Ramasawmy Rajendranath, Cunha-Neto Edecio, Fae Kellen C, Martello Fernanda G, Müller Natalie G, Cavalcanti Vanessa L, Ianni Barbara, Mady Charles, Kalil Jorge, Goldberg Anna C
Laboratory of Immunology, Heart Institute (InCor), São Paulo, SP, Brazil.
Clin Infect Dis. 2006 Aug 1;43(3):305-11. doi: 10.1086/505395. Epub 2006 Jun 16.
Only a subset of individuals infected with Trypanosoma cruzi develop chronic Chagas cardiomyopathy (CCC). Familial aggregation of CCC in areas of endemicity indicates that susceptibility may be genetic, which may be a plausible explanation for why only one-third of T. cruzi-infected individuals develop CCC. The monocyte chemoattractant protein-1 (CCL2/MCP-1) has been shown to enhance the uptake of T. cruzi in murine macrophages and to up-regulate the inducible nitric oxide synthase/nitric oxide system, with a consequent increased production of nitric oxide that controls the replication of the parasite.
We assessed CCL2 variants at position -2518A/G, which are known to influence transcriptional activity, by polymerase chain reaction and restriction fragment-length polymorphism in 245 individuals, all of whom were infected with T. cruzi. One hundred sixty-nine patients had CCC, and 76 were asymptomatic.
Genotype distributions differed between the CCC and asymptomatic groups (chi2 = 9.4; P = .009), with an excess of genotypes with the A allele (AA + AG) in the CCC group. Among patients with CCC, 5% were homozygous for the G allele, compared with 16% of the asymptomatic subjects (odds ratio [OR], 4.1; 95% confidence interval [CI], 1.7-11; P = .001). A similar trend was observed when individuals heterozygous for the G allele were compared with individuals homozygous for the G allele between the CCC and asymptomatic groups (OR, 2.7; 95% CI, 0.97-7.2; P = .026). The A allele seems to confer susceptibility to CCC (OR, 1.9; 95% CI, 1.3-2.9; P = .001).
The CCL2 variant correlated with a low transcriptional level behaves as a genetic modifier of clinical outcome for T. cruzi infection, and subjects with the CCL2 -2518AA genotype have a 4-fold greater risk of developing CCC than do those without this genotype.
仅一部分感染克氏锥虫的个体发展为慢性查加斯心肌病（CCC）。在流行地区，CCC的家族聚集现象表明易感性可能具有遗传性，这或许可以解释为何仅有三分之一感染克氏锥虫的个体发展为CCC。单核细胞趋化蛋白-1（CCL2/MCP-1）已被证明可增强鼠巨噬细胞对克氏锥虫的摄取，并上调诱导型一氧化氮合酶/一氧化氮系统，从而使一氧化氮产量增加，进而控制寄生虫的复制。
我们通过聚合酶链反应和限制性片段长度多态性，对245名均感染克氏锥虫的个体评估了已知会影响转录活性的位于-2518A/G位置的CCL2变体。其中169例患者患有CCC，76例无症状。
CCC组和无症状组的基因型分布存在差异（χ2 = 9.4；P = 0.009），CCC组中携带A等位基因（AA + AG）的基因型更多。在患有CCC的患者中，5%为G等位基因纯合子，而无症状受试者中这一比例为16%（优势比[OR]，4.1；95%置信区间[CI]，1.7 - 11；P = 0.001）。当比较CCC组和无症状组中G等位基因杂合子个体与G等位基因纯合子个体时，观察到类似趋势（OR，2.7；95% CI，0.97 - 7.2；P = 0.026）。A等位基因似乎赋予了对CCC的易感性（OR，1.9；95% CI，1.3 - 2.9；P = 0.001）。
与低转录水平相关的CCL2变体是克氏锥虫感染临床结局的遗传修饰因子，携带CCL2 -2518AA基因型的个体患CCC的风险比未携带该基因型的个体高4倍。
