Sazci Ali, Ozel Mavi Deniz, Emel Ergul, Idrisoglu Halil Atilla
Department of Medical Biology and Genetics, Faculty of Medicine, University of Kocaeli, Kocaeli, Turkey.
Genet Test Mol Biomarkers. 2012 Jul;16(7):716-21. doi: 10.1089/gtmb.2011.0313. Epub 2012 Mar 2.
Studies have revealed that elevated homocysteine levels can cause damage to motor neurons through multiple neurotoxic mechanisms, thus leading to the pathogenesis of amyotrophic lateral sclerosis (ALS). One way by which homocysteine levels are increased in the body is the consequence of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms. Therefore, to address this question, we studied the MTHFR C677T and A1298C polymorphisms in 437 sporadic ALS (SALS) and 439 healthy controls to learn whether they were associated with SALS. The overall SALS were not associated with MTHFR C677T and A1298C polymorphisms (χ(2)=1.378; p=0.502; χ(2)=1.304; p=0.521, respectively). However, when we stratified results in terms of gender, we found that the MTHFR C677T polymorphism (χ(2)=6.376; p=0.041), T677T genotype (χ(2)=5.508; p=0.019; odds ratio [OR]=2.561; 95% confidence interval [CI]=1.142-5.744), C677C/A1298A (χ(2)=5.216; p=0.022; OR=0.424, 95% CI=0.199-0.900), and T677T/A1298A (χ(2)=6.639; p=0.010; OR=2.900; 95% CI=1.252-6.717) compound genotypes were associated with SALS in female patients only. Moreover, stratification of SALS according to the onset of disease indicated that there was no association between MTHFR C677T (χ(2)=1.565; p=0.457; A1298C χ(2)=3.461; p=0.177) polymorphisms and overall spinal onset SALS. Further stratification analysis according to gender revealed that there was a remarkable association between MTHFR C677T (χ(2)=9.728, p=0.008), T677T genotype (χ(2)=7.820; p=0.005; OR=3.126; 95% CI=1.361-7.178) and T allele (χ(2)=5.000; p=0.025; OR=1.711; 95% CI=1.067-2.745), and T677T/A1298A compound genotype (χ(2)=9.108; p=0.003; OR=3.540; 95% CI=1.494-8.387) and spinal onset female SALS only. Likewise, there was also association between MTHFR A1298C polymorphism (χ(2)=5.946; p=0.051) and the C1298C genotype (χ(2)=5.282; p=0.022; OR=2.524; 95% CI=1.125-5.658), and the C677T/C1298C compound genotype (χ(2)=7.155; p=0.007; OR=1.045; 95% CI=0.983-1.112) and bulbar onset SALS only in women. In conclusion, the evidence we provide here clearly shows that MTHFR C677T and A1298C polymorphisms are genetic risk factors for SALS in women in a gender-specific manner whether they are of spinal or bulbar onset.
研究表明，同型半胱氨酸水平升高可通过多种神经毒性机制对运动神经元造成损害，进而导致肌萎缩侧索硬化症（ALS）的发病。体内同型半胱氨酸水平升高的一种方式是亚甲基四氢叶酸还原酶（MTHFR）基因多态性的结果。因此，为解决这个问题，我们研究了437例散发性ALS（SALS）患者和439例健康对照者的MTHFR C677T和A1298C多态性，以了解它们是否与SALS相关。总体SALS与MTHFR C677T和A1298C多态性无关（χ(2)=1.378；p=0.502；χ(2)=1.304；p=0.521）。然而，当我们按性别对结果进行分层时，我们发现MTHFR C677T多态性（χ(2)=6.376；p=0.041）、T677T基因型（χ(2)=5.508；p=0.019；优势比[OR]=2.561；95%置信区间[CI]=1.142 - 5.744）、C677C/A1298A（χ(2)=5.216；p=0.022；OR=0.424，95% CI=0.199 - 0.900）以及T677T/A1298A（χ(2)=6.639；p=0.010；OR=2.900；95% CI=1.252 - 6.717）复合基因型仅与女性患者的SALS相关。此外，根据疾病起病情况对SALS进行分层表明，MTHFR C677T（χ(2)=1.565；p=0.457；A1298C χ(2)=3.461；p=0.177）多态性与总体脊髓起病的SALS之间无关联。根据性别进一步分层分析显示，MTHFR C677T（χ(2)=9.728，p=0.008）、T677T基因型（χ(2)=7.820；p=0.005；OR=3.126；95% CI=1.361 - 7.178）和T等位基因（χ(2)=5.000；p=0.025；OR=1.711；95% CI=1.067 - 2.745）以及T677T/A1298A复合基因型（χ(2)=9.108；p=0.003；OR=3.540；95% CI=1.494 - 8.387）仅与脊髓起病的女性SALS相关。同样，MTHFR A1298C多态性（χ(2)=5.946；p=0.051）与C1298C基因型（χ(2)=5.282；p=0.022；OR=2.524；95% CI=1.125 - 5.658）以及C677T/C1298C复合基因型（χ(2)=7.155；p=0.007；OR=1.045；95% CI=0.983 - 1.112）仅与延髓起病的女性SALS相关。总之，我们在此提供的证据清楚地表明，MTHFR C677T和A1298C多态性是以性别特异性方式成为女性SALS的遗传危险因素，无论其为脊髓起病还是延髓起病。
