ClinVar Genomic variation as it relates to human health

The Fy(a-b-) phenotype is rare among white and Asian populations, whereas it is the predominant phenotype among populations of black people, especially those originating in West Africa. Tournamille et al. (1995) demonstrated that the molecular basis of the Fy(a-b-) phenotype is a T-to-C transition at nucleotide -46, numbering relative to the erythroid transcriptional start site, in the GATA box of the FYB promoter. This mutation disrupts the binding site for the GATA1 (305371) erythroid transcription factor, results in a silent FYB allele in erythroid cells, and is considered to be responsible for most cases of Fy(a-b-) erythrocytes in black populations. The GATA mutation generates a StyI restriction site, allowing the identification of this mutation by RFLP. The Fy(a-b-) phenotype provides complete protection from Plasmodium vivax infection (see 611162). Iwamoto et al. (1996) reported the same DARC promoter mutation as Tournamille et al. (1995). The mutation, which Iwamoto et al. (1996) called -365T-C, was found in the proximal GATA motif from 3 black Fy(a-b-) individuals. Iwamoto et al. (1996) found that the black-type mutation abolished chloramphenicol acetyltransferase transcription in human erythroleukemia cells but not in human microvascular endothelial cells. Deletion mutagenesis studies revealed that the proximal GATA motif represents the erythroid regulatory core region for the Duffy gene. Gel shift assay showed that the proximal GATA motif is the target sequence of GATA1 (305371). These studies indicated that the black-type mutation abolishes Duffy gene expression in erythroid but not in postcapillary venule endothelium, which is compatible with the Northern blot and immunohistochemical observation in black Fy(a-b-) individuals. In their review, Pogo and Chaudhuri (2000) referred to this SNP as -33T-C, numbering relative to the major erythroid transcriptional start site reported by Iwamoto et al. (1996), which is located 34 nucleotides upstream of the translation initiation codon for the major DARC isoform. Pogo and Chaudhuri (2000) referred to the allele as FYB-erythroid silent, or FYB-ES. In another review, Meny (2010) referred to this SNP as -67T-C, numbering relative to the translational start site of the major DARC isoform. In a P. vivax-endemic region of Papua New Guinea where the resident Abelam-speaking population is characterized by a frequency of alpha(+)-thalassemia of 98% or greater, Zimmerman et al. (1999) discovered that the mutation responsible for erythrocyte Duffy antigen-negativity, Fy(a-b-), is located on the FY*A allele. In this study population, there were 23 heterozygous and no homozygous individuals bearing the new allele, giving an allele frequency of 23/1062, or 0.022. Flow cytometric analysis illustrated a 2-fold difference in erythroid-specific Fy-antigen expression between heterozygous-null and homozygous-normal individuals, suggesting a gene dosage effect. In further comparisons, Zimmerman et al. (1999) observed a higher prevalence of P. vivax infection in homozygous normals (83/508, or 0.163) compared with heterozygous FY*A/FY*A(null) (2/23, or 0.087) individuals, giving an odds ratio of 2.05. Emergence of FY*A(null) in this population suggests that P. vivax is involved in selection of this erythroid polymorphism. This mutation would ultimately compromise the alpha(+)-thalassemia/P. vivax-mediated protection against severe P. falciparum malaria. In a review of the evolutionary significance of cis-regulatory mutations, Wray (2007) listed a common polymorphism of DARC resulting in resistance to infection with malaria. They argued that changes in cis-regulatory sequences constitute an important part of the genetic basis for adaptation. The claim was empirically well supported by studies, such as those of DARC, identifying cis-regulatory mutations that have functionally significant consequences for morphology, physiology, and behavior. The -46T-C promoter SNP in DARC is widely prevalent in populations of African descent, and -46CC genotype results in selective loss of DARC expression on RBCs. He et al. (2008) found that, in the admixed African-American population, the DARC -46C allele was in Hardy-Weinberg equilibrium in human immunodeficiency virus (HIV; see 609423)-negative subjects, but it was in disequilibrium in HIV-positive patients. Genotype analysis indicated that the prevalence of -46CC was greater in HIV-positive patients, and -46CC individuals had a 50% higher risk of acquiring HIV. Calculation of the population attributable fraction for excess HIV burden was estimated to be 11% for DARC -46CC in African settings. In contrast, DARC -46CC was associated with slower disease progression in terms of death or development of dementia. Kulkarni et al. (2009) found that ethnic leukopenia present in healthy African Americans was also present in the setting of HIV infection. The disease course among HIV+ African Americans with low WBC was slower than that of HIV+ European Americans with low WBC. DARC -46CC was present nearly exclusively in African Americans (69.1%) compared to European Americans (0.2%), and there was a trend toward a survival