han has 2.697- fold in increased risk of primary hyperuricemia than Uygur. (2)Univariate regression analyses found that the relationship with uric acid were FINS, DBP, SBP, BMI, WHR, CREA, BUN, TG, HDL-C, LDL-C and VLDC-C in Han people. AGE, DBP, SBP, BMI, WHR, SCR, TG, TC, HDL, LDL-C and VLDC-C in Uygur (P<0.05). (3) Compared with normal group, except LDL-C, other biochemical criterion were higher than normal groupof Han people,but only SUA、SBP、DBP、BMI、WHR、FINS、SCR、TG、VLDL-C, have stastisignificence (P<0.05).In Uygur,except HDL-C,other biochemical criterion SUA、SBP、DBP、Serum leptin、BMI、WHR、FINS、CREA、TG、VLDL-C were higher than mormal group, have stastisignificence (P<0.05); Between normal groups in two ethnicities, the SUA、BMI、WHR、FINS、Serum leptin level in Uygur were higher than Han people(P<0.05); between hyperuricamia groups in two ethnicities, the BMI、Serum leptin level in Uygur were higher than Han people, but SCR、HDL-C level were lower than Han people (P<0.05). (4) From low to the high uric level group, except the Leptin and FBS , HDL-C has the decresed trend ,other biochemical criterions were increased in Han and Uygur ethnicity (P<0.05). The prevalence of obesity, Hypertension, Diabetes mellitus, hypertriglyceridemia, hypercholesterolemia, hypertriglyceridemia combination hypercholesterolemia and metabolic syndyome have the increasing trend when SUA level increasing, but only the prevalence of obesity, hypertriglyceridemia has significantly (P<0.05) in Han people,however in the Uygur ethnic,except the Diabetes mellitus,other diseases were significantly (P<0.05) too in different uria acid level groups. (5) Compared with normal group, the primary hyperuricemia group, the prevalence of obesity, hypertriglyceridemia, hypertriglyceridemia combination hypercholesterolemia and metabolic syndyome in Han people had the increasing trend (P<0.05). The Odds ratios of obesity, hypertriglyceridemia, hypertriglyceridemia combination hypercholesterolemia and metabolic syndyome in the presence of primary hyperuricemia were 2.362-times, 3.812-times, 3.163-times, 0.924-times and 4.971-times to SUA normal group. In about Uygur people, the prevalence of obesity, Hypertension, hypertriglyceridemia, hypercholesterolemia, hypertriglyceridemia combination hypercholesterolemia and metabolic syndyome in Han people had the increasing trend (P<0.05). The Odds ratios of these diseses were 3.626-times, 2.593-times, 1.905-times, 3.403-times, 4.016-times and 2.575-times to normal group.
Conclusion
The uric acid level and prevalence of primary hyperuricemia were different in Han and Uygur ethnicity and sexes. Han were higher than Uygur ethnicity, man was higher than woman. Logistic regression analyses found tha tnationality, FINS, Hypertriglyceridemia, Hypercholesterolemia,BMI,serum Leptin, hypercholesterolemia, hypertriglyceridemia, low HDL cholesterol, diabetes, hypertension occupation (commerce), like drinking broth and chicken soup may be the risk factors ,and eating muscle, drinking milk, may be the protect factors of primar y hyperuricemia. Related Gene SNP Analysis found theε4 allele gene of ApoE gene , A allele of leptin G2548A and MTHFR T allele may be a genetic factor that may contribute to individual susceptibility for primary hyperuricemia. In the main while,Hyperuricemia were corrected with obesity, hypertriglyceridemia, hypertriglyceridemia combination hypercholesterolemia and metabolic syndyome et al matsbilc diseases. It is suggested that primary hyperuricemia was a component of metabolic syndrome and often accompanied by obesity, hypertension, hyperlipidemia, glucose intolerance, and cardiovascular risk factor clustering.In conclusion, primary hyperuricemia was a complx genic traits caused by mutiple genetic and environmental components. And corrected with matablic diseases.
引文
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