title: CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: a case-control study.
abstract: 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 (IVS2-36A>G and IVS8 +119 C>T) and in coding sequence (c.157 G>A in exon 2, c.358 G>A in exon 4 and c.915 G>A 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 IVS2-36A>G and c.915 G>A showed statistically significant differences in frequencies between patients and controls [(χ2, 6.583; P<0.037); (χ2, 14.205; P<0.001)]. 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 (IVS2-36A>G) 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 G> A (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 G>A in exon 4 (χ2, 15.977; P<0.04) and c.915 G>A in exon 8 (χ2, 18.109; P<0.02) were significantly associated with different types of symptoms. Haplotype analysis, performed only on polymorphisms c.358 G>A (p.Val120Ile), c.915 G>A (p.Thr305 Thr) and IVS2-36A>G, 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 IVS2-36A>G and c.915 G>A polymorphisms indicating their possible association with sporadic CCMs and an increased risk of CCM. On the other hand, polymorphisms c.358 G>A and c.915 G>A were associated with a more benign course of the disease. These data were confirmed by the haplotype GAG (+--) frequencies.
authors.affiliation: Department of Biomorphology and Biotechnologies, Division of Biology and Genetics, University of Messina, I-98125 Messina, Italy. rdangelo@unime.it
authors.forename: Rosalia
authors.initials: R
authors.lastname: D'Angelo
authors.forename: Concetta
authors.initials: C
authors.lastname: Scimone
authors.forename: Carmela
authors.initials: C
authors.lastname: Rinaldi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Trimarchi
authors.forename: Domenico
authors.initials: D
authors.lastname: Italiano
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.forename: Aldo
authors.initials: A
authors.lastname: Amato
authors.forename: Antonina
authors.initials: A
authors.lastname: Sidoti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D020786:Hemangioma, Cavernous, Central Nervous System / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D007223:Infant; D007558:Italy; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D011859:Radiography; D012307:Risk Factors; D012984:Software; D055815:Young Adult
chemical_list: C502544:CCM2 protein, human; D002352:Carrier Proteins