ClinVar Genomic variation as it relates to human health

In an HIV-1-exposed patient with slow disease progression (see 609423), Samson et al. (1996) identified a homozygous 32-bp deletion in the CMKBR5 gene that results in a frameshift and premature termination. Samson et al. (1996) found that the mutation had an allelic frequency of 0.092 in Caucasian populations but was absent in populations from western and central Africa and from Japan. Among HIV-1-infected Caucasian subjects, no homozygous individuals were found, and the frequency of heterozygotes was 35% lower in infected individuals than in the general population. Samson et al. (1996) speculated that a 10-bp direct repeat that flanks the deleted region promoted a recombination event leading to the 32-bp deletion. Independently and simultaneously, Liu et al. (1996) identified the same homozygous 32-bp deletion in the CMKBR5 gene in 2 individuals who, though multiply exposed to HIV-1, remained uninfected. The deletion comprises nucleotides 794 to 825 of their cDNA sequence (codons 175 to 185) and results in a reading frameshift after amino acid 174, inclusion of 31 novel amino acids, and truncation at codon 206. The severely truncated protein could not be detected at the surface of cells that normally express the protein. They stated that the defect had no other obvious phenotype. Liu et al. (1996) stated that the frequency of CKR5-deleted homozygotes is about 1% in persons of western European heritage. The investigators also stated that heterozygous individuals were common (approximately 20%) in unrelated individuals of western European heritage but were present at a much lower frequency in a panel of individuals from Venezuela. Ansari-Lari et al. (1997) stated that this mutation results in a frameshift at codon 185, causing a deletion of 168 amino acids and the gain of 31 new residues in the C terminus of the putative translation product. Martinson et al. (1997) followed up on the observation that, although a gene frequency of approximately 10% was found for the 32-bp deletion in the CCR5 gene in populations of European descent, no mutant alleles were reported in indigenous non-European populations. They devised a rapid PCR assay for the deletion and used it to screen 3,342 individuals from a globally distributed range of populations. They found that the deletion in the CCR5 gene is not confined to persons of European descent but is found at frequencies of 2 to 5% throughout Europe, the Middle East, and the Indian subcontinent. Isolated occurrences were seen elsewhere throughout the world, but these most likely represented recent European gene flow into the indigenous populations. Martinson et al. (1997) suggested that the interpopulation differences in the frequency of the CCR5 deletion may influence the pattern of HIV transmission, and if so, the differences will need to be incorporated into future predictions of HIV levels. In a study of genomic DNA from random blood donors from North America, Asia, and Africa, Zimmerman et al. (1997) found the inactive CCR5 allele, designated by them CCR5-2, as the only mutant allele. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in 111 highly exposed-seronegative (4.5%) and 614 HIV-1-seropositive (0%) Caucasians relative to 387 Caucasian random blood donors (0.8%). This difference was highly significant (p less than 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same 3 groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of 2 cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1-positive Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconverters had a 52.6% lower risk of developing AIDS than homozygous wildtype seroconverters. Zimmerman et al. (1997) suggested that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. They suggested that since the majority (approximately 96%) of highly exposed-seronegative individuals tested were not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of normal antiretroviral therapy. See, however, Biti et al. (1997). Libert et al. (1998) investigated the frequency of the delta-CCR5 polymorphism in 18 European populations. A north-south gradient was found, with the highest allele frequencies in Finnish and Mordvinian populations (16%) and the lowest in Sardinia (4%). Highly polymorphic microsatellite markers flanking the CCR5 gene deletion were used to determine the haplotype of the chromosomes carrying the variant. More than 95% of the delta-CCR5 chromosomes carried an allele that was found in only 2% of the chromosomes carrying a wildtype CCR5 gene. From these data, it was inferred that most, if not all, delta-CCR5 alleles originated from a single mutation event, and that this mutation event probably took place a few thousand years ago in northeastern Europe. The high frequency of the delta-CCR5 allele in Caucasian populations cannot be explained easily by random genetic drift, suggesting that a selection advantage is or has been associated with the homozygous or heterozygous carriers of the mutant allele. Husain et al. (1998) described a family with heterozygosity for the 32-bp deletion in CCR5. They stated that this was the first such finding in an Indian without European admixture, and they estimated that the frequency of the deleted allele in India is likely to be very low (less than 1%). Alvarez et al. (1998) analyzed DNA from 150 HIV-1 positive intravenous drug users and 250 healthy controls from northern Spain for the presence of the delta-CCR5 mutation. The deletion was rare among seropositive intravenous drug users, and the authors found that patients carrying the deletion allele tended to show a fuller progression of HIV-1-related disease. Using a mathematical model, Sullivan et al. (2001) characterized epidemic HIV within 3 dynamic subpopulations: homozygous wildtype, heterozygous CCR5-del32, and homozygous CCR5-del32. The results indicated that the prevalence of HIV/AIDS is greater in populations lacking the CCR5-del32 alleles (homozygous wildtypes only) as compared with populations that include persons heterozygous or homozygous for the mutation. Also, they showed that HIV can provide selective pressure for CCR5-del32, increasing the frequency of this allele. Hall et al. (1999) reported that individuals carrying the 32-bp deletion in the CCR5 gene are at reduced risk of developing asthma. They suggested that this is a possible explanation for the high prevalence of this mutation in the general population. Szalai et al. (2000) determined the CCR5del32 allelic frequencies in 121 nonasthmatic, atopic children aged 1 to 14 years and in 295 age-matched controls in Hungary. They found no