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Complement and HLA. Further definition of high-risk haplotypes in insulin-dependent diabetes
Insights
This study investigates human leukocyte antigen (HLA) and complement gene variations in families with insulin-dependent diabetes mellitus (IDDM). Specific HLA and complement alleles significantly increase or decrease the risk of developing IDDM.
Area of Science:
- Immunogenetics
- Human Molecular Genetics
- Endocrinology
Background:
- Type 1 diabetes mellitus (insulin-dependent diabetes mellitus, IDDM) has a strong genetic component.
- Human leukocyte antigen (HLA) and complement system genes on chromosome 6 are implicated in IDDM susceptibility.
- Previous studies identified specific HLA alleles associated with altered IDDM risk.
Purpose of the Study:
- To analyze HLA and complement polymorphisms in families of IDDM probands.
- To confirm and refine the relative risks (RR) associated with specific alleles and haplotypes.
- To investigate the role of complement polymorphisms (C2, C4A, C4B, Bf) in IDDM risk.
Main Methods:
- Typing of HLA-A, HLA-B, HLA-DR, C2, C4A, C4B, and Bf loci in 41 IDDM families.
- Calculation of relative risks (RR) for associated alleles and haplotypes.
- Analysis of high-risk haplotypes by incorporating complement polymorphism data.
Main Results:
- Confirmed increased RR for HLA-B8 (3.1), HLA-DR3 (5.2), HLA-DR4 (4.3), BfF1 (7.1), C4AQ0 (2.8), and C4B2.9 (12.6).
- Confirmed decreased RR for HLA-DR2 (0.1).
- Refined three high-risk haplotypes by including complement polymorphisms; one haplotype (B40-BfS-DR4) showed no complement clustering.
Conclusions:
- Specific HLA and complement alleles significantly influence IDDM risk.
- Complement polymorphisms provide further detail in defining high-risk IDDM haplotypes.
- The C4B2.9 variant presents a particularly high relative risk for IDDM.
Abstract:
The families of 41 probands with type I (insulin-dependent) diabetes mellitus (IDDM) were typed for HLA-A, HLA-B, and HLA-DR antigens in addition to the complement polymorphisms C2, C4A, C4B, and Bf. All of these loci are encoded on the short arm of human chromosome 6 in a narrow region. Alleles at HLA-B (8, 15, 18, and 40), HLA-DR (3 and 4), and Bf (F1) have been associated with increased relative risk (RR) for IDDM, while HLA-B7 and HLA-DR2 have been associated with decreased RR for IDDM. This study confirms those significant risks in addition to confirming increased risk for the null (silent) allele for C4A (C4AQ0) and a rare C4B variant (C4B2.9). The significantly associated antigens (alleles) and risks were: HLA-B8 (RR = 3.1), HLA-DR3 (RR = 5.2), HLA-DR4 (RR = 4.3), and BfF1 (RR = 7.1), in addition to C4AQ0 (RR = 2.8) and C4B2.9 (RR = 12.6). Significantly low risk was associated only with HLA-DR2 (RR = 0.1). In a recent study, we defined five high-risk haplotypes that were determined solely by HLA-B, Bf, and HLA-DR (B8-BfS-DR3, B8-BfS-DR4, B15-BfS-DR4, B18-BfF1-DR3, and B40-BfS-DR4). By inclusion of information from the complement polymorphism, we have defined in greater detail three of these five high-risk haplotypes. One previously identified haplotype (B40-BfS-DR4) showed no complement clustering, while the rare high-risk haplotype (B8-BfS-DR4) was seen only once in this smaller sample.(ABSTRACT TRUNCATED AT 250 WORDS)