advantage for HIV+ African Americans with -46 CC compared to HIV+ European Americans or to African Americans with DARC -46CT or -46TT. However, the survival advantage associated with -46CC was highly dependent on WBC counts, as this association was greatly magnified in subjects with low WBC and muted in those with high WBC. Overall, the observations indicated that ethnic leukopenia in HIV-infected African Americans may be associated with a more benign phenotype, despite HIV-induced immunodeficiency. White blood cell count is lower among African Americans compared to European Americans (see 611862). In a study of 2 African American populations using admixture mapping to identify loci that influence white blood cell count, Nalls et al. (2008) found a significant association of low white blood cell count with a higher proportion of African ancestry, and identified the strongest association with the DARC single-nucleotide polymorphism rs2814778, which controls expression of the Duffy blood group antigen. Nalls et al. (2008) noted that this is one of the alleles in the genome with the largest allele frequency difference between West Africans and European Americans. By quadrupling the sample size from the Nalls et al. (2008) study, Reich et al. (2009) showed that low white blood cell count in African Americans primarily results from reduced neutrophil count due to homozygosity for the Duffy-null SNP, rs2814778, rather than to ancestry alone. Reich et al. (2009) noted the clinical significance of the lower neutrophil counts in individuals homozygous for the Duffy-null variant in medical decision making, as white blood cell count is a marker of immunocompetence, infection, and inflammation, and they proposed the potential utility of rs2814778 genotyping. (less)

The Fy(a-b-) phenotype is rare among white and Asian populations, whereas it is the predominant phenotype among populations of black people, especially those originating in West Africa. Tournamille et al. (1995) demonstrated that the molecular basis of the Fy(a-b-) phenotype is a T-to-C transition at nucleotide -46, numbering relative to the erythroid transcriptional start site, in the GATA box of the FYB promoter. This mutation disrupts the binding site for the GATA1 (305371) erythroid transcription factor, results in a silent FYB allele in erythroid cells, and is considered to be responsible for most cases of Fy(a-b-) erythrocytes in black populations. The GATA mutation generates a StyI restriction site, allowing the identification of this mutation by RFLP. The Fy(a-b-) phenotype provides complete protection from Plasmodium vivax infection (see 611162). Iwamoto et al. (1996) reported the same DARC promoter mutation as Tournamille et al. (1995). The mutation, which Iwamoto et al. (1996) called -365T-C, was found in the proximal GATA motif from 3 black Fy(a-b-) individuals. Iwamoto et al. (1996) found that the black-type mutation abolished chloramphenicol acetyltransferase transcription in human erythroleukemia cells but not in human microvascular endothelial cells. Deletion mutagenesis studies revealed that the proximal GATA motif represents the erythroid regulatory core region for the Duffy gene. Gel shift assay showed that the proximal GATA motif is the target sequence of GATA1 (305371). These studies indicated that the black-type mutation abolishes Duffy gene expression in erythroid but not in postcapillary venule endothelium, which is compatible with the Northern blot and immunohistochemical observation in black Fy(a-b-) individuals. In their review, Pogo and Chaudhuri (2000) referred to this SNP as -33T-C, numbering relative to the major erythroid transcriptional start site reported by Iwamoto et al. (1996), which is located 34 nucleotides upstream of the translation initiation codon for the major DARC isoform. Pogo and Chaudhuri (2000) referred to the allele as FYB-erythroid silent, or FYB-ES. In another review, Meny (2010) referred to this SNP as -67T-C, numbering relative to the translational start site of the major DARC isoform. In a P. vivax-endemic region of Papua New Guinea where the resident Abelam-speaking population is characterized by a frequency of alpha(+)-thalassemia of 98% or greater, Zimmerman et al. (1999) discovered that the mutation responsible for erythrocyte Duffy antigen-negativity, Fy(a-b-), is located on the FY*A allele. In this study population, there were 23 heterozygous and no homozygous individuals bearing the new allele, giving an allele frequency of 23/1062, or 0.022. Flow cytometric analysis illustrated a 2-fold difference in erythroid-specific Fy-antigen expression between heterozygous-null and homozygous-normal individuals, suggesting a gene dosage effect. In further comparisons, Zimmerman et al. (1999) observed a higher prevalence of P. vivax infection in homozygous normals (83/508, or 0.163) compared with heterozygous FY*A/FY*A(null) (2/23, or 0.087) individuals, giving an odds ratio of 2.05. Emergence of FY*A(null) in this population suggests that P. vivax is involved in selection of this erythroid polymorphism. This mutation would ultimately compromise the alpha(+)-thalassemia/P. vivax-mediated protection against severe P. falciparum malaria. In