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Polymorphism in the transporter associated with antigen processing (TAP2) gene
Abstracts
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POLYMORPHISM IN THE TRANSPORTER ASSOCIATED WITH ANTIGEN PROCESSING (TAP2) GENE. DP Sine~l, M Ye, X Qiu and M D'Souza. Department of Pathology, McMaster University, Hamilton, Ontario, Canada. The human major histocompatibility complex (MHC) contains two closely related genes (TAP) that encode a family of transporter proteins. Since the genes in the MHC are in linkage disequilibrium, it is likely that the TAP genes like other MHC genes are polymorphic. In this study, we investigated polymorphisms in the TAP2 gene and examined the relationship of polymorphism in TAP2 gene to susceptibility to rheumatoid arthritis (RA). We define new polymorphism at position 1693 in the ATP-binding domain of the TAP2 gene; the nucleotide substitution from G to A results in change in amino acid residue from alanine-565 to threonine-565. In addition, the present data demonstrate that the two variants of TAP2 gene (TAP2*0101 and TAP2*0201) defined earlier by nucleotide sequencing and oligonucleotide typing can also be identified by Southern blot analysis, a relatively simpler and less expensive technique. Analysis of distribution of these polymorphisms show that there are two subtypes of TAP2*0101 allele (TAP2*0101-1693.G and TAlr2*0101-1693.A) and only one of TAF2*0201 gene (TAP2*0201-1693.G). The prevalence of the new variant (nucleotide A at position 1693), and thus also of the TAP2*0101-1693.A allele, was significantly (p<0.006,RR=4.25) higher in RA patients (35.3%) than in normal controls (11.4%). In addition, the TAP2*0101-1693.A allele showed significant (r = 0.45, p<0.0003) association with HLA-DR4 only in RA patients and the prevalence of both TAP2*01011693.A and DR4 genes gave the RR value for RA (p < 0.0002, R R = 19.21). These data suggest that the MHC region containing both class ll and TAP genes confers the strongest susceptibility to RA, with highest RR value reported so far. It is likely that the genetic variability in the putative peptide transporter could also be implicated in immunological disorders associated with MHC.
Novel Alleles Found in Australia Indicate Multiple Mechanisms in the evolution of I-ILA-DRB1 XGao, SW Serjeantson. The Human Genetics Group, JCSMR, Australian National University Canberra, Australia. Hypermutational events involving segmental transfer and intro-exonic recombination have been suggested responsible for the diversification of HLA class I loci, while in the class II evolution their role is arguable. Using PCR, SSO (sequence specific oligonucleotide) hybridization and DNA sequencing of the second exon of HLA-DRB1 genes, we have recently defined in Australian Aborigines four novel HLA-DRB1 alleles designated DRB 1"0012, 1408, 1409 and 1410. The analysis of nucleotide sequence phylogeny of the four alleles and the extended class II haplotypes strongly supports the hypothesis that in addition to point mutation, other mechanisms were also involved in the molecular evolution of HLA-DRB1. DRB 1" 1408 and 1409 both have a single nonsynonemous point mutation from the putative progenitor DRB 1" 1401 and 1402 respectively. The 3rd HVR of the novel Aboriginal DR4 subtype DRBI*0412 apparently came from the most common Aboriginal DRB 1 allele DRB 1"0803 through segmental transfer. DRB 1" 1410 was generated from progenitors DR4 and DRB 1" 1401; an unusual intra-exonic recombination apparently happened between codons 13 and 19 resulting in a DRB1 exon 2 with combined features from both DR4 and DRB 1" 1401. The analysis of extended class II haplotypes including DRB3, DRB4, DQA1 and DQB 1 loci of DRB 1" 1410 also supports the intra-exonic recombination scenario. The latter two novel alleles have created unique peptide binding sites which have important implication for functional studies. The Australian Aborigines have been isolated for at least 50,000 years. The novel DRB 1 alleles have substantially replaced their progenitors in these populations; the Aboriginal DRB 1 profile has virtually nothing overlapped with Caucasoids. DRB 1"0412 has become the dominant DR4 subtype in the Aborigines from northwestern Australia while the four novel DRB1 alleles were detected in 45% of the Aboriginal individuals tested.
