Linkage disequilibrium analysis of chromosome 12q14-15 in multiple sclerosis: delineation of a 118-kb interval around interferon-gamma (IFNG) that is involved in male versus female differential susceptibility.
We have recently reported the association of a polymorphic intronic CA-repeat in the interferon-gamma gene (IFNG) with gender bias in susceptibility to multiple sclerosis (MS) in a Sardinian population. This association could refer to a functional polymorphism within IFNG or could be due to linkage disequilibrium between the IFNG marker and a neighbouring susceptibility locus. Within the average reach of linkage disequilibrium, various other candidate genes are located. Among these the most striking ones are the genes coding for the cytokines interleukin-22 (IL-22) and interleukin-26 (IL-26) that constitute together with IFNG a cytokine cluster on chromosome 12q14. To determine more precisely the location of this gender-associated susceptibility locus, we have now performed a more extensive linkage disequilibrium screen of this region using nine additional microsatellite markers. This locus appeared to be confined to a 118-kb interval that is bordered by the markers D12S313 and D12S2511, in which IFNG itself remains the main candidate gene. Haplotype analysis confirmed that this MS-associated locus protects males from developing MS according to a recessive or allele-dosage model. Our results indicate that the well-documented gender differences in susceptibility to MS are at least partially caused by genetic factors in the region surrounding IFNG.
Goris
A
A
Rega Institute, University of Leuven, Leuven, Belgium.
Heggarty
S
S
Marrosu
M G
MG
Graham
C
C
Billiau
A
A
Vandenbroeck
K
K
D000293:Adolescent; D000328:Adult; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics*; D012727:Sex Characteristics
D007371:Interferon-gamma