significant differences between allergic and control children, and suggested that the CCR5del32 mutation, even in homozygous form, has no protective effect on the development of allergic inflammation. Although functional evidence might suggest that CCR5 is a good candidate gene for atopic asthma, a study by Mitchell et al. (2000) of 2 panels of nuclear families containing 1,284 individuals found no genetic evidence that the CCR5del32 polymorphism is related to atopy or asthma/wheeze. Barcellos et al. (2000) found that patients with multiple sclerosis (MS; 126200) carrying the CCR5-delta-32 deletion showed an age at onset approximately 3 years later than did patients without the deletion. Studying 256 Israeli patients with MS, Kantor et al. (2003) presented evidence suggesting that the CCR5-delta-32 deletion may contribute to a slower rate of disease progression in MS. Fischereder et al. (2001) demonstrated another benefit of homozygosity for the CCR5del32 mutation: longer survival of renal transplants, suggesting a pathophysiologic role for CCR5 in transplant loss. This receptor may be a useful target for the prevention of transplant loss. Strieter and Belperio (2001) reviewed evidence on the implication of various chemokine receptors and their respective ligands in promoting allograft rejection. They commented on the expanding critical role of chemokine biology in transplantation immunology, which should pave the way for the development of pharmaceutical agents that will target pathogenetic steps in chemokine biology and provide new treatments for enhancing long-term allograft survival. In a genotype survey of 4,166 individuals, Stephens et al. (1998) identified a cline of CCR5-del32 allele frequencies of 0 to 14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and 2 microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, Stephens et al. (1998) estimated the origin of the CCR5-del32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275 to 1,875 years. The geographic cline of mutation frequencies and its recent emergence are consistent with a historic strong selective event (i.e., an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations. Majumder and Dey (2001) studied 1,438 unrelated individuals belonging to 40 ethnic groups from India. The CCR5del32 allele was absent in most ethnic populations, but was present in some populations of the northern and western regions. The authors suggested that the allele might have been introduced by Caucasian gene flow, consistent with the historical fact that Caucasoid migrants from central Asia and western Eurasia had entered India about 8,000 to 10,000 earlier. Using a population genetic model based on the demography of Europe, Duncan et al. (2005) suggested that annual widespread epidemics of plague, a viral hemorrhagic fever, from 1347 until 1670 forced up the frequency of the delta-32 mutation. Novembre et al. (2005) evaluated the selection hypothesis for the origin and maintenance of the delta-32 mutation in Europe. Assuming uniform selection across Europe and western Asia, they found support for northern European origin of delta-32 and Viking-mediated dispersal, which was originally proposed by Lucotte and Mercier (1998). On the other hand, if gradients in selection intensity were assumed, Novembre et al. (2005) estimated the origin to be outside of northern Europe and selection intensities to be strongest in the northwestern part of the continent. Using denser genetic maps and more extensive control data than previous studies, Sabeti et al. (2005) determined that genetic variation at delta-32 is not exceptional relative to other loci across the genome. They estimated that the delta-32 allele arose more than 5,000 years ago, considerably earlier than the origin proposed by Stephens et al. (1998). While not ruling out selection, especially given the biology of the gene, Sabeti et al. (2005) concluded that the results imply that the pattern of genetic variation at delta-32 is consistent with neutral evolution. Glass et al. (2006) analyzed the distribution of CCR5 delta-32 in independent cohorts of West Nile virus (see 610379)-seropositive individuals. They observed a strong deviation from Hardy-Weinberg equilibrium due to an increased frequency of delta-32 homozygotes. The delta-32 homozygotes also had increased risk of fatal WNV infection. Glass et al. (2006) concluded that CCR5 delta-32 is a risk factor for symptomatic WNV infection. Goulding et al. (2005) genotyped 283 Irish women exposed to hepatitis C virus (HCV; see 609532) genotype-1b from a single donor for CCR5, CCR2 (601267), and CCL5 (187011) polymorphisms. They found that CCR5 delta-32 heterozygotes showed significantly higher spontaneous clearance of HCV compared with wildtype CCR5 homozygotes. In addition, the authors observed a trend toward lower hepatic inflammation scores in CCR5 delta-32 heterozygotes compared with wildtype CCR5 homozygotes. No significant relationships were found with CCR2 or CCL5. Thio et al. (2008) stated that 95% of adults recover from acute hepatitis B virus (HBV; see 610424) infection and that the likelihood of recovery is enhanced in those carrying the 32-bp deletion in CCR5. By comparing 181 individuals with persistent HBV infection with 316 who had recovered, Thio et al. (2008) showed that the combination of the 32-bp deletion in CCR5 with the minor allele of a functional promoter polymorphism in CCL5, -403G-A, was significantly associated with recovery (odds ratio = 0.36; P = 0.02). CCL5 -403A without the 32-bp deletion in CCR5 was not associated with HBV recovery, and the 32-bp deletion in CCR5 without CCL5 -403A showed only weak, nonsignificant protection. Thio et al. (2008) noted that -403A is associated with higher levels of CCL5 in cell lines. They proposed that excess CCL5 due to -403A combined with the nonfunctional CCR5 receptor due to the 32-bp deletion favors recovery from HBV infection. However, Thio et al. (2008) stated that they could not totally eliminate the possibility that interaction with the 32-bp deletion in CCR5 is due to another CCL5 SNP, 524T-C, rather than -403A, because 524C is in tight linkage disequilibrium with -403A. In a study involving 8,064 patients with type 1 diabetes and 9,339 controls, Smyth et al. (2008) found significant association between the 32-bp insertion/deletion in the CCR5 gene on chromosome 3p21 and a decreased risk for type 1 diabetes (odds ratio, 0.54; p = 1.88 x 10(-6)); see 612522. The association was validated in 2,828 families providing 3,064 parent-child trios (relative risk, 0.53; p = 1.81 x 10(-8)). The mutation encodes a nonfunctional receptor (Liu et al., 1996; Samson et al., 1996). (less)

