發(fā)布時(shí)間：2019-04-16 09:01

【摘要】：早發(fā)2型糖尿病(T2DM)和2型糖尿病腎病(DN)都是具有遺傳異質(zhì)性的復(fù)雜疾病,不同種族疾病易感基因(KCNJ11,GHRL)的遺傳變異結(jié)果不一致,而相關(guān)遺傳基因的發(fā)現(xiàn)、功能的闡明將有助于疾病的早期診斷、優(yōu)化靶向治療。本研究共分兩章:1)KCNJ11 E23K和A190A變異與早發(fā)T2DM、血壓的相關(guān)性;2)Preproghrelin(GHRL)基因Leu72Met變異與DN之間的關(guān)系1)KCNJ11基因E23K和A190A變異與早發(fā)T2DM、血壓的相關(guān)性KCNJ11變異與晚發(fā)型T2DM(發(fā)病年齡40歲)間的關(guān)系在不同人群的研究結(jié)果不盡相同。我們研究KCNJ11基因E23K(G→A,rs5219),A190A(C→T,rs5218)變異與中國(guó)人群早發(fā)T2DM、血壓的相關(guān)性。研究對(duì)象包括175名無血緣關(guān)系的早發(fā)T2DM(發(fā)病年齡40歲)和182名非糖尿病對(duì)照組(non-DM)。根據(jù)治療措施的不同,將早發(fā)T2DM組分為:胰島素治療組(ins+,n=57)和非胰島素治療組(ins-,n=118)。PCR直接測(cè)序法檢測(cè)KCNJ11 E23K和A190A基因型,分析各組基因型、等位基因分布及臨床變量之間的差異。結(jié)果:a)在早發(fā)T2DM組,E23K-(GA+AA)基因型頻率高于non-DM組、A190A-TT基因型頻率低于non-DM組,尤其在T2DM(ins+)組(p0.01或p0.05);b)在non-DM組,相比于E23K-GG攜帶者,E23K-AA攜帶者的2小時(shí)血糖顯著升高,2小時(shí)胰島素水平顯著降低(both p0.05);c)無論non-DM還是早發(fā)T2DM組,E23K-GG、A190A-TT攜帶者收縮壓分別有意高于AA或CC攜帶者(both p0.05);d)在T2DM(ins+)組,相比于E23K-GG攜帶者,AA攜帶者發(fā)病年齡較小,糖尿病病程較短,BMI較高;而A190A-TT攜帶者的收縮壓顯著高于CC攜帶者(p0.05,for each)。結(jié)論:KCNJ11基因E23K-GA、AA基因型增加早發(fā)T2DM易感性,A190A-TT能防止早發(fā)T2DM發(fā)生;另一方面,A190A-TT或者E23K-GG基因型可能增加中國(guó)人高血壓風(fēng)險(xiǎn)。2)GHRL基因Leu72Met變異與2型糖尿病腎病之間的關(guān)系GHRL基因Leu72Met變異(C→A rs696217)參與肥胖的發(fā)生,引起葡萄糖刺激的胰島素分泌能力減退,并且與T2DM患者血清肌酐(Scr)水平降低有關(guān)。本研究評(píng)價(jià)該變異與白蛋白尿、腎功能的相關(guān)性,同時(shí)測(cè)定了胰島素敏感性等相關(guān)參數(shù),探討其在DN發(fā)病中的作用。將757名研究對(duì)象分為兩組:非糖尿病對(duì)照組(non-DM,n=291)和2型糖尿病組(T2DM,n=466)。T2DM組內(nèi),238名合并糖尿病腎病(DN組)伴顯著蛋白尿(尿白蛋白排泄率AER≥300mg/24h);228名糖尿病病史至少10年,且無腎病癥狀(non-DN組)。Taqman探針法檢測(cè)所有研究對(duì)象的rs696217基因型。a)各組基因型分布符合Hardy-Weinberg平衡;b)Leu72Met基因型(Leu/Leu,Leu/Met,Met/Met)頻率分布在non-DN組、DN組間存在顯著差異(p=0.011),DN組Met72攜帶者頻率顯著低于non-DN組(23.5%vs.36.0%,p=0.003,OR=0.55[95%CI 0.37-0.82]);c)在non-DM組,相比于Leu/Leu或Leu/Met,Met/Met攜帶者BMI和Scr值最低,eGFR值最高(p0.01或p0.05);d)在T2DM組,與Leu72純合子相比,Met72攜帶者AER、Scr顯著降低,eGFR明顯升高(p0.001,for each)。結(jié)論:GHRL基因Leu72Met變異有助于維持正常腎功能,并減少白蛋白尿和改善糖尿病患者腎功能,阻止T2DM腎病的發(fā)生。
[Abstract]:Early onset type 2 diabetes mellitus (T2DM) and type 2 diabetic nephropathy (DN) are complex diseases with genetic heterogeneity. The results of genetic variation of susceptibility genes (KCNJ11,GHRL) of different races are not consistent, but the discovery of related genetic genes. Functional clarification will contribute to the early diagnosis of the disease and to the optimization of targeted therapy. This study is divided into two chapters: 1) the correlation between KCNJ11 E23K and A190A variation and early onset T2DM, blood pressure; 2 the relationship between Leu72Met variation of) Preproghrelin (GHRL) gene and DN (1) the relationship between E23K and A190A mutation of KCNJ11 gene and early onset T2DM, and the relationship between KCNJ11 variation and late-onset T2DM (age of onset 40 years old) were different in different populations. We studied the association between KCNJ11 gene E23K (G, Rs5219), A190A (C, T, rs5218) mutation and early onset T2DM and blood pressure in Chinese population. Subjects included 175 unrelated early onset T2DM (40 years old) and 182 non-diabetic controls (non-DM). According to the different treatment measures, the early-onset T2DM group was divided into two groups: insulin treatment group (ins,) and non-insulin treatment group (ins-,n=118). The genotypes of KCNJ11 E23K and A190A were detected by direct sequencing, and the genotypes of each group were analyzed. Distribution