Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region.
BACKGROUND
Human leukocyte antigen (HLA)-DR2 carriership is associated with an increased risk for MS. Genome searches using microsatellite markers have consistently shown that additional genetic factors contribute to susceptibility for MS.


OBJECTIVE
To identify loci within the HLA region that predispose to relapse-onset MS independently of HLA-DR2.


METHODS
A case-control study involving 159 patients with definite relapse-onset MS and 273 control subjects was conducted. Six highly polymorphic microsatellite markers encoded within the HLA-C to DR region, that is, D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2, three single-nucleotide tumor necrosis factor (TNF) promoter gene polymorphisms at positions -238, -308, and -376, and HLA-DR2 carriership were typed.


RESULTS
These data confirmed the well-known association between the HLA-DR2 haplotype and relapse-onset MS, yielding an odds ratio (OR) of 3.6 (95% CI: 2.4 to 5.4; p < 0.0001). Multivariate analyses revealed that C1_3_2*354 was also associated with an increased risk for developing relapse-onset MS independently of HLA-DR2 (OR: 2.0; 95% CI: 1.2 to 3.1; p = 0.004). This allele is encoded within an ancestral haplotype that is highly linked to HLA-DR3. The joint effect of this ancestral haplotype and HLA-DR2 resulted in an OR of 8.7 (95% CI: 2.7 to 29; p < 0.0001) to develop relapse-onset MS. In addition, a protective risk factor was found: carriers of TNFa*107 had a 0.5-fold lower risk to develop relapse-onset MS (95% CI: 0.3 to 0.9; p = 0.026).


CONCLUSIONS
Within the HLA region, other loci besides HLA-DR2 haplotype modulate susceptibility for relapse-onset MS.
Department of Clinical Epidemiology, LUMC, Leiden, The Netherlands.
B A
BA
de Jong
T W J
TW
Huizinga
E
E
Zanelli
M J
MJ
Giphart
E L E M
EL
Bollen
B M J
BM
Uitdehaag
C H
CH
Polman
R G J
RG
Westendorp
D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D018628:Gene Dosage; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D015802:HLA-DR2 Antigen / Q000235:genetics*; D015803:HLA-DR3 Antigen / Q000235:genetics; D006239:Haplotypes; D006579:Heterozygote; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000453:epidemiology / Q000235:genetics*; D015999:Multivariate Analysis; D009426:Netherlands / Q000453:epidemiology; D016017:Odds Ratio; D011401:Promoter Regions, Genetic / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D015802:HLA-DR2 Antigen; D015803:HLA-DR3 Antigen; D014409:Tumor Necrosis Factor-alpha