In an HIV-1-exposed patient with slow disease progression (see 609423), Samson et al. (1996) identified a homozygous 32-bp deletion in the CMKBR5 gene that results in a frameshift and premature termination. Samson et al. (1996) found that the mutation had an allelic frequency of 0.092 in Caucasian populations but was absent in populations from western and central Africa and from Japan. Among HIV-1-infected Caucasian subjects, no homozygous individuals were found, and the frequency of heterozygotes was 35% lower in infected individuals than in the general population. Samson et al. (1996) speculated that a 10-bp direct repeat that flanks the deleted region promoted a recombination event leading to the 32-bp deletion. Independently and simultaneously, Liu et al. (1996) identified the same homozygous 32-bp deletion in the CMKBR5 gene in 2 individuals who, though multiply exposed to HIV-1, remained uninfected. The deletion comprises nucleotides 794 to 825 of their cDNA sequence (codons 175 to 185) and results in a reading frameshift after amino acid 174, inclusion of 31 novel amino acids, and truncation at codon 206. The severely truncated protein could not be detected at the surface of cells that normally express the protein. They stated that the defect had no other obvious phenotype. Liu et al. (1996) stated that the frequency of CKR5-deleted homozygotes is about 1% in persons of western European heritage. The investigators also stated that heterozygous individuals were common (approximately 20%) in unrelated individuals of western European heritage but were present at a much lower frequency in a panel of individuals from Venezuela. Ansari-Lari et al. (1997) stated that this mutation results in a frameshift at codon 185, causing a deletion of 168 amino acids and the gain of 31 new residues in the C terminus of the putative translation product. Martinson et al. (1997) followed up on the observation that, although a gene frequency of approximately 10% was found for the 32-bp deletion in the CCR5 gene in populations of European descent, no mutant alleles were reported in indigenous non-European populations. They devised a rapid PCR assay for the deletion and used it to screen 3,342 individuals from a globally distributed range of populations. They found that the deletion in the CCR5 gene is not confined to persons of European descent but is found at frequencies of 2 to 5% throughout Europe, the Middle East, and the Indian subcontinent. Isolated occurrences were seen elsewhere throughout the world, but these most likely represented recent European gene flow into the indigenous populations. Martinson et al. (1997) suggested that the interpopulation differences in the frequency of the CCR5 deletion may influence the pattern of HIV transmission, and if so, the differences will need to be incorporated into future predictions of HIV levels. In a study of genomic DNA from random blood donors from North America, Asia, and Africa, Zimmerman et al. (1997) found the inactive CCR5 allele, designated by them CCR5-2, as the only mutant allele. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in 111 highly exposed-seronegative (4.5%) and 614 HIV-1-seropositive (0%) Caucasians relative to 387 Caucasian random blood donors (0.8%). This difference was highly significant (p less than 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same 3 groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of 2 cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1-positive Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconverters had a 52.6% lower risk of developing AIDS than homozygous wildtype seroconverters. Zimmerman et al. (1997) suggested that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. They suggested that since the majority (approximately 96%) of highly exposed-seronegative individuals tested were not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of normal antiretroviral therapy. See, however, Biti et al. (1997). Libert et al. (1998) investigated the frequency of the delta-CCR5 polymorphism in 18 European populations. A north-south gradient was found, with the highest allele frequencies in Finnish and Mordvinian populations (16%) and the lowest in Sardinia (4%). Highly polymorphic microsatellite markers flanking the CCR5 gene deletion were used to determine the haplotype of the chromosomes carrying the variant. More than 95% of the delta-CCR5 chromosomes carried an allele that was found in only 2% of the chromosomes carrying a wildtype CCR5 gene. From these data, it was inferred that most, if not all, delta-CCR5 alleles originated from a single mutation event, and that this mutation event probably took place a few thousand years ago in northeastern Europe. The high frequency of the delta-CCR5 allele in Caucasian populations cannot be explained easily by random genetic drift, suggesting that a selection advantage is or has been associated with the homozygous or heterozygous carriers of the mutant allele. Husain et al. (1998) described a family with heterozygosity for the 32-bp deletion in CCR5. They stated that this was the first such finding in an Indian without European admixture, and they estimated that the frequency of the deleted allele in India is likely to be very low (less than 1%). Alvarez et al. (1998) analyzed DNA from 150 HIV-1 positive intravenous drug users and 250 healthy controls from northern Spain for the presence of the delta-CCR5 mutation. The deletion was rare among seropositive intravenous drug users, and the authors found that patients carrying the deletion allele tended to show a fuller progression of HIV-1-related disease. Using a mathematical model, Sullivan et al. (2001) characterized epidemic HIV within 3 dynamic subpopulations: homozygous wildtype, heterozygous CCR5-del32, and homozygous CCR5-del32. The results indicated that the prevalence of HIV/AIDS is greater in populations lacking the CCR5-del32 alleles (homozygous wildtypes only) as compared with populations that include persons heterozygous or homozygous for the mutation. Also, they showed that HIV can provide selective pressure for CCR5-del32, increasing the frequency of this allele. Hall et al. (1999) reported that individuals carrying the 32-bp deletion in the CCR5 gene are at reduced risk of developing asthma. They suggested that this is a possible explanation for the high prevalence of this mutation in the general population. Szalai et al. (2000) determined the CCR5del32 allelic frequencies in 121 nonasthmatic, atopic children aged 1 to 14 years and in 295 age-matched controls in Hungary. They found no significant