The frequency of the CCR5Δ32 allele in the world is approximately equal to 3% [37]. This allele is mainly present in European Countries (about 10%). The highest frequency of this allele has been reported in the surrounding area of the Baltic and the White Sea and the central regions of Russia (> 15%) [38]. On the other hand, this polymorphism is very rare in North Africa, the Middle East, and Central Asia. Also, CCR5Δ32 is absent in East and Southeast Asia populations, natives of America, Oceania, and sub-Saharan Africa [39]. In Iranian people, the frequency of CCR5Δ32 is estimated at 1.6%, which varies in different ethnicities living in this country [16, 17]. By the end of 2021, 38.4 million HIV Infected individuals worldwide have been detected, with the highest frequency observed in South and West Africa (20.6 million infected) and the lowest in the Middle East and North Africa (18,000 infected) [40]. By the end of 2018, 38,996 people were diagnosed with HIV infection in Iran [41].
In the present study, no frequency of the CCR5Δ32 allele was found in healthy Turkmen people. This is consistent with other studies from Iran [16, 17, 42–44] and other countries [45–52]. In contrast to our research, Trecarichi et al. have shown a significantly higher frequency of Δ32 in the healthy control group compared to HIV-positive people. Moreover, Philpott et al. reported a two-fold higher frequency of Δ32 genotype in the healthy control compared with HIV-1-seropositive people. A plethora of factors contributes to this diversity report, including ethnical variations, which play a significant role in the population. Multiple linear regression analyses by Susan M et al., adjusted for age and race, showed a significant negative association between HIV risk duration and CCR5 expression in monocytes [53]. Another study by Meditz et al. showed that CCR5 expression is reduced in lymph nodes of HIV-1-infected women compared with men but does not mediate sex-based differences in viral loads [54].
The discussed origin of the CCR5Δ32 allele is still controversial. Beyond the proposed theories, Sabeti et al. indicated that this polymorphism became frequent in the European population due to neutral evolution. However, the authors have suggested the possible role of selective pressure in the historical period as an element in CCR5Δ32 frequency [55, 56]. The racial distribution of HIV risk raises the possibility that differences in the distribution of the CCR5Δ32 allele or other heritable host factors/mutations may influence the rate of transmission or the speed of the epidemic in different racial groups [57]. Genetically, Iranians are considered close to North Indians, Greeks, and specific European populations such as Italians, Germans, and British, which can be related to the following factors: 1. Indo-European Same ancestor population (Aryans) 2. significant genetic admixture of Iranians with their neighbors in different eras 3. connecting the Eastern and western Eurasian populations through the Silk Road network, which led to migrations and genetic admixture along this network [42]. Recent data on allele and haplotype frequencies of human leukocyte antigen (HLA) class II have confirmed the similarity in the genetic ancestry of Iranians, Greeks, and Italians [58, 59]. Historical evidence suggests differences between the population of Iran and Europeans of the same ancestry, known as Indo-Europeans. Around 2000 BC, an Indo-European tribe named Aryans invaded central Asia and occupied Iran, Iraq, north of India, and Afghanistan. The significant difference between the western and eastern migrations of Indo-Europeans is that they mixed genetically with similar populations in the West. In contrast, in the East, they mixed with others. Genetically together have produced a primarily mixed population, and the Arabs gradually diluted the primary Indo-Aryan traces over the centuries [60]. The rate of progression to AIDS varies among individuals infected with HIV-1, and it has been shown that CCR5∆32 confers almost complete resistance to HIV-1 infection in homozygotes and partial protection against HIV disease progression in heterozygous adults.
