Global distribution of the CCR2-64I/CCR5-59653T HIV-1 disease-protective haplotype

Objectives: Several natural polymorphisms in the genes for the human CC-che mokine receptors CCR5 and CCR2 are associated with HIV-1 disease. The CCR2- 641 genetic variant [a G to A substitution resulting in a valine (V) to iso leucine (I) change at position 64] is in strong linkage disequilibrium with a mutation within the CCR5 regulatory region (CCR5-59653T). individuals wi th two CCR2-641 alleles are not resistant to sexual transmission of HIV-I, but progress significantly more slowly to HIV-1 disease. It is therefore im portant to determine the global distributions of CCR2-641 and CCR5-59653T g enetic Variants and define the degree of linkage between them. Design and methods: We have developed molecular beacon-based, real-time PCR allele discrimination assays for all three chemokine receptor mutations, a nd used these spectral genotyping assays to genotype 3923 individuals from a globally distributed set of 53 populations. Results: CCR2-641 and CCR5-59653T genetic variants are found in almost all populations studied: their allele frequencies are greatest (similar to 35%) in Africa and Asia but decrease in Northern Europe. We confirm that CCR2-6 41 is in strong linkage disequilibrium with CCR5-59653T (96.92% of individu als had the same genotype for both CCR2-641 and CCR5-59653T polymorphisms). Conclusions: The greater geographical distribution of the CCR2-641/CCR5-596 53T haplotype compared with that of CCR5-Delta 32 suggests that it is a muc h older mutation whose origin predates the dispersal of modern humans. (C) 2000 Lippincott Williams & Wilkins.