differences between allergic and control children, and suggested that the CCR5del32 mutation, even in homozygous form, has no protective effect on the development of allergic inflammation. Although functional evidence might suggest that CCR5 is a good candidate gene for atopic asthma, a study by Mitchell et al. (2000) of 2 panels of nuclear families containing 1,284 individuals found no genetic evidence that the CCR5del32 polymorphism is related to atopy or asthma/wheeze. Barcellos et al. (2000) found that patients with multiple sclerosis (MS; 126200) carrying the CCR5-delta-32 deletion showed an age at onset approximately 3 years later than did patients without the deletion. Studying 256 Israeli patients with MS, Kantor et al. (2003) presented evidence suggesting that the CCR5-delta-32 deletion may contribute to a slower rate of disease progression in MS. Fischereder et al. (2001) demonstrated another benefit of homozygosity for the CCR5del32 mutation: longer survival of renal transplants, suggesting a pathophysiologic role for CCR5 in transplant loss. This receptor may be a useful target for the prevention of transplant loss. Strieter and Belperio (2001) reviewed evidence on the implication of various chemokine receptors and their respective ligands in promoting allograft rejection. They commented on the expanding critical role of chemokine biology in transplantation immunology, which should pave the way for the development of pharmaceutical agents that will target pathogenetic steps in chemokine biology and provide new treatments for enhancing long-term allograft survival. In a genotype survey of 4,166 individuals, Stephens et al. (1998) identified a cline of CCR5-del32 allele frequencies of 0 to 14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and 2 microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, Stephens et al. (1998) estimated the origin of the CCR5-del32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275 to 1,875 years. The geographic cline of mutation frequencies and its recent emergence are consistent with a historic strong selective event (i.e., an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations. Majumder and Dey (2001) studied 1,438 unrelated individuals belonging to 40 ethnic groups from India. The CCR5del32 allele was absent in most ethnic populations, but was present in some populations of the northern and western regions. The authors suggested that the allele might have been introduced by Caucasian gene flow, consistent with the historical fact that Caucasoid migrants from central Asia and western Eurasia had entered India about 8,000 to 10,000 earlier. Using a population genetic model based on the demography of Europe, Duncan et al. (2005) suggested that annual widespread epidemics of plague, a viral hemorrhagic fever, from 1347 until 1670 forced up the frequency of the delta-32 mutation. Novembre et al. (2005) evaluated the selection hypothesis for the origin and maintenance of the delta-32 mutation in Europe. Assuming uniform selection across Europe and western Asia, they found support for northern European origin of delta-32 and Viking-mediated dispersal, which was originally proposed by Lucotte and Mercier (1998). On the other hand, if gradients in selection intensity were assumed, Novembre et al. (2005) estimated the origin to be outside of northern Europe and selection intensities to be strongest in the northwestern part of the continent. Using denser genetic maps and more extensive control data than previous studies, Sabeti et al. (2005) determined that genetic variation at delta-32 is not exceptional relative to other loci across the genome. They estimated that the delta-32 allele arose more than 5,000 years ago, considerably earlier than the origin proposed by Stephens et al. (1998). While not ruling out selection, especially given the biology of the gene, Sabeti et al. (2005) concluded that the results imply that the pattern of genetic variation at delta-32 is consistent with neutral evolution. Glass et al. (2006) analyzed the distribution of CCR5 delta-32 in independent cohorts of West Nile virus (see 610379)-seropositive individuals. They observed a strong deviation from Hardy-Weinberg equilibrium due to an increased frequency of delta-32 homozygotes. The delta-32 homozygotes also had increased risk of fatal WNV infection. Glass et al. (2006) concluded that CCR5 delta-32 is a risk factor for symptomatic WNV infection. Goulding et al. (2005) genotyped 283 Irish women exposed to hepatitis C virus (HCV; see 609532) genotype-1b from a single donor for CCR5, CCR2 (601267), and CCL5 (187011) polymorphisms. They found that CCR5 delta-32 heterozygotes showed significantly higher spontaneous clearance of HCV compared with wildtype CCR5 homozygotes. In addition, the authors observed a trend toward lower hepatic inflammation scores in CCR5 delta-32 heterozygotes compared with wildtype CCR5 homozygotes. No significant relationships were found with CCR2 or CCL5. Thio et al. (2008) stated that 95% of adults recover from acute hepatitis B virus (HBV; see 610424) infection and that the likelihood of recovery is enhanced in those carrying the 32-bp deletion in CCR5. By comparing 181 individuals with persistent HBV infection with 316 who had recovered, Thio et al. (2008) showed that the combination of the 32-bp deletion in CCR5 with the minor allele of a functional promoter polymorphism in CCL5, -403G-A, was significantly associated with recovery (odds ratio = 0.36; P = 0.02). CCL5 -403A without the 32-bp deletion in CCR5 was not associated with HBV recovery, and the 32-bp deletion in CCR5 without CCL5 -403A showed only weak, nonsignificant protection. Thio et al. (2008) noted that -403A is associated with higher levels of CCL5 in cell lines. They proposed that excess CCL5 due to -403A combined with the nonfunctional CCR5 receptor due to the 32-bp deletion favors recovery from HBV infection. However, Thio et al. (2008) stated that they could not totally eliminate the possibility that interaction with the 32-bp deletion in CCR5 is due to another CCL5 SNP, 524T-C, rather than -403A, because 524C is in tight linkage disequilibrium with -403A. In a study involving 8,064 patients with type 1 diabetes and 9,339 controls, Smyth et al. (2008) found significant association between the 32-bp insertion/deletion in the CCR5 gene on chromosome 3p21 and a decreased risk for type 1 diabetes (odds ratio, 0.54; p = 1.88 x 10(-6)); see 612522. The association was validated in 2,828 families providing 3,064 parent-child trios (relative risk, 0.53; p = 1.81 x 10(-8)). The mutation encodes a nonfunctional receptor (Liu et al., 1996; Samson et al., 1996). (less)

