Objectives: Several natural polymorphisms in the genes for the human CC-chemokine receptors CCR5 and CCR2 are associated with HIV-1 disease. The CCR2-64I genetic variant [a G to A substitution resulting in a valine (V) to isoleucine (I) change at position 64] is in strong linkage disequilibrium with a mutation within the CCR5 regulatory region (CCR5-59653T). Individuals with two CCR2-64I alleles are not resistant to sexual transmission of HIV-1, but progress significantly more slowly to HIV-1 disease. It is therefore important to determine the global distributions of CCR2-64I and CCR5-59653T genetic 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, and used these spectral genotyping assays to genotype 3923 individuals from a globally distributed set of 53 populations.
Results: CCR2-64I and CCR5-59653T genetic variants are found in almost all populations studied: their allele frequencies are greatest (∼35%) in Africa and Asia but decrease in Northern Europe. We confirm that CCR2-64I is in strong linkage disequilibrium with CCR5-59653T (96.92% of individuals had the same genotype for both CCR2-64I and CCR5-59653T polymorphisms).
Conclusions: The greater geographical distribution of the CCR2-64I/CCR5-59653T haplotype compared with that of CCR5-Δ32 suggests that it is a much older mutation whose origin predates the dispersal of modern humans.
From the Department of Biological Anthropology, Oxford University, Oxford OX2 6QS, UK and aThe Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 100016, USA.
Sponsorship: Supported by the National Institutes of Health under RO1 AI43868 (L.G.K.), AI41420 (J.P.M.), the Wellcome trust (J.J.M.) and the Pediatric AIDS Foundation, of which J.P.M. is an Elizabeth Glaser Scientist.
Requests for reprints to: L.G. Kostrikis, Aaron Diamond AIDS Research Center, 455 First Avenue, New York, NY 10016, USA or J.J. Martinson, Department of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH UK.
Received: 8 December 1999; accepted: 22 December 1999.