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POLYMORPHISM IN THE TRANSPORTER ASSOCIATED WITH ANTIGEN PROCESSING (TAP2) GENE. DP Sine~l, M Ye, X Qiu and M D'Souza. Department of Pathology, McMaster University, Hamilton, Ontario, Canada. The human major histocompatibility complex (MHC) contains two closely related genes (TAP) that encode a family of transporter proteins. Since the genes in the MHC are in linkage disequilibrium, it is likely that the TAP genes like other MHC genes are polymorphic. In this study, we investigated polymorphisms in the TAP2 gene and examined the relationship of polymorphism in TAP2 gene to susceptibility to rheumatoid arthritis (RA). We define new polymorphism at position 1693 in the ATP-binding domain of the TAP2 gene; the nucleotide substitution from G to A results in change in amino acid residue from alanine-565 to threonine-565. In addition, the present data demonstrate that the two variants of TAP2 gene (TAP2*0101 and TAP2*0201) defined earlier by nucleotide sequencing and oligonucleotide typing can also be identified by Southern blot analysis, a relatively simpler and less expensive technique. Analysis of distribution of these polymorphisms show that there are two subtypes of TAP2*0101 allele (TAP2*0101-1693.G and TAlr2*0101-1693.A) and only one of TAF2*0201 gene (TAP2*0201-1693.G). The prevalence of the new variant (nucleotide A at position 1693), and thus also of the TAP2*0101-1693.A allele, was significantly (p<0.006,RR=4.25) higher in RA patients (35.3%) than in normal controls (11.4%). In addition, the TAP2*0101-1693.A allele showed significant (r = 0.45, p<0.0003) association with HLA-DR4 only in RA patients and the prevalence of both TAP2*01011693.A and DR4 genes gave the RR value for RA (p < 0.0002, R R = 19.21). These data suggest that the MHC region containing both class ll and TAP genes confers the strongest susceptibility to RA, with highest RR value reported so far. It is likely that the genetic variability in the putative peptide transporter could also be implicated in immunological disorders associated with MHC.
Novel Alleles Found in Australia Indicate Multiple Mechanisms in the evolution of I-ILA-DRB1 XGao, SW Serjeantson. The Human Genetics Group, JCSMR, Australian National University Canberra, Australia. Hypermutational events involving segmental transfer and intro-exonic recombination have been suggested responsible for the diversification of HLA class I loci, while in the class II evolution their role is arguable. Using PCR, SSO (sequence specific oligonucleotide) hybridization and DNA sequencing of the second exon of HLA-DRB1 genes, we have recently defined in Australian Aborigines four novel HLA-DRB1 alleles designated DRB 1"0012, 1408, 1409 and 1410. The analysis of nucleotide sequence phylogeny of the four alleles and the extended class II haplotypes strongly supports the hypothesis that in addition to point mutation, other mechanisms were also involved in the molecular evolution of HLA-DRB1. DRB 1" 1408 and 1409 both have a single nonsynonemous point mutation from the putative progenitor DRB 1" 1401 and 1402 respectively. The 3rd HVR of the novel Aboriginal DR4 subtype DRBI*0412 apparently came from the most common Aboriginal DRB 1 allele DRB 1"0803 through segmental transfer. DRB 1" 1410 was generated from progenitors DR4 and DRB 1" 1401; an unusual intra-exonic recombination apparently happened between codons 13 and 19 resulting in a DRB1 exon 2 with combined features from both DR4 and DRB 1" 1401. The analysis of extended class II haplotypes including DRB3, DRB4, DQA1 and DQB 1 loci of DRB 1" 1410 also supports the intra-exonic recombination scenario. The latter two novel alleles have created unique peptide binding sites which have important implication for functional studies. The Australian Aborigines have been isolated for at least 50,000 years. The novel DRB 1 alleles have substantially replaced their progenitors in these populations; the Aboriginal DRB 1 profile has virtually nothing overlapped with Caucasoids. DRB 1"0412 has become the dominant DR4 subtype in the Aborigines from northwestern Australia while the four novel DRB1 alleles were detected in 45% of the Aboriginal individuals tested.