In an HIV-1-exposed patient with slow disease progression (see 609423), Samson et al. (1996) identified a homozygous 32-bp deletion in the CMKBR5 gene that results in a frameshift and premature termination. Samson et al. (1996) found that the mutation had an allelic frequency of 0.092 in Caucasian populations but was absent in populations from western and central Africa and from Japan. Among HIV-1-infected Caucasian subjects, no homozygous individuals were found, and the frequency of heterozygotes was 35% lower in infected individuals than in the general population. Samson et al. (1996) speculated that a 10-bp direct repeat that flanks the deleted region promoted a recombination event leading to the 32-bp deletion. Independently and simultaneously, Liu et al. (1996) identified the same homozygous 32-bp deletion in the CMKBR5 gene in 2 individuals who, though multiply exposed to HIV-1, remained uninfected. The deletion comprises nucleotides 794 to 825 of their cDNA sequence (codons 175 to 185) and results in a reading frameshift after amino acid 174, inclusion of 31 novel amino acids, and truncation at codon 206. The severely truncated protein could not be detected at the surface of cells that normally express the protein. They stated that the defect had no other obvious phenotype. Liu et al. (1996) stated that the frequency of CKR5-deleted homozygotes is about 1% in persons of western European heritage. The investigators also stated that heterozygous individuals were common (approximately 20%) in unrelated individuals of western European heritage but were present at a much lower frequency in a panel of individuals from Venezuela. Ansari-Lari et al. (1997) stated that this mutation results in a frameshift at codon 185, causing a deletion of 168 amino acids and the gain of 31 new residues in the C terminus of the putative translation product. Martinson et al. (1997) followed up on the observation that, although a gene frequency of approximately 10% was found for the 32-bp deletion in the CCR5 gene in populations of European descent, no mutant alleles were reported in indigenous non-European populations. They devised a rapid PCR assay for the deletion and used it to screen 3,342 individuals from a globally distributed range of populations. They found that the deletion in the CCR5 gene is not confined to persons of European descent but is found at frequencies of 2 to 5% throughout Europe, the Middle East, and the Indian subcontinent. Isolated occurrences were seen elsewhere throughout the world, but these most likely represented recent European gene flow into the indigenous populations. Martinson et al. (1997) suggested that the interpopulation differences in the frequency of the CCR5 deletion may influence the pattern of HIV transmission, and if so, the differences will need to be incorporated into future predictions of HIV levels. In a study of genomic DNA from random blood donors from North America, Asia, and Africa, Zimmerman et al. (1997) found the inactive CCR5 allele, designated by them CCR5-2, as the only mutant allele. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in 111 highly exposed-seronegative (4.5%) and 614 HIV-1-seropositive (0%) Caucasians relative to 387 Caucasian random blood donors (0.8%). This difference was highly significant (p less than 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same 3 groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of 2 cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1-positive Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconverters had a 52.6% lower risk of developing AIDS than homozygous wildtype seroconverters. Zimmerman et al. (1997) suggested that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. They suggested that since the majority (approximately 96%) of highly exposed-seronegative individuals tested were not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of normal antiretroviral therapy. See, however, Biti et al. (1997). Libert et al. (1998) investigated the frequency of the delta-CCR5 polymorphism in 18 European populations. A north-south gradient was found, with the highest allele frequencies in Finnish and Mordvinian populations (16%) and the lowest in Sardinia (4%). Highly polymorphic microsatellite markers flanking the CCR5 gene deletion were used to determine the haplotype of the chromosomes carrying the variant. More than 95% of the delta-CCR5 chromosomes carried an allele that was found in only 2% of the chromosomes carrying a wildtype CCR5 gene. From these data, it was inferred that most, if not all, delta-CCR5 alleles originated from a single mutation event, and that this mutation event probably took place a few thousand years ago in northeastern Europe. The high frequency of the delta-CCR5 allele in Caucasian populations cannot be explained easily by random genetic drift, suggesting that a selection advantage is or has been associated with the homozygous or heterozygous carriers of the mutant allele. Husain et al. (1998) described a family with heterozygosity for the 32-bp deletion in CCR5. They stated that this was the first such finding in an Indian without European admixture, and they estimated that the frequency of the deleted allele in India is likely to be very low (less than 1%). Alvarez et al. (1998) analyzed DNA from 150 HIV-1 positive intravenous drug users and 250 healthy controls from northern Spain for the presence of the delta-CCR5 mutation. The deletion was rare among seropositive intravenous drug users, and the authors found that patients carrying the deletion allele tended to show a fuller progression of HIV-1-related disease. Using a mathematical model, Sullivan et al. (2001) characterized epidemic HIV within 3 dynamic subpopulations: homozygous wildtype, heterozygous CCR5-del32, and homozygous CCR5-del32. The results indicated that the prevalence of HIV/AIDS is greater in populations lacking the CCR5-del32 alleles (homozygous wildtypes only) as compared with populations that include persons heterozygous or homozygous for the mutation. Also, they showed that HIV can provide selective pressure for CCR5-del32, increasing the frequency of this allele. Hall et al. (1999) reported that individuals carrying the 32-bp deletion in the CCR5 gene are at reduced risk of developing asthma. They suggested that this is a possible explanation for the high prevalence of this mutation in the general population. Szalai et al. (2000) determined the CCR5del32 allelic frequencies in 121 nonasthmatic, atopic children aged 1 to 14 years and in 295 age-matched controls in Hungary. They found no significant differences between