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Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region
B A de Jong1, T W J Huizinga, E Zanelli
1Department of Clinical Epidemiology, LUMC, Leiden, The Netherlands.
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.
Method:
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).
Conclusion:
Within the HLA region, other loci besides HLA-DR2 haplotype modulate susceptibility for relapse-onset MS.
Insights
Genetic factors beyond HLA-DR2 influence multiple sclerosis (MS) risk. A specific allele within the HLA region increases susceptibility, while another offers protection against MS.
Area of Science:
- Immunogenetics
- Human Genetics
- Neuroimmunology
Background:
- Human leukocyte antigen (HLA)-DR2 carriership is a known risk factor for multiple sclerosis (MS).
- Genome-wide searches indicate additional genetic factors contribute to MS susceptibility.
- Identifying these factors is crucial for understanding MS pathogenesis.
Purpose of the Study:
- To pinpoint genetic loci within the HLA region that independently increase the risk for relapse-onset MS, separate from the known HLA-DR2 association.
- To investigate the role of specific microsatellite markers and tumor necrosis factor (TNF) gene polymorphisms in MS susceptibility.
Main Methods:
- A case-control study was conducted with 159 relapse-onset MS patients and 273 controls.
- Genotyping included microsatellite markers (D6S1014, D6S273, TNFa, MIB, C1_2_5, C1_3_2) and TNF promoter polymorphisms (-238, -308, -376).
- HLA-DR2 carriership was also assessed.
Main Results:
- The study confirmed the association between HLA-DR2 and relapse-onset MS (OR=3.6).
- The C1_3_2*354 allele, linked to HLA-DR3, independently increased MS risk (OR=2.0).
- Combined HLA-DR2 and this ancestral haplotype significantly elevated risk (OR=8.7). TNFa*107 showed a protective effect (OR=0.5).
Conclusions:
- The HLA region contains genetic loci, in addition to HLA-DR2, that influence susceptibility to relapse-onset MS.
- Specific alleles within the HLA complex play a significant role in modulating MS risk.
- These findings highlight the complex genetic architecture of MS within the HLA region.