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HLA-DQA1*0501 is associated with diffuse systemic sclerosis in Caucasian men
N C Lambert1, O Distler, U Müller-Ladner
1Immunogenetics Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Insights
A specific Human Leukocyte Antigen (HLA) DQA1 allele is linked to systemic sclerosis (SSc) in men, suggesting a greater genetic contribution of HLA genes to SSc risk in males. This finding advances understanding of SSc pathogenesis in men.
Area of Science:
- Immunogenetics
- Rheumatology
- Human Genetics
Background:
- Systemic sclerosis (SSc) is a rare autoimmune disease with limited understanding of its pathogenesis in men.
- Human Leukocyte Antigen (HLA) class II alleles are implicated in autoimmune diseases, but their specific role in male SSc is underexplored.
Purpose of the Study:
- To investigate HLA class II alleles (DQA1, DQB1, DRB1) in Caucasian men with SSc.
- To explore the hypothesis that maternal HLA compatibility is a risk factor for SSc in men.
Main Methods:
- Sequence-specific oligonucleotide probe typing was employed to determine HLA DQA1, DQB1, and DRB1 alleles.
- Allele frequencies were compared between SSc patients (50 men, 36 parous women) and healthy controls (59 men, 80 parous women).
- Mothers of SSc patients and healthy men were also genotyped to assess maternal HLA compatibility.
Main Results:
- The DQA1*0501 allele was significantly more frequent in men with SSc compared to healthy men (OR 2.3, P=0.006).
- DQA1*0501 was specifically associated with diffuse SSc in men (OR 3.0, P=0.004).
- No increased risk of SSc in men was associated with maternal HLA compatibility.
Conclusions:
- A specific DQA1 allele (DQA1*0501) is associated with SSc in men, potentially explaining previously observed DRB1 associations due to linkage disequilibrium.
- The genetic contribution of HLA genes to SSc risk appears substantially greater in men than in parous women.
- This study highlights sex-specific genetic factors in SSc pathogenesis.
Objective:
Systemic sclerosis (SSc) is uncommon in men, and relatively little is known about factors contributing to its pathogenesis in this population. In the current study, we investigated HLA class II alleles in men with SSc. We also investigated the hypothesis that HLA compatibility of the mother could be a risk factor for SSc in men.
Methods:
Sequence-specific oligonucleotide probe typing was used to determine DQA1, DQB1, and DRB1 alleles of SSc patients (50 men and 36 parous women), healthy controls (59 men and 80 parous women), 26 mothers of men with SSc, and 44 mothers of healthy men. All study subjects were Caucasian, and allele frequencies were compared with those of Caucasian controls from the Eleventh International Histocompatibility Workshop as well as those of local controls.
Results:
The DQA1*0501 allele was significantly increased among men with SSc compared with healthy men (odds ratio [OR] 2.3, P = 0.006, Pcorr = 0.04). DQA1*0501 was associated with diffuse SSc in men (OR 3.0, P = 0.004, Pcorr = 0.03), but not with limited SSc in men. Maternal HLA compatibility was not a risk factor for SSc in men.
Conclusion:
Previous studies have shown associations of DRB1 alleles with SSc, but have rarely determined DQA1 allele frequencies. Our findings indicate that a specific DQA1 allele is associated with SSc, and that DRB1 associations may be due to linkage disequilibrium with DQA1. Moreover, by analyzing genetic susceptibility according to sex, we found that the contribution of HLA genes to the risk of SSc was substantially greater in men than in parous women.