title: Variations of the perforin gene in patients with multiple sclerosis.
abstract: Perforin is involved in cell-mediated cytotoxicity and mutations of its gene (PRF1) cause familial hemophagocytic lymphohistiocytosis (FLH2). PRF1 sequencing in 190 patients with multiple sclerosis and 268 controls detected two FLH2-associated variations (A91V, N252S) in both groups and six novel mutations (C999T, G1065A, G1428A, A1620G, G719A, C1069T) in patients. All together, carriers of these variations were more frequent in patients than in controls (phenotype frequency: 17 vs 9%, P=0.0166; odds ratio (OR)=2.06, 95% confidence interval (CI): 1.13-3.77). Although A91V was the most frequent variation and displayed a trend of association with multiple sclerosis (MS) in the first population of patients and controls (frequency of the 91V allele: 0.076 vs 0.043, P=0.044), we used it as a marker to confirm PRF1 involvement in MS and assessed its frequency in a second population of 966 patients and 1520 controls. Frequency of the 91V allele was significantly higher in patients than in controls also in the second population (0.075 vs 0.058%, P=0.019). In the combined cohorts of 1156 patients and 1788 controls, presence of the 91V allele in single or double dose conferred an OR=1.38 (95% CI=1.10-1.74). These data suggest that A91V and possibly other perforin variations indicate susceptibility to MS.
authors.affiliation: Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases, A Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cappellano
authors.forename: E
authors.initials: E
authors.lastname: Orilieri
authors.forename: C
authors.initials: C
authors.lastname: Comi
authors.forename: A
authors.initials: A
authors.lastname: Chiocchetti
authors.forename: S
authors.initials: S
authors.lastname: Bocca
authors.forename: E
authors.initials: E
authors.lastname: Boggio
authors.forename: I S
authors.initials: IS
authors.lastname: Bernardone
authors.forename: A
authors.initials: A
authors.lastname: Cometa
authors.forename: R
authors.initials: R
authors.lastname: Clementi
authors.forename: N
authors.initials: N
authors.lastname: Barizzone
authors.forename: S
authors.initials: S
authors.lastname: D'Alfonso
authors.forename: L
authors.initials: L
authors.lastname: Corrado
authors.forename: D
authors.initials: D
authors.lastname: Galimberti
authors.forename: E
authors.initials: E
authors.lastname: Scarpini
authors.forename: F R
authors.initials: FR
authors.lastname: Guerini
authors.forename: D
authors.initials: D
authors.lastname: Caputo
authors.forename: D
authors.initials: D
authors.lastname: Paolicelli
authors.forename: M
authors.initials: M
authors.lastname: Trojano
authors.forename: L
authors.initials: L
authors.lastname: Figà-Talamanca
authors.forename: M
authors.initials: M
authors.lastname: Salvetti
authors.forename: F
authors.initials: F
authors.lastname: Perla
authors.forename: M
authors.initials: M
authors.lastname: Leone
authors.forename: F
authors.initials: F
authors.lastname: Monaco
authors.forename: U
authors.initials: U
authors.lastname: Dianzani
mesh_terms: D001483:Base Sequence; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000235:genetics*; D054353:Perforin / Q000235:genetics*; D012015:Reference Standards
chemical_list: D054353:Perforin