Chromosome 7q21-22 and multiple sclerosis: evidence for a genetic susceptibility effect in vicinity to the protachykinin-1 gene.
Chromosome 7q21-22 and, in particular, the region surrounding D7S554 emerged from the recent American genome screen in multiple sclerosis (MS) as the most promising region genome-wide for harboring a disease susceptibility gene. We tested association between D7S554 and MS in 217 Sardinian trio MS families by the transmission disequilibrium test (TDT), and in a Northern Irish case-control study comprising 542 individuals. In both populations, we found evidence for significant allelic association (P(c)=0.04 and P(c)=0.0002, respectively). In a second stage, we analysed five microsatellite markers in a 4 megabase interval on chromosome 7q21-22 in the same set of Sardinian families. Parental transmission of a single allele of one of these markers, i.e. D7S3126, was significantly distorted (P(c)=0.008). D7S554 and D7S3126 are located at distances of, respectively, 40 and 81 kb 5' from the startcodon of the protachykinin-1 gene (TAC1), and occur in strong linkage disequilibrium (P<10(-7)). Our study indicates that the previous finding of linkage with D7S554 refers possibly to the presence of an MS susceptibility effect in vicinity to TAC1. In addition, a second independent association was uncovered between a microsatellite polymorphism in the plasminogen activator inhibitor-1 gene, i.e. D7S477, and MS. Overall, the analysis presented here may contribute to the increasingly refined genomic map of MS and underscores the requirement for a further high-resolution screening of chromosome 7q21-22.
Vandenbroeck
Koen
K
Rega Institute for Medical Research, University of Leuven, B-3000 Louvain, Belgium. k.vandenbroeck@qub.ac.uk
Fiten
Pierre
P
Heggarty
Shirley
S
Goris
An
A
Cocco
Eleonora
E
Hawkins
Stanley A
SA
Graham
Colin A
CA
Marrosu
Maria G
MG
Opdenakker
Ghislain
G
D000328:Adult; D016022:Case-Control Studies; D002897:Chromosomes, Human, Pair 7; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D007494:Ireland; D007558:Italy; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D009103:Multiple Sclerosis / Q000235:genetics*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011110:Polymorphism, Genetic; D011498:Protein Precursors / Q000235:genetics*; D013373:Substance P / Q000235:genetics; D015320:Tachykinins / Q000235:genetics*; D013947:Thymosin / Q000031:analogs & derivatives* / Q000235:genetics; D014452:Ubiquitins / Q000235:genetics
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D017395:Plasminogen Activator Inhibitor 1; D011498:Protein Precursors; D015320:Tachykinins; D014452:Ubiquitins; C054618:protachykinin; D013373:Substance P; C047192:thymosin beta(1); D013947:Thymosin