CC chemokine receptor 5 (CCR5) mediates activation of T lymphocytes and macrophages by functioning physiologically as a receptor for the leukocyte chemo-attractants macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and RANTES, as an important part of a protective immune response to injury and infection. Also, CCR5 functions pathologically as a key cell entry co-receptor for M-tropic strain of HIV-1 that is the primary transmitting form of the virus.
The CCR5 gene is located at the chemokine receptor gene cluster region at 3p21 and spans approximately 6 kb of genomic DNA with a coding sequence consisting of four exons and only two introns. It expresses in T lymphocytes and macrophages. The protein product of this gene comprises 352 amino acids long with a molecular mass of 40524 Da.
CCR5 has rapidly become the object of intense interest since the discovery of its role in the entry of HIV-1 into target cells. In contrast to that, one mutant allele, a 32-bp deletion (denoted DCCR5) in the open reading frame (ORF) of this gene, which has been intensively studied, was found to prevent cell invasion by HIV-1 virus. Individuals homozygous for this deletion do not express the protein on the cell surface, and are relatively resistant to developing HIV-1 infection, but this resistance appears not absolute, as isolated cases of HIV-positive deletion homozygotes are emerging. In contrast, individuals who display the heterozygous state (CCR5/DCCR5 genotype) can develop HIV-1 infection; however, their progression to AIDS may be slower.
Salem et al. (2009) investigated the frequencies of CCR5-Delta32 and CCR5-m303 mutations as well as the frequencies of CCR2-64I and SDF1-3-prime-A mutations in 304 unrelated healthy Bahraini individuals without any known history of HIV-1 infection or AIDS symptoms. The frequency of the CCR5-Delta32 allele was found to be 2.8%. No mutant alleles were detected for the CCR5-m303 mutation in the studied population. Salem et al. (2009) suggested that the presence of the CCR5-Delta32 allele among Bahrainis may be attributed to the admixture with people of European descent.
Salem and Batzer (2007) evaluated the frequency distribution of the CCR5-Delta32 polymorphism among 200 Egyptians (154 from Ismailia and 46 from Sinai). Only two heterozygous individuals from Ismailia carried the CCR5-Delta32 allele (0.6%), and no homozygous (Delta32/Delta32) individuals were detected among the tested samples. Salem and Batzer (2007) hypothesized that the presence of the CCR5-Delta32 allele among Egyptians may be attributed to the admixture with people of European descent. They concluded that the protective deletion CCR5-Delta32 is largely absent in the Egyptian population.
[See also: Kuwait > Voevodin et al., 1998].
Voevodin et al. (1998a) undertook a survey of delta CCR-5 in 353 Arab healthy individuals residing in Kuwait (270 Kuwaiti citizens and 83 Bedouins). Eight heterozygotes; four in each group, and no homozygotes were detected for the delta CCR-5 deletion. The frequency of the delta CCR-5 allele in the Bedouins (2.4%) was found to be more than three times higher than among the Kuwaiti citizens (0.74%). Voevodin et al. (1998a) concluded that the delta CCR-5 mutation is present in indigenous Arab populations residing in Kuwait, though its frequency is quite low and can hardly influence the pace of HIV-1 spreading in Kuwait. Soon after, Voevodin et al. (1998b) surveyed for the 32 nucleotide deletion in the CCR-5 chemokine receptor gene (deltaccr-5) through genotyping 1,105 human subjects from different Middle Eastern nationalities (mainly Arab) and Russians, and 33 common chimpanzees. Carriers of the delta CCR-5 mutation were found among Arabs, Iranians, and Russians. The highest frequency of the mutation was seen in Russians (24.4% of the delta CCR-5 heterozygotes, allele frequency-0.1221). Surprisingly, the only delta CCR-5 homozygote identified in this study was found to be an Egyptian. Voevodin et al. (1998b) proposed that the origin of the delta CCR-5 mutation in the Middle Eastern populations, both Arab and non-Arab, is most probably due to a gene flow from the Europeans. None of the chimpanzees tested was found to be positive for delta CCR-5. Interestingly, the DNA sequence of the chimpanzee CCR-5 