HLA-DQA2 (DX alpha) polymorphism and insulin dependent diabetes.

Area of Science:

• Immunogenetics
• Molecular Biology
• Endocrinology

Background:

• The HLA-DQA2 locus TaqI fragment, DX alpha"U", has been previously associated with insulin-dependent diabetes mellitus (IDDM).
• Conflicting reports exist regarding the strength and nature of this association, particularly concerning its relationship with HLA-DR3 and HLA-DR4 haplotypes and potential linkage disequilibrium.

Purpose of the Study:

• To confirm the association between the HLA-DQA2 locus TaqI fragment DX alpha"U" and IDDM using a specific probe.
• To investigate the association of DQA2"U" with IDDM within subgroups defined by HLA-DR3 and HLA-DR4 status.
• To analyze the sequence of the DQA2 gene's second exon for polymorphisms in individuals with different DQA2 genotypes.

Main Methods:

• Southern blot analysis using a synthetic 97-base probe targeting a DQA2 intron.
• Analysis of IDDM and control subjects from Wisconsin, stratified by HLA-DR3 and HLA-DR4 status.
• DNA sequencing of the second exon of the DQA2 gene from individuals homozygous for DQA2"U" or DQA2"L".

Main Results:

• The study confirmed the association of DQA2"U" with IDDM.
• No significant association was found between DQA2"U" and IDDM in HLA-DR3 positive subjects (p = 0.26).
• A non-significant association between IDDM and DQA2"U" in HLA-DR4 positive subjects was fully explained by linkage disequilibrium with DQw8. Sequencing revealed minimal polymorphisms in the DQA2 second exon.

Conclusions:

• The DQA2"U" fragment is associated with IDDM, but this association is complex and influenced by other genetic factors.
• The lack of association in DR3 subjects and the linkage disequilibrium in DR4 subjects suggest that DQA2"U" may not be the primary causal factor for IDDM in these specific genetic contexts.
• Further investigation into the DQA2 gene and its surrounding regions is warranted to fully understand its role in the pathogenesis of IDDM.