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HLA-DR4 and Gm(1,3;5,21) are associated with U1-nRNP antibody positive connective tissue disease
Insights
Human leukocyte antigen (HLA) -DR4 and IgG heavy chain allotypes Gm(1,3;5,21) are associated with U1-nRNP antibody formation. These genetic markers may influence disease onset but not disease expression in connective tissue diseases.
Area of Science:
- Immunogenetics
- Rheumatology
- Autoimmunity
Background:
- Patients with U1-nRNP antibodies present with heterogeneous clinical features, including systemic lupus erythematosus, scleroderma, rheumatoid arthritis, and mixed connective tissue disease (MCTD).
- The genetic factors influencing U1-nRNP antibody formation and subsequent disease expression remain incompletely understood.
Purpose of the Study:
- To investigate the association of human leukocyte antigen (HLA) and IgG heavy chain allotypes with the presence of U1-nRNP antibodies.
- To determine if these genetic markers correlate with specific clinical manifestations or disease onset in patients with U1-nRNP antibodies.
Main Methods:
- Patients with U1-nRNP antibodies (n=35) were genotyped for HLA-A, -B, -C, and -DR antigens and IgG heavy chain allotypes (G1m and G3m).
- Clinical data, including American Rheumatism Association criteria for various connective tissue diseases and presence of MCTD, were collected.
- Frequencies of HLA and Gm allotypes in patients were compared with those in healthy blood donors (controls).
Main Results:
- A significantly higher frequency of HLA-DR4 (66% vs 28%, p=0.00053) and Gm(1,3;5,21) phenotype (46% vs 25%, p=0.0247) was observed in patients with U1-nRNP antibodies compared to controls.
- The combined presence of HLA-DR4 and Gm(1,3;5,21) showed a strong association with U1-nRNP antibody formation (relative risk = 8.0).
- These genetic markers were associated with earlier disease onset (mean 27.9 vs 40.1 years, p<0.05) but did not differ in frequency between patients with or without MCTD, suggesting a role in antibody formation rather than disease expression.
Conclusions:
- HLA-DR4 and Gm(1,3;5,21) are significantly associated with the presence of U1-nRNP antibodies.
- These genetic factors appear to influence the propensity for U1-nRNP antibody formation and may contribute to an earlier onset of disease.
- The identified genetic markers are not directly linked to the specific clinical manifestations or disease expression in patients with U1-nRNP antibodies.
Abstract:
Patients with U1-nRNP antibodies (n = 35, 31 female, four male) were typed for HLA-A, -B, -C, and -DR antigens and IgG heavy chain allotypes G1m(1), -(2), -(3), G3m(5), and -(21). The patient group was clinically heterogeneous. Four met the American Rheumatism Association criteria for systemic lupus erythematosus, six for progressive scleroderma, and 14 for rheumatoid arthritis. Sicca syndrome was present in seven cases. Twenty three had overlapping features compatible with mixed connective tissue disease (MCTD). Healthy blood donors served as controls for HLA typing (n = 64), Gm typing (n = 228), or both (n = 56). Sixty six per cent of the patients with U1-nRNP antibodies were DR4 positive compared with 28% of the controls (relative risk = 4.9, p = 0.00053). The Gm(1,3;5,21) phenotype was found in 46% of the patients and 25% of the controls (relative risk = 2.47, p = 0.0247). Within the patient group Gm(1,3;5,21) was found only in DR4 positive individuals. The coincidence of HLA-DR4 and Gm(1,3;5,21) increases the relative risk values to 8.0 (compared with the group with neither risk factor). DR4 and Gm(1,3;5,21) primarily seem to be related to U1-nRNP antibody formation and not to disease expression. Patients with or without MCTD did not differ with respect to DR4 or Gm(1,3;5,21) frequency. Disease onset was earlier in patients with HLA-DR4/Gm(1,3;5,21) than in patients without both markers (mean 27.9 v 40.1 years; p less than 0.05).