Haplospecific polymorphism between HLA B and tumor necrosis factor

Area of Science:

• Human Genetics
• Immunogenetics
• Molecular Biology

Background:

• The human major histocompatibility complex (MHC) is a highly polymorphic region crucial for immune response.
• Understanding the organization and conservation of genes within the MHC, such as HLA B and tumor necrosis factor (TNF), is vital for disease association studies.

Purpose of the Study:

• To investigate genetic polymorphisms between the HLA B and TNF genes.
• To determine the inheritance patterns and conservation of these polymorphisms within ancestral haplotypes (AH).
• To explore potential associations between specific haplotypes and disease resistance, such as insulin-dependent diabetes mellitus (IDDM).

Main Methods:

• Genomic DNA from 50 cell lines, including 37 homozygotes representing 21 ancestral haplotypes, was analyzed.
• Restriction fragment length polymorphism (RFLP) analysis was performed using three genomic probes (X, Y, V) after Taq I and Rsa I digestion.
• Family studies were conducted to trace the inheritance of identified alleles and haplotypes.

Main Results:

• Extensive polymorphism was detected between HLA B and TNF, with multiple allelic patterns observed for probes X, Y, and V.
• Identified alleles (Y, X, V) were inherited and segregated with HLA haplotypes, demonstrating haplotypic conservation.
• Eleven out of 15 observed Y-X-V haplotypes were specific to particular AHs, indicating strong haplospecificity.
• Two race-specific AHs associated with IDDM resistance shared the same Y-X-V haplotype, suggesting a potential link to IDDM susceptibility genes.

Conclusions:

• The region between HLA B and TNF, including specific ancestral haplotypes, is conserved as a block.
• The shared Y-X-V haplotype in IDDM-resistant individuals points to the possibility of localizing genes influencing IDDM.
• These findings reinforce the concept of MHC ancestral haplotypes being conserved en bloc.