CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: A case-control study

Cerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Among our group of CCM Italian patients, we selected a cohort of sporadic cases negative for mutations in CCM genes. In this cohort, five variants in CCM2 gene were detected, which proved to be the known polymorphisms in intronic regions (IVS2-36AG and IVS8 +119 CT) and in coding sequence (c.157 GA in exon 2, c.358 GA in exon 4 and c.915 GA in exon 8). Therefore, we undertook a case-control study to investigate the possible association of these polymorphisms with sporadic CCMs. The five polymorphisms were identified in 91 CCM sporadic patients and in 100 healthy controls by direct sequencing methods using lymphocyte DNA. Polymorphisms IVS2-36AG and c.915 GA showed statistically significant differences in frequencies between patients and controls [(χ2, 6.583; P0.037); (χ2, 14.205; P0.001)]. The prevalence of the wild-type genotype was significantly lower in the CCM group than in the control sample. Patients with the A/G and G/G genotypes (IVS2-36AG) had a significant increase for CCM risk (OR, 3.08; 95% CI, 1.5-5.9 and OR, 4.3; 95% CI, 1.4-22.6) and the same was observed for the polymorphism c.915 GA (genotype G/A OR, 6.1; 95% CI, 3.0-12.6 and genotype A/A OR, 2.79). In addition, the polymorphisms c.358 GA in exon 4 (χ2, 15.977; P0.04) and c.915 GA in exon 8 (χ2, 18.109; P0.02) were significantly associated with different types of symptoms. Haplotype analysis, performed only on polymorphisms c.358 GA (p.Val120Ile), c.915 GA (p.Thr305 Thr) and IVS2-36AG, shows that haplotype GAG (+--) significantly increased among CCM sporadic patients compared to the control group. Significant differences between patients and controls were observed only for IVS2-36AG and c.915 GA polymorphisms indicating their possible association with sporadic CCMs and an increased risk of CCM. On the other hand, polymorphisms c.358 GA and c.915 GA were associated with a more benign course of the disease. These data were confirmed by the haplotype GAG (+--) frequencies.