allergic and control children, and suggested that the CCR5del32 mutation, even in homozygous form, has no protective effect on the development of allergic inflammation. Although functional evidence might suggest that CCR5 is a good candidate gene for atopic asthma, a study by Mitchell et al. (2000) of 2 panels of nuclear families containing 1,284 individuals found no genetic evidence that the CCR5del32 polymorphism is related to atopy or asthma/wheeze. Barcellos et al. (2000) found that patients with multiple sclerosis (MS; 126200) carrying the CCR5-delta-32 deletion showed an age at onset approximately 3 years later than did patients without the deletion. Studying 256 Israeli patients with MS, Kantor et al. (2003) presented evidence suggesting that the CCR5-delta-32 deletion may contribute to a slower rate of disease progression in MS. Fischereder et al. (2001) demonstrated another benefit of homozygosity for the CCR5del32 mutation: longer survival of renal transplants, suggesting a pathophysiologic role for CCR5 in transplant loss. This receptor may be a useful target for the prevention of transplant loss. Strieter and Belperio (2001) reviewed evidence on the implication of various chemokine receptors and their respective ligands in promoting allograft rejection. They commented on the expanding critical role of chemokine biology in transplantation immunology, which should pave the way for the development of pharmaceutical agents that will target pathogenetic steps in chemokine biology and provide new treatments for enhancing long-term allograft survival. In a genotype survey of 4,166 individuals, Stephens et al. (1998) identified a cline of CCR5-del32 allele frequencies of 0 to 14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and 2 microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, Stephens et al. (1998) estimated the origin of the CCR5-del32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275 to 1,875 years. The geographic cline of mutation frequencies and its recent emergence are consistent with a historic strong selective event (i.e., an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations. Majumder and Dey (2001) studied 1,438 unrelated individuals belonging to 40 ethnic groups from India. The CCR5del32 allele was absent in most ethnic populations, but was present in some populations of the northern and western regions. The authors suggested that the allele might have been introduced by Caucasian gene flow, consistent with the historical fact that Caucasoid migrants from central Asia and western Eurasia had entered India about 8,000 to 10,000 earlier. Using a population genetic model based on the demography of Europe, Duncan et al. (2005) suggested that annual widespread epidemics of plague, a viral hemorrhagic fever, from 1347 until 1670 forced up the frequency of the delta-32 mutation. Novembre et al. (2005) evaluated the selection hypothesis for the origin and maintenance of the delta-32 mutation in Europe. Assuming uniform selection across Europe and western Asia, they found support for northern European origin of delta-32 and Viking-mediated dispersal, which was originally proposed by Lucotte and Mercier (1998). On the other hand, if gradients in selection intensity were assumed, Novembre et al. (2005) estimated the origin to be outside of northern Europe and selection intensities to be strongest in the northwestern part of the continent. Using denser genetic maps and more extensive control data than previous studies, Sabeti et al. (2005) determined that genetic variation at delta-32 is not exceptional relative to other loci across the genome. They estimated that the delta-32 allele arose more than 5,000 years ago, considerably earlier than the origin proposed by Stephens et al. (1998). While not ruling out selection, especially given the biology of the gene, Sabeti et al. (2005) concluded that the results imply that the pattern of genetic variation at delta-32 is consistent with neutral evolution. Glass et al. (2006) analyzed the distribution of CCR5 delta-32 in independent cohorts of West Nile virus (see 610379)-seropositive individuals. They observed a strong deviation from Hardy-Weinberg equilibrium due to an increased frequency of delta-32 homozygotes. The delta-32 homozygotes also had increased risk of fatal WNV infection. Glass et al. (2006) concluded that CCR5 delta-32 is a risk factor for symptomatic WNV infection. Goulding et al. (2005) genotyped 283 Irish women exposed to hepatitis C virus (HCV; see 609532) genotype-1b from a single donor for CCR5, CCR2 (601267), and CCL5 (187011) polymorphisms. They found that CCR5 delta-32 heterozygotes showed significantly higher spontaneous clearance of HCV compared with wildtype CCR5 homozygotes. In addition, the authors observed a trend toward lower hepatic inflammation scores in CCR5 delta-32 heterozygotes compared with wildtype CCR5 homozygotes. No significant relationships were found with CCR2 or CCL5. Thio et al. (2008) stated that 95% of adults recover from acute hepatitis B virus (HBV; see 610424) infection and that the likelihood of recovery is enhanced in those carrying the 32-bp deletion in CCR5. By comparing 181 individuals with persistent HBV infection with 316 who had recovered, Thio et al. (2008) showed that the combination of the 32-bp deletion in CCR5 with the minor allele of a functional promoter polymorphism in CCL5, -403G-A, was significantly associated with recovery (odds ratio = 0.36; P = 0.02). CCL5 -403A without the 32-bp deletion in CCR5 was not associated with HBV recovery, and the 32-bp deletion in CCR5 without CCL5 -403A showed only weak, nonsignificant protection. Thio et al. (2008) noted that -403A is associated with higher levels of CCL5 in cell lines. They proposed that excess CCL5 due to -403A combined with the nonfunctional CCR5 receptor due to the 32-bp deletion favors recovery from HBV infection. However, Thio et al. (2008) stated that they could not totally eliminate the possibility that interaction with the 32-bp deletion in CCR5 is due to another CCL5 SNP, 524T-C, rather than -403A, because 524C is in tight linkage disequilibrium with -403A. In a study involving 8,064 patients with type 1 diabetes and 9,339 controls, Smyth et al. (2008) found significant association between the 32-bp insertion/deletion in the CCR5 gene on chromosome 3p21 and a decreased risk for type 1 diabetes (odds ratio, 0.54; p = 1.88 x 10(-6)); see 612522. The association was validated in 2,828 families providing 3,064 parent-child trios (relative risk, 0.53; p = 1.81 x 10(-8)). The mutation encodes a nonfunctional receptor (Liu et al., 1996; Samson et al., 1996). (less)