gene in the region including the site of the delta CCR-5 mutation, and flanking areas, was found to be virtually identical to the homologous human sequence, only two mismatches (silent substitutions) were found. Later, Voevodin et al. (1999) undertook a molecular study to determine the frequency of the CCR5-m303 mutation in a population sample of native Kuwaitis. The frequency of the CCR5-m303 mutant allele was found to be less than 0.0025. Further, Al-Turab and Voevodin (2001) genotyped the 59029-G>A polymorphism in the CCR5 gene in 109 healthy unrelated Kuwaitis to assess its association with the slow or rapid progression to AIDS. Among the 109 individuals genotyped for the 59029-G>A polymorphism, 10, 44 and 55 were identified as 59029-A/A homozygous, 59029-G/G homozygous and 59029-G/A heterozygous, respectively. The frequencies of the G allele and the A allele were found to be 0.66 (95% CI: 0.59-0.72) and 0.34 (95% CI: 0.28-0.41), respectively. The frequency of the AIDS-'protective' 59029-G allele in Kuwaitis was found to be significantly higher than the frequency of the 'rapid-progression' 59029-A allele. Moreover, the frequency of the 59029-G allele in Kuwaitis was found among the highest reported. However, Al-Turab and Voevodin (2001) observed that the difference from the 59029-G allele frequencies of other ethnic groups in some cases is not statistically significant.
Messadi et al. (2010) conducted a DNA analysis on 58 patients with multiple sclerosis and 72 healthy controls to test for the MCP-1 -2518 A>G polymorphism. The MCP-1 -2518G (p=0.43) variant did not reveal any contribution to the risk of multiple sclerosis in Tunisians.
Krichen et al. (2011) studied the possible association of recipient monocyte chemoattractant protein-1 (MCP-1), chemokine receptor (CCR2, CCR5), and adhesion molecule (ICAM-1, PECAM-1 and L/E selectin) polymorphisms on acute rejection after renal transplantation. The study included 169 healthy blood donors and 173 renal transplant recipients for analysis according to the presence or absence of graft rejection in the first 30 days after transplantation. DNA was genotyped for 11 polymorphisms of these inflammatory molecules genes. No association was detected between adhesion molecule polymorphisms and the incidence of acute rejection episodes.
Ksiaa et al. (2011) studied chemokines and chemokine receptor genes polymorphisms in relation to the spontaneous clearance or the persistence of HCV infection in 96 hemodialysis (HD) patients and 170 healthy blood donors. These patients were classified into two groups: G1 included 73 patients with persistently positive HCV-RNA and G2 included 23 HD patients who have spontaneously eliminated the virus. Results showed a statistically significant increase in the frequency of the CCR2 (64Ile) allele in patients infected with HCV (36%) compared to G1 (41%) and compared to controls (20%). Ksiaa et al. (2011) also observed a lower frequency of the MCP-1 G allele and a greater frequency of the CCR5 32-bp deletion variant in G2 (15% and 6%) compared to G1 (23% and 1%) that was not statistically significant.
[See also: UAE > Al-Jaberi et al., 2013].
Al-Jaberi et al. (2013) aimed to determine the frequency of the CCR5D32 variant in the Emirati and Tunisian populations. DNA samples were obtained from 253 Emiratis and 150 Tunisians with no known history of HIV-1 infections. Genotyping studies helped identify the CCR5D32 loss-of-function deletion in a heterozygous state in 1 Emirati and 4 Tunisian individuals, giving an allele frequency of 0.002 and 0.013 respectively. It was noted that UAE had the lowest frequency of the CCR5D32 allele compared to other previously studied Arab populations. The authors further screened for A29S, C101X, C178R, and FS299 variations and other possible novel variants in the coding region of the CCR5 gene in 200 Emiratis. While none of these were identified, the variants rs55639502 (c.477G>A, A159) and rs1799863 (c.164T>A, L55Q) were seen in a heterozygous state in one individual. While A159 is a silent mutation predicted to be benign, L55Q affects a highly conserved amino acid resulting in a truncated protein and partial defect in the activation of the mutant receptor.
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