a review of the evolutionary significance of cis-regulatory mutations, Wray (2007) listed a common polymorphism of DARC resulting in resistance to infection with malaria. They argued that changes in cis-regulatory sequences constitute an important part of the genetic basis for adaptation. The claim was empirically well supported by studies, such as those of DARC, identifying cis-regulatory mutations that have functionally significant consequences for morphology, physiology, and behavior. The -46T-C promoter SNP in DARC is widely prevalent in populations of African descent, and -46CC genotype results in selective loss of DARC expression on RBCs. He et al. (2008) found that, in the admixed African-American population, the DARC -46C allele was in Hardy-Weinberg equilibrium in human immunodeficiency virus (HIV; see 609423)-negative subjects, but it was in disequilibrium in HIV-positive patients. Genotype analysis indicated that the prevalence of -46CC was greater in HIV-positive patients, and -46CC individuals had a 50% higher risk of acquiring HIV. Calculation of the population attributable fraction for excess HIV burden was estimated to be 11% for DARC -46CC in African settings. In contrast, DARC -46CC was associated with slower disease progression in terms of death or development of dementia. Kulkarni et al. (2009) found that ethnic leukopenia present in healthy African Americans was also present in the setting of HIV infection. The disease course among HIV+ African Americans with low WBC was slower than that of HIV+ European Americans with low WBC. DARC -46CC was present nearly exclusively in African Americans (69.1%) compared to European Americans (0.2%), and there was a trend toward a survival advantage for HIV+ African Americans with -46 CC compared to HIV+ European Americans or to African Americans with DARC -46CT or -46TT. However, the survival advantage associated with -46CC was highly dependent on WBC counts, as this association was greatly magnified in subjects with low WBC and muted in those with high WBC. Overall, the observations indicated that ethnic leukopenia in HIV-infected African Americans may be associated with a more benign phenotype, despite HIV-induced immunodeficiency. White blood cell count is lower among African Americans compared to European Americans (see 611862). In a study of 2 African American populations using admixture mapping to identify loci that influence white blood cell count, Nalls et al. (2008) found a significant association of low white blood cell count with a higher proportion of African ancestry, and identified the strongest association with the DARC single-nucleotide polymorphism rs2814778, which controls expression of the Duffy blood group antigen. Nalls et al. (2008) noted that this is one of the alleles in the genome with the largest allele frequency difference between West Africans and European Americans. By quadrupling the sample size from the Nalls et al. (2008) study, Reich et al. (2009) showed that low white blood cell count in African Americans primarily results from reduced neutrophil count due to homozygosity for the Duffy-null SNP, rs2814778, rather than to ancestry alone. Reich et al. (2009) noted the clinical significance of the lower neutrophil counts in individuals homozygous for the Duffy-null variant in medical decision making, as white blood cell count is a marker of immunocompetence, infection, and inflammation, and they proposed the potential utility of rs2814778 genotyping. (less)

The Fy(a-b-) phenotype is rare among white and Asian populations, whereas it is the predominant phenotype among populations of black people, especially those originating in West Africa. Tournamille et al. (1995) demonstrated that the molecular basis of the Fy(a-b-) phenotype is a T-to-C transition at nucleotide -46, numbering relative to the erythroid transcriptional start site, in the GATA box of the FYB promoter. This mutation disrupts the binding site for the GATA1 (305371) erythroid transcription factor, results in a silent FYB allele in erythroid cells, and is considered to be responsible for most cases of Fy(a-b-) erythrocytes in black populations. The GATA mutation generates a StyI restriction site, allowing the identification of this mutation by RFLP. The Fy(a-b-) phenotype provides complete protection from Plasmodium vivax infection (see 611162). Iwamoto et al. (1996) reported the same DARC promoter mutation as Tournamille et al. (1995). The mutation, which Iwamoto et al. (1996) called -365T-C, was found in the proximal GATA motif from 3 black Fy(a-b-) individuals. Iwamoto et al. (1996) found that the black-type mutation abolished chloramphenicol acetyltransferase transcription in human erythroleukemia cells but not in human microvascular endothelial cells. Deletion mutagenesis studies revealed that the proximal GATA motif represents the erythroid regulatory core region for the Duffy gene. Gel shift assay showed that the proximal GATA motif is the target sequence of GATA1 (305371). These studies indicated that the black-type mutation abolishes Duffy gene expression in erythroid but not in postcapillary venule endothelium, which is compatible with the Northern blot and immunohistochemical