Frequencies of 32 base pair deletion of the (Δ32) allele of the CCR5 HIV-1 co-receptor gene in Caucasians: a comparative analysis

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Abstract

The CCR5 gene encodes for the co-receptor for the major macrophage-tropics strains of human immunodeficiency virus (HIV-1), and a mutant allele of this gene (Δ32) provide to homozygotes a strong resistance against infection by HIV. The frequency of the Δ32 allele was investigated in 40 populations of 8842 non-infected subjects coming from Europe, the Middle-East and North Africa. A clear north–south decreasing gradient was evident for Δ32 frequencies, with a significant correlation coefficient (r=0.83). The main frequency value of Δ32 for Sweden, Norway, Denmark, Finland and Iceland (0.134) is significantly (χ2=63.818, P<0.001) highest than the Δ32 mean value, indicating that probably the Vikings might have been instrumental in disseminating the Δ32 allele during the eighth to the tenth centuries during historical times. Possibly variola virus has discriminated the Δ32 carriers in Europe since the eighth century AD, explaining the high frequency of the Δ32 allele in Europe today.

Introduction

The CCR5 gene product encodes a seven-transmembrane G-protein-coupled chemokine receptor, that serves as an entry port for primary human immunodeficiency virus (HIV-1) strains that infect monocytes and macrophages. The mechanism of resistance to repeated exposure by the virus has been provided by the identification in individuals of Caucasian origin of a null mutation of CCR5 (Liu et al., 1996, Samson et al., 1996, Dean et al., 1996): homozygotes for the 32 bp deletion (Δ32) in the gene segment encoding the second extracellular loop of CCR5 appear to resist infection. The 16 and 1% of healthy Europeans were reported to be heterozygous and homozygous for Δ32, respectively (Samson et al., 1996, Dean et al., 1996), and the mutant allele was not observed in black Africans or Japaneses. In North American Caucasians, the frequency of heterozygosity for Δ32 was 21.7%, and it was much less common in African–Americans (5.8%), Hispanics (6.9.%), and 0.6% in Asian–Americans (Zimmerman et al., 1997).

A high allele frequency of Δ32 was found among several Caucasian populations (Martinson et al., 1997, Libert et al., 1998, Stephens et al., 1998), leading to the most parsimonious hypothesis that the mutation occurred only once in the ancestry of the Caucasian ethnic group. After our two successive studies on the subject in France (Lucotte and Mercier, 1998a) and in Europe (Lucotte and Mercier, 1998b), we present here a comparative analysis on Δ32 frequencies (based on a total of 8442 unrelated non-infected control individuals from 40 populations) from Europe, the Middle-East and North Africa.

Section snippets

Molecular methods used

In most of the studies compiled here, extraction of DNA from blood samples and PCR amplification was performed as previously described in our own first study on the subject (Lucotte, 1997); after EcoRI restriction, the 735 bp PCR product using Samson et al. (1996) primers was cleaved into a common band of 332 bp for both alleles, and into a 403 bp product for the normal type (+) and a 371 bp for the mutant (Δ32) alleles.

Allelic frequencies in 40 populations

The Δ32 allele of the CCR5 gene was found in all the populations studied, but with some important difference in frequencies among countries. All the population tested (Table 1) showed no significant deviation from Hardy–Weinberg equilibrium. Fig. 1 shows the spatial distribution of Δ32 allele frequencies in the 40 populations studied.

From the 8442 individuals screened, the mean percentage of Δ32 is 7.7%. A significant genetic heterogeneity was observed among the population samples (χ2=365.985, P

Discussion

As suggested by previous authors (Martinson et al., 1997, Libert et al., 1998, Stephens et al., 1998), a northward–southward latitudinal gradient of Δ32 allele frequencies in Caucasians is established on a quantitative basis in our present comparative analysis, including more recent published studies. In this work we formally described the equation of the decreasing cline, and we analyzed in details the gradual decline in Δ32 frequencies among the successive steps of latitude north decrease in

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