of alleles and differences in clinical variables. Results the frequency of E23K-(GA AA) genotype in early-onset T2DM group was higher than that in non-DM group, while the frequency of A190A-TT genotype in: a) group was lower than that in non-DM group, especially in T2DM (ins) group (p0.01 or p0.05). B) in non-DM group, compared with E23K-GG carriers, the level of 2h blood glucose in E23K-AA carriers was significantly higher and the level of insulin in 2h was significantly lower than that in E23K-AA carriers (both p0.05). C) systolic blood pressure (SBP) of E23K and A190A TT carriers in both non-DM and early-onset T2DM groups were significantly higher than those in AA or CC carriers (both p0.05). D) in T2DM (ins) group, compared with E23K-GG carriers, AA carriers had younger onset age, shorter duration of diabetes mellitus and higher BMI, while systolic blood pressure in A190A-TT carriers was significantly higher than that in CC carriers (p0.05, for each). Conclusion: KCNJ11 gene E23K / GA, AA genotype increases the susceptibility to premature T2DM, and A190A-TT can prevent the occurrence of premature T2DM. On the other hand, A190A-TT or E23K-GG genotype may increase the risk of hypertension in Chinese. 2) the relationship between Leu72Met mutation of GHRL gene and type 2 diabetic nephropathy is associated with GHRL gene Leu72Met rs696217, which is involved in the occurrence of obesity. Impaired glucose-stimulated insulin secretion was associated with decreased serum creatinine (Scr) levels in patients with T2DM. This study evaluated the correlation between the variation and albuminuria and renal function. At the same time, the insulin sensitivity and other related parameters were measured to explore its role in the pathogenesis of DN. Seven hundred and fifty-seven subjects were divided into two groups: non-diabetic control group (non-DM,n=291) and type 2 diabetic group (T2DM, n = 466). In T2DM group, 238patients with diabetic nephropathy (DN group) with significant proteinuria (urinary albumin excretion rate of 300mg/24h) were divided into two groups: non-diabetic control group (DM) and type 2 diabetic group (T2DM, n = 466). The history of diabetes mellitus was at least 10 years, and there were no nephrotic symptoms (rs696217 genotype was detected by). Taqman probe method in non-DN group). A) the distribution of rs696217 genotype in each group was in line with Hardy-Weinberg balance. B) the frequency of Leu72Met genotype (Leu/Leu,Leu/Met,Met/Met) was significantly lower in non-DN group than that in non-DN group (23.5% vs. 36.0%, p < 0.003), and the frequency of Met72 carriers in DN group was significantly lower than that in non-DN group (23.5% vs. 36.0%, P < 0.05). OR=0.55 [95%CI 0.37 / 0.82]; C) in non-DM group, compared with Leu/Leu or Leu/Met,Met/Met carriers, the BMI and scrum values were the lowest and the EGFR values were the highest (p0.01 or p0.05). (d) in T2DM group, compared with Leu72 homozygote, AER,Scr in Met72 carriers was significantly lower and eGFR was significantly higher (p0.001, for each). Conclusion: Leu72Met mutation of GHRL gene may help to maintain normal renal function, reduce albuminuria and improve renal function in diabetic patients, and prevent the occurrence of T2DM nephropathy.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R587.2;R692.9

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