Stratta Piero, Bermond Francesca, Guarrera Simonetta, Canavese Caterina, Carturan Sonia, Dall'Omo Annamaria, Ciccone Giovannino, Bertola Laura, Mazzola Gina, Fasano Edvige, Matullo Giuseppe
Department of Internal Medicine, Section Nephrology, S.Giovanni-Molinette Hospital, Torino, Italy.
Nephrol Dial Transplant. 2004 Mar;19(3):587-95. doi: 10.1093/ndt/gfg604.
The renin-angiotensin system (RAS) and nitric oxide synthase (NOS) play a key role in the progression of primary glomerulonephritis (GN). Although previous studies have examined genetic risk associated with single gene variations, experiments assessing risk conferred by multiple gene variations are still scanty.
The effect of combination of variant alleles of four genes encoding for three components of the RAS [angiotensin converting enzyme insertion/deletion (ACE I/D), angiotensin II receptor 1 (AT1R 1166A/C), angiotensinogen (AGT M235T)] and for NOS (ecNOS4b/a) on the development and progression of membranous GN (MGN) were evaluated in a longitudinal study comparing 117 patients with serum creatinine (s-Cr) <1.5 mg/dl at renal biopsy and follow-up > or = 5 years (Kaplan-Meier and Cox multivariate analysis). The control group consisted of DNA from 171 organ donors.
We found no relationship between single or combined variations of the four gene polymorphisms and development of MGN. Among single gene variations, there were no independent genetic risk factors for the progression of renal disease, after adjustment for age, sex, hypertension, proteinuria, s-Cr, chronicity and activity index. However, double variation coincidences such as the combination of the allele a of ecNOS4b/a and both the allele D of ACE I/D (chi(2) =4.80, P = 0.028; HR = 1.97, 95% CI 0.98-3.96) and the allele T of AGT (M235T) (chi(2) = 5.09, P = 0.024; HR = 2.84, 95% CI 1.39-5.82) exerted an additional effect that was higher than that of the single gene variations.
This study is the first to demonstrate a role for an interaction between simultaneous variations of genes encoding for NOS and components of RAS in the progression of MGN. Interactions between various polymorphisms may explain conflicting results obtained in previous studies that examined single gene variations, since the effect of a single locus variation may be influenced by the simultaneous presence of other variant alleles in polygenic diseases such as primary GN. However, the small sample sizes and possible multiple interactions limited the interpretation of the current findings, which may represent true biological interaction or simply statistical interactions or spurious results due to the small sample sizes.
肾素 - 血管紧张素系统（RAS）和一氧化氮合酶（NOS）在原发性肾小球肾炎（GN）的进展中起关键作用。尽管先前的研究已经考察了与单基因变异相关的遗传风险，但评估多个基因变异所赋予风险的实验仍然很少。
在一项纵向研究中，比较了117例肾活检时血清肌酐（s-Cr）<1.5 mg/dl且随访时间≥5年的患者（采用Kaplan-Meier法和Cox多变量分析），评估了编码RAS三个组分[血管紧张素转换酶插入/缺失（ACE I/D）、血管紧张素II受体1（AT1R 1166A/C）、血管紧张素原（AGT M235T）]以及NOS（ecNOS4b/a）的四个基因的变异等位基因组合对膜性肾小球肾炎（MGN）发生和进展的影响。对照组由171名器官捐赠者的DNA组成。
我们发现这四个基因多态性的单基因或联合变异与MGN的发生之间没有关系。在单基因变异中，在对年龄、性别、高血压、蛋白尿、s-Cr、病程和活动指数进行校正后，没有独立的基因危险因素可预测肾脏疾病的进展。然而，双重变异巧合，如ecNOS4b/a的等位基因a与ACE I/D的等位基因D的组合（χ² = 4.80，P = 0.028；风险比[HR] = 1.97，95%可信区间[CI] 0.98 - 3.96）以及AGT（M235T）的等位基因T（χ² = 5.09，P = 0.024；HR = 2.84，95% CI 1.39 - 5.82）产生的额外影响高于单基因变异。
本研究首次证明编码NOS和RAS组分的基因同时变异之间的相互作用在MGN进展中的作用。各种多态性之间的相互作用可能解释了先前研究单基因变异时获得的相互矛盾的结果，因为在原发性GN等多基因疾病中，单个位点变异的效应可能会受到其他变异等位基因同时存在的影响。然而，样本量小以及可能存在的多种相互作用限制了对当前研究结果的解释，这些结果可能代表真正的生物学相互作用，也可能仅仅是统计上的相互作用或由于样本量小而产生的虚假结果。
