Comparative genomic analysis, diversity and evolution of two KIR haplotypes A and B.

Members of the killer immunoglobulin (Ig)-like receptor (KIR) gene family are tightly clustered on human chromosome 19q13.4. Despite considerable variation in KIR gene content and allelic polymorphism, most KIR haplotypes belong to one of two broad groups termed A and B. The availability of contiguous genomic sequences for these haplotypes has allowed us to compare their genomic organization, nucleotide (nt) diversity and reconstruct their evolutionary history. The haplotypes have a framework of three conserved blocks containing (i) KIR3DL3, (ii) KIR3DP1, 2DL4, and (iii) KIR3DL2 that are interrupted by two variable segments that differ in the number and type of KIR genes. Low (0.05%) nucleotide diversity was detected across the centromeric and telomeric boundaries of the KIR gene cluster while higher SNP density (0.2%) occurred within the central region containing the KIR2DL4 gene. Phylogenetic and genomic analyses have permitted the reconstruction of a hypothetical ancestral haplotype that has revealed common groupings and differences between the KIR genes of the two haplotypes. The present phylogenetic and genomic comparison of the two sequenced KIR haplotypes provides a framework for a more thorough examination of KIR haplotype variations, diversity and evolution in human populations and between humans and non-human primates.

The poliovirus receptor related 2 (PRR2) and apolipoprotein E genes and coronary heart disease.

BACKGROUND: Recently, we localized the Human Poliovirus Receptor Related 2 Gene (PRR2) 17kb centromeric to the gene for apolipoprotein E (APOE). Common polymorphisms in the latter have been found, in some studies, to be related to coronary heart disease (CHD) but the PRR2 gene has not been studied in this context. Here, we examined relationships between a PRR2 Sau96I (A/G) polymorphism, the epsilon2, 3 and 4 alleles of APOE and CHD. DESIGN AND METHODS: Consecutive Caucasian patients (n = 640) < 50 years with angiographically documented coronary obstructive disease and/or with unequivocal myocardial infarction were compared with 624 control subjects, aged 30-50 years, randomly selected from the community and without a history of CHD. RESULTS: An excess of PRR2-A homozygotes was observed in cases (20% vs. 15%; OR 1.4, CI 1.04-1.86, P = 0.026) particularly in those with single vessel disease (OR 1.7, CI 1.2-2.4, P <0.01). The A allele was in linkage disequilibrium with the epsilon4 allele and the G allele with the epsilon2. Overrepresentation of the A allele and underrepresentation of the G allele in the CHD group did not reach significance (P = 0.054). While the epsilon2 allele was underrepresented in the CHD group (OR 0.64, CI 0.46-0.89, P = 0.009), the epsilon4 allele was not significantly overrepresented. CONCLUSION: The relationship between the PRR2 Sau96I (A/G) polymorphism and early onset coronary artery disease may be due to linkage disequilibrium with the APOE gene and underrepresentation, or a protective effect, of the epsilon2 allele. Alternatively, since A allele homozygosity is particularly overrepresented, the relationship could be more direct, perhaps through a viral association.