In an HIV-1-exposed patient with slow disease progression (see 609423), Samson et al. (1996) identified a homozygous 32-bp deletion in the CMKBR5 gene that results in a frameshift and premature termination. Samson et al. (1996) found that the mutation had an allelic frequency of 0.092 in Caucasian populations but was absent in populations from western and central Africa and from Japan. Among HIV-1-infected Caucasian subjects, no homozygous individuals were found, and the frequency of heterozygotes was 35% lower in infected individuals than in the general population. Samson et al. (1996) speculated that a 10-bp direct repeat that flanks the deleted region promoted a recombination event leading to the 32-bp deletion. Independently and simultaneously, Liu et al. (1996) identified the same homozygous 32-bp deletion in the CMKBR5 gene in 2 individuals who, though multiply exposed to HIV-1, remained uninfected. The deletion comprises nucleotides 794 to 825 of their cDNA sequence (codons 175 to 185) and results in a reading frameshift after amino acid 174, inclusion of 31 novel amino acids, and truncation at codon 206. The severely truncated protein could not be detected at the surface of cells that normally express the protein. They stated that the defect had no other obvious phenotype. Liu et al. (1996) stated that the frequency of CKR5-deleted homozygotes is about 1% in persons of western European heritage. The investigators also stated that heterozygous individuals were common (approximately 20%) in unrelated individuals of western European heritage but were present at a much lower frequency in a panel of individuals from Venezuela. Ansari-Lari et al. (1997) stated that this mutation results in a frameshift at codon 185, causing a deletion of 168 amino acids and the gain of 31 new residues in the C terminus of the putative translation product. Martinson et al. (1997) followed up on the observation that, although a gene frequency of approximately 10% was found for the 32-bp deletion in the CCR5 gene in populations of European descent, no mutant alleles were reported in indigenous non-European populations. They devised a rapid PCR assay for the deletion and used it to screen 3,342 individuals from a globally distributed range of populations. They found that the deletion in the CCR5 gene is not confined to persons of European descent but is found at frequencies of 2 to 5% throughout Europe, the Middle East, and the Indian subcontinent. Isolated occurrences were seen elsewhere throughout the world, but these most likely represented recent European gene flow into the indigenous populations. Martinson et al. (1997) suggested that the interpopulation differences in the frequency of the CCR5 deletion may influence the pattern of HIV transmission, and if so, the differences will need to be incorporated into future predictions of HIV levels. In a study of genomic DNA from random blood donors from North America, Asia, and Africa, Zimmerman et al. (1997) found the inactive CCR5 allele, designated by them CCR5-2, as the only mutant allele. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in 111 highly exposed-seronegative (4.5%) and 614 HIV-1-seropositive (0%) Caucasians relative to 387 Caucasian random blood donors (0.8%). This difference was highly significant (p less than 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same 3 groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of 2 cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1-positive Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconverters had a 52.6% lower risk of developing AIDS than homozygous wildtype seroconverters. Zimmerman et al. (1997) suggested that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. They suggested that since the majority (approximately 96%) of highly exposed-seronegative individuals tested were not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of normal antiretroviral therapy. See, however, Biti et al. (1997). Libert et al. (1998) investigated the frequency of the delta-CCR5 polymorphism in 18 European populations. A north-south gradient was found, with the highest allele frequencies in Finnish and Mordvinian populations (16%) and the lowest in Sardinia (4%). Highly polymorphic microsatellite markers flanking the CCR5 gene deletion were used to determine the haplotype of the chromosomes carrying the variant. More than 95% of the delta-CCR5 chromosomes carried an allele that was found in only 2% of the chromosomes carrying a wildtype CCR5 gene. From these data, it was inferred that most, if not all, delta-CCR5 alleles originated from a single mutation event, and that this mutation event probably took place a few thousand years ago in northeastern Europe. The high frequency of the delta-CCR5 allele in Caucasian populations cannot be explained easily by random genetic drift, suggesting that a selection advantage is or has been associated with the homozygous or heterozygous carriers of the mutant allele. Husain et al. (1998) described a family with heterozygosity for the 32-bp deletion in CCR5. They stated that this was the first such finding in an Indian without European admixture, and they estimated that the frequency of the deleted allele in India is likely to be very low (less than 1%). Alvarez et al. (1998) analyzed DNA from 150 HIV-1 positive intravenous drug users and 250 healthy controls from northern Spain for the presence of the delta-CCR5 mutation. The deletion was rare among seropositive intravenous drug users, and the authors found that patients carrying the deletion allele tended to show a fuller progression of HIV-1-related disease. Using a mathematical model, Sullivan et al. (2001) characterized epidemic HIV within 3 dynamic subpopulations: homozygous wildtype, heterozygous CCR5-del32, and homozygous CCR5-del32. The results indicated that the prevalence of HIV/AIDS is greater in populations lacking the CCR5-del32 alleles (homozygous wildtypes only) as compared with populations that include persons heterozygous or homozygous for the mutation. Also, they showed that HIV can provide selective pressure for CCR5-del32, increasing the frequency of this allele. Hall et al. (1999) reported that individuals carrying the 32-bp deletion in the CCR5 gene are at reduced risk of developing asthma. They suggested that this is a possible explanation for the high prevalence of this mutation in the general population. Szalai et al. (2000) determined the CCR5del32 allelic frequencies in 121 nonasthmatic, atopic children aged 1 to 14 years and in 295 age-matched controls in Hungary. They found no significant differences between allergic and