人類血管收縮素轉化酶及血管收縮素原基因之多型性與台灣第2型糖尿病腎病變進展在不同性別上之差異性

The gender dependent effect of angiotensin converting enzyme and angiotensinogen gene polymorphisms on the progression of diabetic nephropathy in Taiwanese with type 2 diabetes

田凱仁(Kai-Jen Tien)

指導教授 ： 謝明家

高雄醫學大學/醫學院/醫學研究所/碩士(2008年)

https://doi.org/10.6832/KMU.2008.00005

摘要

目的：
腎素-血管收縮素系統(renin-angiotensin system, RAS)的基因多型性已經被發現與糖尿病腎病變有關。在這系統中的一部分，血管收縮素轉化酶(angiotensin converting enzyme, ACE)與血管收縮素原(angiotensinogen, AGT)的基因是高度的多型性變化並且被廣泛的研究。此外，在過往的一些研究報告指出糖尿病腎病變的進展在性別上有差異。但目前文獻上並沒有太多關於腎素-血管收縮素系統基因多型性與性別相關性的研究。本研究的目的即在探討血管收縮素轉化酶與血管收縮素原基因多型性在不同性別上與糖尿病腎病變的相關性。
研究方法：
我們設計一個觀察追蹤性的研究，自西元2005年一月至2006年一月，從高雄醫學大學附設醫院新陳代謝內科共選取525名第2型糖尿病病人，其中女性有249名，男性有276名，並且完成追蹤到2007年八月。我們對這些糖尿病的病患研究血管收縮素轉化酶及血管收縮素原基因的單一核甘酸多型性變化，並且以聚合酵素連鎖反應(polymerase chain reaction, PCR)及限制片段長度多型性(restriction fragment length polymorphism, RFLP)分析方式來做多型性的檢查。在糖尿病腎病變的變化上，將腎病變惡化者定為蛋白尿進展到下一期或者血清肌酐酸大於基礎值兩倍以上或者腎病變進展到末期腎病變。我們分析這些基因的多型性和臨床資料上的相關性，並且以性別分組以統計的方式去深入探討，更加去研究這些基因的多型性在不同性別上的重要性。
結果：
在這個平均追蹤時間是17.4個月的研究中，我們發現男性比女性糖尿病患者在研究一開始有較高的舒張壓，腰圍，以及血中肌酐酸值，而血中總膽固醇以及高密度膽固醇則以女性糖尿病患者較高。不論在男性或女性糖尿病患中，腎病變惡化組跟非惡化組兩組之間的臨床檢驗數值並沒有顯著的差異。在多變項邏輯回歸分析中，帶有ACE D對偶基因的女性糖尿病患相較於帶有II基因型的女性糖尿病患有較高的腎病變惡化之罹病風險(OR: 2.176, 95%CI:1.111-4.263, p=0.024)，但是於男性糖尿病患者中並未發現這樣的關係(OR: 1.20, 95%CI:0.630-2.288, p=0.619)。在調整過ㄧ些干擾因子，包括有收縮壓，舒張壓，糖化血色素，腰圍，總膽固醇，三酸甘油脂，高密度膽固醇，以及低密度膽固醇，仍可發現帶有ACE D對偶基因的女性糖尿病患相較於帶有II基因型的女性糖尿病患有較高的腎病變惡化之罹病風險(OR: 2.535, 95% CI:1.207-5.328, p=0.014)，但是在男性糖尿病患者仍未發現這樣的關係(OR:1.227,95%CI:0.206-2.483, p=0.570)。不論在男性或女性糖尿病患中，ACE對偶基因頻率的分布在腎病變惡化組跟非惡化組並未發現有顯著的差異，但於調整干擾因子過後，其分布在女性糖尿病患中則接近顯著的差異(OR:1.649, 95%CI:0.973-2.796, p=0.063)。在AGT基因多型性中，不論是TT基因型或者是T對偶基因頻率的分布上，在男性及女性患者中均與腎病變的惡化無關。
結論：
此追蹤研究的結果顯示，帶有ACE D對偶基因的女性糖尿病患會有較高的腎病變罹病風險。而AGT基因的多型性在台灣第2型糖尿病患中，不論是男性或女性，並不會影響到腎病變的惡化。

關鍵字

第2型糖尿病 ； 糖尿病腎病變 ； 性別差異 ； ACE基因多型性 ； AGT基因多型性

並列摘要

Objective
Genetic polymorphisms of the renin-angiotensin system (RAS) had been found to be associated with diabetic nephropathy(DN). Some components of RAS, ACE and AGT gene are highly polymorphic and have received extensive attention. Besides, sex–related differences in the progression of renal disease have ever been reported. The aim of the present study was to investigate the prognostic effect of ACE I/D and AGT M235T polymorphisms on diabetic nephropathy in relation to gender variance.
Research design and methods
A total of 525 type 2 diabetes (female: 249; male:276) were enrolled in a prospective observational follow-up study during Jan,2005-Jan,2006 and followed until Aug, 2007. ACE and AGT gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymorphism. The progression of DN was defined as shifting to higher stages of DN or doubling of the baseline serum creatinine level or progressing to the end stage renal disease at the end of the study.
Results
During the study (mean follow-up: 17.4 months), the male diabetes had a significant higher level of diastolic blood pressure, waist circumference, and serum creatinine than female diabetes at baseline. The serum cholesterol and high density lipoprotein cholesterol (HDL-C) concentration were significantly higher in female diabetes. The clinical biophysical parameters were not different between the progression and non-progression of DN in both sexes. In multiple logistic regression analyses, the female diabetes with ACE D allele carrier increased risk of DN progression than those with II genotypes (p = 0.024, OR: 2.176, 95%CI: 1.111-4.263), but the relationship was not seen in male patients (p = 0.619, OR: 1.20, 95%CI: 0.630-2.288). After adjustment of confounding factors (SBP, DBP, HbA1c, waist circumference, total cholesterol, TG, HDL-C, LDL-C), the risk of DN progression was still evident in female (p = 0.014, OR: 2.535, 95%CI: 1.207-5.328) but not in male patients (p = 0.570, OR: 1.227, 95%CI: 0.206-2.483). The allele frequency of ACE gene polymorphism were not different between the progression and non-progression patients in both sexes, but the difference could reach borderline significance in female patients in adjusted analyses (p = 0.063, OR: 1.649, 95%CI: 0.973-2.796). Both the AGT TT genotype and T allele were not associated with the progression of DN in both sexes whether adjustment or not.
Conclusions
Our follow-up study demonstrated that the ACE D carrier might serve as a predictor of DN progression in female but not in male diabetes. The AGT M235T polymorphism was not associated with DN progression in both sexes in Taiwanese type 2 diabetes.

並列關鍵字

Type 2 diabetes mellitus ； diabetic nephropathy ； gender variance ； ACE gene polymorphism ； AGT gene polymorphism

參考文獻

1. Atkins, R.C., et al., The epidemiology of chronic kidney disease. Kidney Int Suppl, 2005(94): p. S14-8.

2. Parving, H.H., et al., Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int, 2006. 69(11): p. 2057-63.

3. Parving, H.H., et al., Genetics of diabetic nephropathy. J Am Soc Nephrol, 1996. 7(12): p. 2509-17.

4. Standards of medical care in diabetes--2007. Diabetes Care, 2007. 30 Suppl 1: p. S4-S41.

5. Predictors of the development of microalbuminuria in patients with Type 1 diabetes mellitus: a seven-year prospective study. The Microalbuminuria Collaborative Study Group. Diabet Med, 1999. 16(11): p. 918-25.