CCR5 (formerly CKR5) plays a crucial role in the chemotaxis of the immune cells to inflammation sites and in mediating inflammatory responses. Beyond cell migration, CCR5 is involved in the surveillance of the immune cells, inflammation, and the pathogenesis of inflammatory diseases and cancers [3]. CCR5Δ32 is a 32 bp deletion in the CCR5 gene on the second extracellular loop encoding region. This variation results in a frameshift in the CCR5 protein sequences, leading to a prematurely truncated protein lacking three transmembrane domains. CCR5Δ32 mutant protein has no function and does not localize on the cell surface [61, 62]. The CCR5Δ32 has received much attention due to its protective role against HIV infection and disease progression [20]. Beyond HIV infection, data has shown that this polymorphism is correlated to other conditions such as autoimmune diseases and pathogenic infections [3, 63].
A protective effect of CCR5Δ32 allele variation on some conditions such as childhood asthma [64], type 2 diabetes (non-insulin-dependent diabetes mellitus) [65], Hepatitis B Virus (HBV) [66], liver inflammation in HCV infection [67, 68], osteomyelitis of Staphylococcus aureus infection [69] and Toxoplasmosis [70, 71] has been reported. On the other hand, this polymorphism has been considered a risk factor for multiple sclerosis (MS) [72], symptomatic West Nile virus (WNV) infection [73], the severity of Influenza virus [74] severe form of coronavirus disease-2019 (COVID-19) [24], Streptococcus pneumoniae infection [75], and Tuberculosis [76].
The gradient distribution of the CCR5Δ32 polymorphism from north to south with the highest frequency in the Nordic population suggests a Scandinavian origin of this polymorphism. Subsequently, this variant spread to the European population through raids of the Vikings in the 8th-10th centuries [77, 78]. CCR5Δ32 allele frequency around the world is estimated at approximately 3% based on the information obtained from various studies on more than 5000 samples [79, 80]. This genetic variation is primarily observed in Caucasian populations (European ethnicity), where the average mutant allele frequency is about 10% of this population [81]. In contrast to the European population, CCR5Δ32 polymorphism is virtually absent in Asians, Sub-Saharan Africans, and Native American ethnicities [82]. The CCR5Δ32 allele frequency in Asian countries and Iran is about 2.06% of the population [83]. The CCR5Δ32 allele frequency in the Iranian population is listed in Table 2. This study aimed to determine the distribution of CCR5Δ32 polymorphism in the Turkmen population in the north of Iran. The CCR5Δ32 allele was utterly absent from our study population. In this study, we had a limitation on sample size and no access to HIV-infected patients in the Turkmen population. Also, due to the absence of mutant alleles (homozygous or heterozygous) among this study's samples, it was impossible to calculate the Hardy-Weinberg equilibrium. Further studies with large sample sizes are needed to investigate the frequency of CCR5 mutations and their association with diseases.
Table 2
CCR5Δ32 allele frequency (%) distribution in the Iranian population living in different geographical locations
Population
|
Sample size
|
Genotypes (%)
|
Δ32 Allele frequency
|
Reference
|
WT/WT
|
WT/Δ32
|
Δ32/Δ32
|
Turkmen
(North of Iran)
|
400
|
400 (100)
|
0 (0)
|
0 (0)
|
0%
|
Current
study
|
Fars province
(South of Iran)
|
395
|
384 (97.2)
|
11 (2.8)
|
0 (0)
|
1.4%
|
[42]
|
Urmia city
(North-West of Iran)
|
200
|
186 (97.89)
|
4 (2.105)
|
0 (0)
|
1.05%
|
[43]
|
Mashhad city
(North-East of Iran)
|
400
|
388 (97)
|
11 (2.75)
|
1 (0.25)
|
1.6%
|
[84]
|
Golestan province
(Southeast of the Caspian Sea)
|
300
|
291 (97)
|
9 (3)
|
0 (0)
|
1.5%
|
[44]
|
Tehran province
(Capital of Iran)
|
371
|
357 (96.2)
|
14 (3.8)
|
0 (0)
|
3.8%
|
[36]
|
Iran
|
530
|
523 (98.5)
|
6 (1.1)
|
1 (0.19)
|
1.1%
|
[17]
|