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TWO SNPs AT HSPA1B AND HLA-DQA1 IDENTIFY ANCESTRAL MHC CLASS II LINEAGES.
Wenshuo Shao, MD, Richard A. Kaslow, MD MPH and M.Tevfik Dorak, MD PhD. Birmingham AL, USA, University of Alabama at Birmingham, 35294, Epidemiology.

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Haplotypes marked by the second expressed DRB genes DRB3, DRB4 and DRB5 represent ancestral lineages. Phylogenetic analysis of DRB1 exon 2 sequences has identified the DRB4/DRB5 group [group I] and the DRB3 group [group II] as distinct lineages. An earlier study suggested a correlation between a bi-allelic DQA1 RFLP and these two lineages. To elaborate this relationship, we typed 101 reference cell lines and 415 Caucasian newborn DNAs at two SNP sites. The first SNP was at DQA1 3' UTR site (selected by aligning available DQA1 genomic DNA sequences). The other one was the previously known HSPA1B (HSP70-2) 1267A>G PstI polymorphism. The DQA1 SNP *499C>A (at nucleotide 499 after translation termination) was typed by PCR-RFLP using BglII. The two groups of conserved extended haplotypes showed a correlation with two HSPA1B-DQA1 haplotypes identified by these SNPs. All members of group I had DQA1*499C along with a subset of rare group II haplotypes characterized by DQA1*01-DQB1*06. All other members of group II, mainly the major DRB1*03 haplotypes of Africans, Caucasians and Mongolians, had the *499A allele. In general, the haplotypes that had DQA1*499C (group I) also had HSPA1B allele 1267A and group II had 1267G. These relationships did not extend to other loci telomeric to HSPA1B. The results in the already HLA-typed population sample mainly confirmed these results by showing following linkage disequilibrium (LD) patterns (P<0.001): HSPA1B-DQA1 SNPs (Δ=0.0512); DQA1*499A-DRB3 (Δ=0.0796), and DQA1*499C-DRB5 (Δ=0.0374). DQA1*499C was also in LD with DRB4 (P<0.05). The two SNP haplotypes described here may be used in evolutionary-based haplotype association studies. They also define simple polymorphisms needed for studies of heterozygote advantage in this region.