observation in black Fy(a-b-) individuals. In their review, Pogo and Chaudhuri (2000) referred to this SNP as -33T-C, numbering relative to the major erythroid transcriptional start site reported by Iwamoto et al. (1996), which is located 34 nucleotides upstream of the translation initiation codon for the major DARC isoform. Pogo and Chaudhuri (2000) referred to the allele as FYB-erythroid silent, or FYB-ES. In another review, Meny (2010) referred to this SNP as -67T-C, numbering relative to the translational start site of the major DARC isoform. In a P. vivax-endemic region of Papua New Guinea where the resident Abelam-speaking population is characterized by a frequency of alpha(+)-thalassemia of 98% or greater, Zimmerman et al. (1999) discovered that the mutation responsible for erythrocyte Duffy antigen-negativity, Fy(a-b-), is located on the FY*A allele. In this study population, there were 23 heterozygous and no homozygous individuals bearing the new allele, giving an allele frequency of 23/1062, or 0.022. Flow cytometric analysis illustrated a 2-fold difference in erythroid-specific Fy-antigen expression between heterozygous-null and homozygous-normal individuals, suggesting a gene dosage effect. In further comparisons, Zimmerman et al. (1999) observed a higher prevalence of P. vivax infection in homozygous normals (83/508, or 0.163) compared with heterozygous FY*A/FY*A(null) (2/23, or 0.087) individuals, giving an odds ratio of 2.05. Emergence of FY*A(null) in this population suggests that P. vivax is involved in selection of this erythroid polymorphism. This mutation would ultimately compromise the alpha(+)-thalassemia/P. vivax-mediated protection against severe P. falciparum malaria. In a review of the evolutionary significance of cis-regulatory mutations, Wray (2007) listed a common polymorphism of DARC resulting in resistance to infection with malaria. They argued that changes in cis-regulatory sequences constitute an important part of the genetic basis for adaptation. The claim was empirically well supported by studies, such as those of DARC, identifying cis-regulatory mutations that have functionally significant consequences for morphology, physiology, and behavior. The -46T-C promoter SNP in DARC is widely prevalent in populations of African descent, and -46CC genotype results in selective loss of DARC expression on RBCs. He et al. (2008) found that, in the admixed African-American population, the DARC -46C allele was in Hardy-Weinberg equilibrium in human immunodeficiency virus (HIV; see 609423)-negative subjects, but it was in disequilibrium in HIV-positive patients. Genotype analysis indicated that the prevalence of -46CC was greater in HIV-positive patients, and -46CC individuals had a 50% higher risk of acquiring HIV. Calculation of the population attributable fraction for excess HIV burden was estimated to be 11% for DARC -46CC in African settings. In contrast, DARC -46CC was associated with slower disease progression in terms of death or development of dementia. Kulkarni et al. (2009) found that ethnic leukopenia present in healthy African Americans was also present in the setting of HIV infection. The disease course among HIV+ African Americans with low WBC was slower than that of HIV+ European Americans with low WBC. DARC -46CC was present nearly exclusively in African Americans (69.1%) compared to European Americans (0.2%), and there was a trend toward a survival advantage for HIV+ African Americans with -46 CC compared to HIV+ European Americans or to African Americans with DARC -46CT or -46TT. However, the survival advantage associated with -46CC was highly dependent on WBC counts, as this association was greatly magnified in subjects with low WBC and muted in those with high WBC. Overall, the observations indicated that ethnic leukopenia in HIV-infected African Americans may be associated with a more benign phenotype, despite HIV-induced immunodeficiency. White blood cell count is lower among African Americans compared to European Americans (see 611862). In a study of 2 African American populations using admixture mapping to identify loci that influence white blood cell count, Nalls et al. (2008) found a significant association of low white blood cell count with a higher proportion of African ancestry, and identified the strongest association with the DARC single-nucleotide polymorphism rs2814778, which controls expression of the Duffy blood group antigen. Nalls et al. (2008) noted that this is one of the alleles in the genome with the largest allele frequency difference between West Africans and European Americans. By quadrupling the sample size from the Nalls et al. (2008) study, Reich et al. (2009) showed that low white blood cell count in African Americans primarily results from reduced neutrophil count due to homozygosity for the Duffy-null SNP, rs2814778, rather than to ancestry alone. Reich et al. (2009) noted the clinical significance of the lower neutrophil counts in individuals homozygous for the Duffy-null variant in medical decision making, as white blood cell count is a marker of immunocompetence, infection, and inflammation, and they proposed the potential utility of rs2814778 genotyping. (less)