Genetic association between polymorphisms in the ADAMTS14 gene and multiple sclerosis.
ADAMTS14 is a novel member of the ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 modules) metalloproteinase family which processes extracellular matrix proteins. In the present study we performed a comprehensive investigation of the ADAMTS14 as a candidate gene for susceptibility to multiple sclerosis (MS). Eight single nucleotide polymorphisms (SNPs) were analyzed in a case-control study of 287 patients with MS [192 with relapsing-remitting MS (RRMS) and 95 with primary-progressive MS (PPMS)], and 285 age- and sex-matched controls. Allele and genotype frequencies were compared between controls and the MS subgroups, and gene-based haplotypes were reconstructed by computational procedures. Pairwise linkage disequilibrium values (D') suggested that three locus pairs (SNPs 3 through 5) had alleles in strong disequilibrium and constituted a haplotype block spanning 14 kb. Overall comparisons of allele and genotype frequencies showed association for SNPs 3 and 6 with MS. Stratification of MS patients according to major clinical forms revealed an increased frequency of both allele C (p = 0.006) and CC homozygosity (p = 0.008) at SNP6 in RRMS patients compared with controls. PPMS was associated with allele A at SNP2 compared with RRMS (p = 0.003) and controls (p = 0.009), and with CG heterozygosity at SNP3 compared with controls (p = 0.005). Haplotype frequency comparisons showed significant association between PPMS and the AGGGC haplotype compared with controls (p = 0.0004), and negative association between RRMS and the GGAGT haplotype compared with controls (p = 0.0026). No association was detected between different genotypes and disease severity measured by the Multiple Sclerosis Severity Score (MSSS). These findings suggest a potentially important role for the ADAMTS14 gene in predisposition to MS.
Goertsches
Robert
R
Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron (HUVH), Escuela de Enfermeria 2(a) planta, Psg Vall d'Hebron 119-129, 08035 Barcelona, Spain.
Comabella
Manuel
M
Navarro
Arcadi
A
Perkal
Hector
H
Montalban
Xavier
X
D051722:ADAM Proteins; D000071096:ADAMTS Proteins; D000328:Adult; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10; D019295:Computational Biology / Q000379:methods; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000145:classification / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C447060:ADAMTS14 protein, human; D008666:Metalloendopeptidases