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Molecular analysis reveals extensive diversity among HLA-DR2 haplotypes
Abstracts
31
C-2.3 #49
MOLECULAR ANALYSIS REVEALS EXTENSIVE DIVERSITY AMONG HLA-DR2 HAPLOTYPES. AG Smith, EW Petersdorf, L Regen, LA Guthrie, EM Mickelsen, PJ Martin, and JA Hansen, Fred Hutchinson Cancer Research Center, Seattle, WA. The DR2 alloantigen can be subdivided by serologic and cellular methods into four distinct phenotypes: DR15 (Dw2 and Dwl2) and DR16 (Dw21 and Dw22). Molecular analysis has shown that the DR2 family of haplotypes represents the products of two polymorphic genes, DRB1 and DRB5, with 5 alleles at each locus. DR2 haplotypes often show strong linkage disequilibrium between the DRB1, DRB5, DQA1 and DQB1 alleles, and also with certain HLA-B and A alleles. The analysis of DR2 haplotypes from racially diverse groups has shown novel DRB1, DRB5, DQA1, and DQB1 associations. We used PCR/SSOP to study the HLA class II alleles encoded by 40 DR2 haplotypes derived from 6 different racial]ethnic groups. The results are summarized as follows: HLA-B DRB1 DRB5 DOA1 DOB1 n Race B57 "1501 "0101 "0501 "0301 1 B B18,22,55 "1501 "0101 "0102 *0603 5 C B7,18,44,53,58,70 "1503 "0101 "0102 *0602 15 AB,B,H,C B7,45,53,57,61,67 "1602 *02 "0102 *0502 9 C,AB,H,O B38,7,51,60,62 "1502 "0101 "0102 *0502 10 F AB (American Black), B (Brazilian), H (North American Hispanic), C (North American Caucasian), O (Oriental), F (Filipino). The unusual extended haplotype, DRBI*1502,DRB5*0101,DQAI*0102,DQBI*0502 was associated with HLA-B38 in six of ten samples. These results demonstrate the heterogeneity of DRB, DQB, and DQA alleles encoded by DR2-positive haplotypes found in ethnically diverse populations. Characterization of DR2 haplotypes among different ethnic groups will help in carrying out unrelated marrow donor searches and in understanding HLA associations with susceptibility and resistance to autoimmune disease.
C-2.3 #50
ANALYSIS OF HLA-DRB1 ALLELES AMONG 23 BRAZILIAN FAMILIES REVEALS A PUTATIVE NEW DR8 ALLELE. AG Smith. E Donadi +, S McKinney, B Nisperos, EM Mickelson, PJ Martin, and JA Hansen, Fred Hutchinson Cancer Research Center, Seattle, WA, and +Univerity of Sao Paulo, Ribeirao Preto, Brazil. We have used PCR]SSOP to identify the HLA-DRB1 alleles of 85 haplotypes derived from 23 Brazilian families of marrow transplant and rheumatic fever patients. The donors included individuals described as having Caucasian, Black, Japanese, or mixed racial origin. In order of frequency, the DR specificities identified were DR4 (15.3%), DRll (14.1%), DR7 (12.9%), DR13 (11.8%), DR3 (10.6%), DR8 (10.6%), DR2 (9.4%), DR1 (5.9%), DR14 (4.7%), DR10 (3.5%) and DR9 (1.2%). Twenty-seven different DRB1 alleles were identified. Among DR4 alleles, DRBI*0402 was the most frequent (3), with all instances occurring with a single haplotype, HLA-A2,B51,DRBI*0402. The DRBI*0401 (2), *0405 (2), "0411 (2), "0410 (1) and *0407 (1) alleles were also identified. Within the DRll family, the DRBI*ll01 (6), "1103 (2) and "1104 (4) alleles were identified. Only the DRBI*1301 (6), "1302 (4) and "1401 (4) alleles were identified within the DR6 family. DR2 alleles were represented by DRBI*1501 (3), "1502 (1), "1503 (3) and "1601 (1), and DR1 alleles identified included DRBI*0101 (1) and "0102 (3). The DR8 alleles showed striking heterogeneity, with DRBI*0801 (2), *0802 (2), *0804 (2) and a new DR8 allele being identified (2). The new DR8 allele was observed in two families and closely resembles DRBI*0801 and *0802, but differs from both in the region between codons 55 and 59. The new allele fails to hybridize to oligonucleotide probes corresponding to "RPSAE" ('0801) and "RPDAE" (*0802). Sequencing is in progress to confirm the variant DR8 allele and to identify the amino acid differences that may be encoded.
