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C4A gene deletion and HLA associations in black Americans with systemic lupus erythematosus
M L Olsen1, R Goldstein, F C Arnett
1Department of Internal Medicine, University of Texas Health Science Center Houston 77225.
Insights
A C4A, CYP21A gene deletion is a significant genetic risk factor for systemic lupus erythematosus (SLE) in Black Americans. This deletion is strongly associated with specific HLA alleles, particularly HLA-DR2 and HLA-DR3.
Area of Science:
- Genetics
- Immunology
- Molecular Biology
Background:
- Systemic lupus erythematosus (SLE) has known genetic associations in Caucasian populations, including deletions in the C4A, CYP21A gene linked to specific HLA haplotypes.
- Previous studies have not identified consistent HLA associations for SLE in Black populations, though some reported an increased frequency of C4A null alleles.
Purpose of the Study:
- To investigate if a C4A, CYP21A gene deletion is a genetic risk factor for SLE in Black Americans.
- To characterize the nature of this deletion and identify associated HLA phenotypes.
Main Methods:
- Restriction fragment length polymorphism (RFLP) analysis was used to study 79 Black American SLE patients and 68 Black controls.
- Phenotypic and genotypic frequencies of the C4A, CYP21A gene deletion were determined.
- Associations with various HLA alleles (HLA-B8, -DR3, -DR2, -B44) were analyzed.
Main Results:
- A C4A, CYP21A gene deletion was found in 24% of SLE patients versus 7.4% of controls (P = .005), indicating a fourfold increased risk.
- Genotypic analysis revealed a deletion frequency of 14.5% in SLE patients compared to 3.7% in controls (P = .001), a 4.5-fold increased risk.
- The deletion was significantly associated with HLA-DR2 (P = .03) and HLA-DR3 (P = .03), with all deleted subjects carrying at least one of these alleles.
- HLA-B44 (P = .02) and HLA-B8 (P = .08) also showed associations with the deletion.
- A unique C4B gene polymorphism was observed, with 80% of the Black population having the C4B 'short' form compared to 40% in whites.
Conclusions:
- A large C4A, CYP21A gene deletion, particularly linked with HLA-B44, -DR2, and -DR3 alleles, is the most significant genetic risk factor identified for SLE susceptibility in Black Americans.
- The high frequency of the C4B 'short' gene form in this population may contribute to the formation of the C4A, CYP21A deletion.
Abstract:
In North America and European Caucasoids with systemic lupus erythematosus (SLE) there is an increased frequency of a C4A, CYP21A gene deletion, largely associated with the HLA-B8,DR3,C4A*QO extended haplotype. There have been no consistent HLA associations reported for SLE in blacks, although an increased frequency of serologically determined C4A null alleles has been reported in two studies. We studied 79 black American SLE patients and 68 black controls by restriction fragment length polymorphism analysis to determine if a C4A gene deletion was a genetic risk factor for SLE. Moreover, the nature of the deletion and any HLA phenotypic associations were sought. Nineteen of 79 (24%) patients compared to 5 of 68 (7.4%) controls had a phenotypic C4A,CYP21A gene deletion (P = .005; RR = 4). A homozygous deletion in four patients gave a genotypic frequency of 23/158 (14.5%) SLE patients vs 5/136 (3.7%) controls (P = .001; RR = 4.5). The deletion was associated with HLA-DR2 (P = .03) and HLA-DR3 (P = .03). Moreover, all subjects with the deletion had HLA-DR2 or DR3 (P = 7.7 x 10(-6). HLA-B44 was also associated with the deletion (P = .02), and eight of the nine HLA-B44 positives also carried HLA-DR2. HLA-B8 approached significance (P = .08) and was always accompanied by HLA-DR3. Finally, this black population demonstrated a unique C4B gene size polymorphism with 80% C4B "short" as compared to the 40% C4B "short" frequency reported in whites. We conclude that a large C4A,CYP21A gene deletion, particularly associated with the HLA-B44, -DR2, and -DR3 alleles, is the strongest genetic risk factor thus far identified for SLE susceptibility in black Americans. Furthermore, the unique preponderance of the C4B "short" gene form may be a factor in the actual formation of the deletion.