The degree to which the genotype frequencies at each locus agree with Hardy–Weinberg equilibrium (HWE) expectations is also shown in Table 1. This was determined at the regional level, and not for individual populations, as many of the individual samples were too small to allow the agreement with HWE to be calculated accurately. Agreement with HWE (P > 0.05) was seen in 16 out of 18 comparisons. In some cases, the expected values obtained for some genotype frequencies were so low as to introduce bias into the chi-square calculation , which may explain the disagreement seen at CCR5-Δ32 in Asian populations. The other exception (CCR5-59653T in the Americas) was due to an observed excess of homozygotes and a deficit of heterozygotes. The reason for this is not clear, but instead of reflecting an aspect of population structure, this could be a Type I error; a probability threshold of 0.05 would result in HWE being falsely rejected in one out of every 20 tests performed. We conclude that there is little or no selective or other effect of CCR2-64I or CCR5-59653T that is sufficient to perturb the genotype frequencies.
The authors thank the many researchers who provided the samples for our original study of CCR5-Δ32, and to C. Christodoulou and A. Hatzakis for additional samples.
1. Moore JP. Coreceptors: implications for HIV pathogenesis and therapy.
Science 1997, 276: 51 –52.
2. Berger EA, Murphy PM, Farber MT. Chemokine receptors as HIV-1 coreceptors: Roles in viral entry, tropism, and disease.
Ann Rev Immunol 1999, 17: 657 –700.
3. Fauci AS. Host factors and the pathogenesis of HIV-induced disease.
Nature 1996, 384: 529 –534.
4. O'Brien TR, Goedert JJ. Chemokine receptors and genetic variability: another leap in HIV research.
J Am Med Assoc 1998, 279: 317 –318.
5. Alkhatib G, Combadiere C, Broder CC. et al
. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1.
Science 1996, 272: 1955 –1958.
6. Choe H. et al
. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates.
Cell 1996, 85: 1135 –1148.
7. Deng HK, Unutmaz D, KewalRamani VN, Littman DR. Expression cloning of new receptors used by simian and human immunodeficiency viruses.
Nature 1997, 388: 296 –300.
8. Doranz BJ, Rucker J, Yi Y. et al
. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors.
Cell 1996, 85: 1149 –1158.
9. Dragic T, Litwin V, Allaway GP. et al
. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5.
Nature 1996, 381: 667 –673.
10. Dean M, Carrington M, Winkler C. et al
. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene.
Science 1996, 273: 1856 –1862.
11. Huang Y, Paxton WA, Wolinsky SM. et al
. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression.
Nature Med 1996, 2: 1240 –1243.
12. Liu R, Paxton WA, Choe S. et al
. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection.
Cell 1996, 86: 367 –377.
13. Samson M, Libert F, Doranz BJ. et al
. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene.
Nature 1966, 382: 722 –725.
14. Ioannidis JP, O'Brien TR, Rosenberg PS, Contopoulos-Ioannidis DG, Goedert JJ. Genetic effects on HIV disease progression.
Nature Med 1998, 4: 536. 536.
15. O'Brien TR, Winkler C, Dean M. et al
. HIV-1 infection in a man homozygous for CCR5Δ32.
Lancet 1997, 349: 1219. 1219.
16. Theodorou I, Meyer L, Magierowska M, Katlama C, Rouzioux C. HIV-1 infection in an individual homozygous for CCR5Δ32.
Lancet 1997, 349: 1219 –1220.
17. Biti R, French R, Young J, Bennetts B, Stewart G. HIV-1 infection in an individual homozygous for the CCR5 deletion allele.
Nature Med. 1997, 3: 252 –253.
18. Michael NL, Chang G, Louie LG. et al
. The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression.
Nature Med 1997, 3: 338 –340.
19. Misrahi M, Teglas J-P, N'Go N. et al
. CCR5 chemokine receptor variant in HIV-1 mother-to-child transmission and disease progression in children.
J Am Med Assoc 1998, 279: 277 –280.
20. Zimmerman PA, Buckler-White A, Alkhatib G. et al
. Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: Studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk.
Mol Med 1997, 3: 23 –36.
21. Smith MW, Dean M, Carrington M. et al
. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression.
Science 1997, 277: 959 –965.
22. Kostrikis L, Huang X, Moore JP. et al
. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation.
Nature Med 1998, 4: 350 –353.
23. Lee B, Doranz BJ, Rana S. et al
. Influence of the CCR2-V64I polymorphism on human immunodeficiency virus type 1 coreceptor activity and on chemokine receptor function of CCR2b, CCR3, CCR5, and CXCR4. J Virol 1998, 72: 7450 –7458.
24. Mummidi S, Ahuja S, Gonzalez E. et al
. Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression.
Nature Med 1998, 4: 786 –793.
25. Martinson JJ, Chapman NH, Rees DC, Liu YT, Clegg JB. Global distribution of the CCR5 gene 32-basepair deletion.
Nature Genet 1997, 16: 100 –103.
26. Christodoulou C, Poullikas M, Neumann AU, Kostrikis LG. Low frequency of CCR5Δ32 allele among Greeks in Cyprus.
AIDS Res Hum Retroviruses 1997, 13: 1373 –1374.
27. Nasioulas G, Dean M, Koumbarelis E. et al
. Allele frequency of the CCR5 mutant chemokine receptor in Greek Caucasians.
J Acquir Immune Defic Syndr Hum Retrovirol 1998, 17: 181 –182.
28. Lucotte G, Mercier G. Distribution of the CCR5 gene 32-bp deletion in Europe.
J Acquir Immune Defic Syndr Hum Retrovirol 1998, 19: 174 –177.
29. Kostrikis LG, Tyagi S, Mhlanga MM, Ho DD, Kramer FR. Spectral genotyping of human alleles.
Science 1998, 279: 1228 –1229.
30. Stephens JC, Reich DE, Goldstein DB. et al
. Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes.
Am J Hum Genet 1998, 62: 1507 –1515.
31. Libert F, Cochaux P, Beckman G. et al
. The DCCR5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe.
Hum Mol Genet 1998, 7: 399 –406.
32. Weir BS. Genetic Data Analysis.
Sunderland MA: Sinauer; 1990.
33. Flint J, Boyce AJ, Martinson JJ, Clegg JB. Population bottlenecks in Polynesia revealed by minisatellites.
Hum Genet 1989, 83: 257 –263.