31
C-2.3 #49
MOLECULAR ANALYSIS REVEALS EXTENSIVE DIVERSITY AMONG HLA-DR2 HAPLOTYPES. AG Smith, EW Petersdorf, L Regen, LA Guthrie, EM Mickelsen, PJ Martin, and JA Hansen, Fred Hutchinson Cancer Research Center, Seattle, WA. The DR2 alloantigen can be subdivided by serologic and cellular methods into four distinct phenotypes: DR15 (Dw2 and Dwl2) and DR16 (Dw21 and Dw22). Molecular analysis has shown that the DR2 family of haplotypes represents the products of two polymorphic genes, DRB1 and DRB5, with 5 alleles at each locus. DR2 haplotypes often show strong linkage disequilibrium between the DRB1, DRB5, DQA1 and DQB1 alleles, and also with certain HLA-B and A alleles. The analysis of DR2 haplotypes from racially diverse groups has shown novel DRB1, DRB5, DQA1, and DQB1 associations. We used PCR/SSOP to study the HLA class II alleles encoded by 40 DR2 haplotypes derived from 6 different racial]ethnic groups. The results are summarized as follows: HLA-B DRB1 DRB5 DOA1 DOB1 n Race B57 "1501 "0101 "0501 "0301 1 B B18,22,55 "1501 "0101 "0102 *0603 5 C B7,18,44,53,58,70 "1503 "0101 "0102 *0602 15 AB,B,H,C B7,45,53,57,61,67 "1602 *02 "0102 *0502 9 C,AB,H,O B38,7,51,60,62 "1502 "0101 "0102 *0502 10 F AB (American Black), B (Brazilian), H (North American Hispanic), C (North American Caucasian), O (Oriental), F (Filipino). The unusual extended haplotype, DRBI*1502,DRB5*0101,DQAI*0102,DQBI*0502 was associated with HLA-B38 in six of ten samples. These results demonstrate the heterogeneity of DRB, DQB, and DQA alleles encoded by DR2-positive haplotypes found in ethnically diverse populations. Characterization of DR2 haplotypes among different ethnic groups will help in carrying out unrelated marrow donor searches and in understanding HLA associations with susceptibility and resistance to autoimmune disease.
C-2.3 #50
ANALYSIS OF HLA-DRB1 ALLELES AMONG 23 BRAZILIAN FAMILIES REVEALS A PUTATIVE NEW DR8 ALLELE. AG Smith. E Donadi +, S McKinney, B Nisperos, EM Mickelson, PJ Martin, and JA Hansen, Fred Hutchinson Cancer Research Center, Seattle, WA, and +Univerity of Sao Paulo, Ribeirao Preto, Brazil. We have used PCR]SSOP to identify the HLA-DRB1 alleles of 85 haplotypes derived from 23 Brazilian families of marrow transplant and rheumatic fever patients. The donors included individuals described as having Caucasian, Black, Japanese, or mixed racial origin. In order of frequency, the DR specificities identified were DR4 (15.3%), DRll (14.1%), DR7 (12.9%), DR13 (11.8%), DR3 (10.6%), DR8 (10.6%), DR2 (9.4%), DR1 (5.9%), DR14 (4.7%), DR10 (3.5%) and DR9 (1.2%). Twenty-seven different DRB1 alleles were identified. Among DR4 alleles, DRBI*0402 was the most frequent (3), with all instances occurring with a single haplotype, HLA-A2,B51,DRBI*0402. The DRBI*0401 (2), *0405 (2), "0411 (2), "0410 (1) and *0407 (1) alleles were also identified. Within the DRll family, the DRBI*ll01 (6), "1103 (2) and "1104 (4) alleles were identified. Only the DRBI*1301 (6), "1302 (4) and "1401 (4) alleles were identified within the DR6 family. DR2 alleles were represented by DRBI*1501 (3), "1502 (1), "1503 (3) and "1601 (1), and DR1 alleles identified included DRBI*0101 (1) and "0102 (3). The DR8 alleles showed striking heterogeneity, with DRBI*0801 (2), *0802 (2), *0804 (2) and a new DR8 allele being identified (2). The new DR8 allele was observed in two families and closely resembles DRBI*0801 and *0802, but differs from both in the region between codons 55 and 59. The new allele fails to hybridize to oligonucleotide probes corresponding to "RPSAE" ('0801) and "RPDAE" (*0802). Sequencing is in progress to confirm the variant DR8 allele and to identify the amino acid differences that may be encoded.