control children, and suggested that the CCR5del32 mutation, even in homozygous form, has no protective effect on the development of allergic inflammation. Although functional evidence might suggest that CCR5 is a good candidate gene for atopic asthma, a study by Mitchell et al. (2000) of 2 panels of nuclear families containing 1,284 individuals found no genetic evidence that the CCR5del32 polymorphism is related to atopy or asthma/wheeze. Barcellos et al. (2000) found that patients with multiple sclerosis (MS; 126200) carrying the CCR5-delta-32 deletion showed an age at onset approximately 3 years later than did patients without the deletion. Studying 256 Israeli patients with MS, Kantor et al. (2003) presented evidence suggesting that the CCR5-delta-32 deletion may contribute to a slower rate of disease progression in MS. Fischereder et al. (2001) demonstrated another benefit of homozygosity for the CCR5del32 mutation: longer survival of renal transplants, suggesting a pathophysiologic role for CCR5 in transplant loss. This receptor may be a useful target for the prevention of transplant loss. Strieter and Belperio (2001) reviewed evidence on the implication of various chemokine receptors and their respective ligands in promoting allograft rejection. They commented on the expanding critical role of chemokine biology in transplantation immunology, which should pave the way for the development of pharmaceutical agents that will target pathogenetic steps in chemokine biology and provide new treatments for enhancing long-term allograft survival. In a genotype survey of 4,166 individuals, Stephens et al. (1998) identified a cline of CCR5-del32 allele frequencies of 0 to 14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and 2 microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, Stephens et al. (1998) estimated the origin of the CCR5-del32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275 to 1,875 years. The geographic cline of mutation frequencies and its recent emergence are consistent with a historic strong selective event (i.e., an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations. Majumder and Dey (2001) studied 1,438 unrelated individuals belonging to 40 ethnic groups from India. The CCR5del32 allele was absent in most ethnic populations, but was present in some populations of the northern and western regions. The authors suggested that the allele might have been introduced by Caucasian gene flow, consistent with the historical fact that Caucasoid migrants from central Asia and western Eurasia had entered India about 8,000 to 10,000 earlier. Using a population genetic model based on the demography of Europe, Duncan et al. (2005) suggested that annual widespread epidemics of plague, a viral hemorrhagic fever, from 1347 until 1670 forced up the frequency of the delta-32 mutation. Novembre et al. (2005) evaluated the selection hypothesis for the origin and maintenance of the delta-32 mutation in Europe. Assuming uniform selection across Europe and western Asia, they found support for northern European origin of delta-32 and Viking-mediated dispersal, which was originally proposed by Lucotte and Mercier (1998). On the other hand, if gradients in selection intensity were assumed, Novembre et al. (2005) estimated the origin to be outside of northern Europe and selection intensities to be strongest in the northwestern part of the continent. Using denser genetic maps and more extensive control data than previous studies, Sabeti et al. (2005) determined that genetic variation at delta-32 is not exceptional relative to other loci across the genome. They estimated that the delta-32 allele arose more than 5,000 years ago, considerably earlier than the origin proposed by Stephens et al. (1998). While not ruling out selection, especially given the biology of the gene, Sabeti et al. (2005) concluded that the results imply that the pattern of genetic variation at delta-32 is consistent with neutral evolution. Glass et al. (2006) analyzed the distribution of CCR5 delta-32 in independent cohorts of West Nile virus (see 610379)-seropositive individuals. They observed a strong deviation from Hardy-Weinberg equilibrium due to an increased frequency of delta-32 homozygotes. The delta-32 homozygotes also had increased risk of fatal WNV infection. Glass et al. (2006) concluded that CCR5 delta-32 is a risk factor for symptomatic WNV infection. Goulding et al. (2005) genotyped 283 Irish women exposed to hepatitis C virus (HCV; see 609532) genotype-1b from a single donor for CCR5, CCR2 (601267), and CCL5 (187011) polymorphisms. They found that CCR5 delta-32 heterozygotes showed significantly higher spontaneous clearance of HCV compared with wildtype CCR5 homozygotes. In addition, the authors observed a trend toward lower hepatic inflammation scores in CCR5 delta-32 heterozygotes compared with wildtype CCR5 homozygotes. No significant relationships were found with CCR2 or CCL5. Thio et al. (2008) stated that 95% of adults recover from acute hepatitis B virus (HBV; see 610424) infection and that the likelihood of recovery is enhanced in those carrying the 32-bp deletion in CCR5. By comparing 181 individuals with persistent HBV infection with 316 who had recovered, Thio et al. (2008) showed that the combination of the 32-bp deletion in CCR5 with the minor allele of a functional promoter polymorphism in CCL5, -403G-A, was significantly associated with recovery (odds ratio = 0.36; P = 0.02). CCL5 -403A without the 32-bp deletion in CCR5 was not associated with HBV recovery, and the 32-bp deletion in CCR5 without CCL5 -403A showed only weak, nonsignificant protection. Thio et al. (2008) noted that -403A is associated with higher levels of CCL5 in cell lines. They proposed that excess CCL5 due to -403A combined with the nonfunctional CCR5 receptor due to the 32-bp deletion favors recovery from HBV infection. However, Thio et al. (2008) stated that they could not totally eliminate the possibility that interaction with the 32-bp deletion in CCR5 is due to another CCL5 SNP, 524T-C, rather than -403A, because 524C is in tight linkage disequilibrium with -403A. In a study involving 8,064 patients with type 1 diabetes and 9,339 controls, Smyth et al. (2008) found significant association between the 32-bp insertion/deletion in the CCR5 gene on chromosome 3p21 and a decreased risk for type 1 diabetes (odds ratio, 0.54; p = 1.88 x 10(-6)); see 612522. The association was validated in 2,828 families providing 3,064 parent-child trios (relative risk, 0.53; p = 1.81 x 10(-8)). The mutation encodes a nonfunctional receptor (Liu et al., 1996; Samson et al., 1996). (less)