The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in RAI and CD3EAP

Annette J Vangsted, Tobias Wirenfeldt Klausen, Peter Gimsing, Niels Abildgaard, Niels F Andersen, Henrik Gregersen, Bjørn Andersen Nexø, Ulla Birgitte Vogel

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor κB (NF-κB). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated with interferon-α (INF-α) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NFКB1. By linkage disequilibrium mapping, we found that variant alleles of several polymorphisms in a sub-region of 19q13.3 spanning the regions RAI-intron1-1 to RAI intron1-3 and the region exon1 to exon3-6 in CD3EAP were associated with prolonged time-to-treatment failure (TTF; p = 0.003) and overall survival (OS; p = 0.02). Haplotype analyses revealed that none of the haplotypes were more strongly associated to TTF or OS than the two strongly linked SNPs, RAI-intron1-1 (rs4572514) and CD3EAP G-21A (rs967591). The association of RAI-intron1-1 and CD3EAP G-21A with TTF was independent of NFKB1-94 ins/del, but homozygous ins-allele carriers which were also variant allele carriers of RAI-intron1-1 or CD3EAP G-21A had the longest OS. Among patients treated with INF-α or thalidomide, no effect was seen in relation to genotype. Our results indicate that polymorphism in RAI and CD3EAP are associated with outcome of myeloma patients treated with HDT. Combination analyses with the functional polymorphism in NFKB1 suggest that a possibly functional effect of RAI or CD3EAP could be related to NF-κB availability.
OriginalsprogEngelsk
TidsskriftAnnals of Hematology
Vol/bind90
Udgave nummer6
Sider (fra-til)675-84
Antal sider10
ISSN0939-5555
DOI
StatusUdgivet - 2011

Fingeraftryk

Chromosome Mapping
Linkage Disequilibrium
Alleles
Haplotypes
Treatment Failure
Single Nucleotide Polymorphism

Citer dette

Vangsted, Annette J ; Klausen, Tobias Wirenfeldt ; Gimsing, Peter ; Abildgaard, Niels ; Andersen, Niels F ; Gregersen, Henrik ; Nexø, Bjørn Andersen ; Vogel, Ulla Birgitte. / The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in RAI and CD3EAP. I: Annals of Hematology. 2011 ; Bind 90, Nr. 6. s. 675-84.
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abstract = "The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor κB (NF-κB). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated with interferon-α (INF-α) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NFКB1. By linkage disequilibrium mapping, we found that variant alleles of several polymorphisms in a sub-region of 19q13.3 spanning the regions RAI-intron1-1 to RAI intron1-3 and the region exon1 to exon3-6 in CD3EAP were associated with prolonged time-to-treatment failure (TTF; p = 0.003) and overall survival (OS; p = 0.02). Haplotype analyses revealed that none of the haplotypes were more strongly associated to TTF or OS than the two strongly linked SNPs, RAI-intron1-1 (rs4572514) and CD3EAP G-21A (rs967591). The association of RAI-intron1-1 and CD3EAP G-21A with TTF was independent of NFKB1-94 ins/del, but homozygous ins-allele carriers which were also variant allele carriers of RAI-intron1-1 or CD3EAP G-21A had the longest OS. Among patients treated with INF-α or thalidomide, no effect was seen in relation to genotype. Our results indicate that polymorphism in RAI and CD3EAP are associated with outcome of myeloma patients treated with HDT. Combination analyses with the functional polymorphism in NFKB1 suggest that a possibly functional effect of RAI or CD3EAP could be related to NF-κB availability.",
author = "Vangsted, {Annette J} and Klausen, {Tobias Wirenfeldt} and Peter Gimsing and Niels Abildgaard and Andersen, {Niels F} and Henrik Gregersen and Nex{\o}, {Bj{\o}rn Andersen} and Vogel, {Ulla Birgitte}",
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The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in RAI and CD3EAP. / Vangsted, Annette J; Klausen, Tobias Wirenfeldt; Gimsing, Peter; Abildgaard, Niels; Andersen, Niels F; Gregersen, Henrik; Nexø, Bjørn Andersen; Vogel, Ulla Birgitte.

I: Annals of Hematology, Bind 90, Nr. 6, 2011, s. 675-84.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in RAI and CD3EAP

AU - Vangsted, Annette J

AU - Klausen, Tobias Wirenfeldt

AU - Gimsing, Peter

AU - Abildgaard, Niels

AU - Andersen, Niels F

AU - Gregersen, Henrik

AU - Nexø, Bjørn Andersen

AU - Vogel, Ulla Birgitte

PY - 2011

Y1 - 2011

N2 - The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor κB (NF-κB). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated with interferon-α (INF-α) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NFКB1. By linkage disequilibrium mapping, we found that variant alleles of several polymorphisms in a sub-region of 19q13.3 spanning the regions RAI-intron1-1 to RAI intron1-3 and the region exon1 to exon3-6 in CD3EAP were associated with prolonged time-to-treatment failure (TTF; p = 0.003) and overall survival (OS; p = 0.02). Haplotype analyses revealed that none of the haplotypes were more strongly associated to TTF or OS than the two strongly linked SNPs, RAI-intron1-1 (rs4572514) and CD3EAP G-21A (rs967591). The association of RAI-intron1-1 and CD3EAP G-21A with TTF was independent of NFKB1-94 ins/del, but homozygous ins-allele carriers which were also variant allele carriers of RAI-intron1-1 or CD3EAP G-21A had the longest OS. Among patients treated with INF-α or thalidomide, no effect was seen in relation to genotype. Our results indicate that polymorphism in RAI and CD3EAP are associated with outcome of myeloma patients treated with HDT. Combination analyses with the functional polymorphism in NFKB1 suggest that a possibly functional effect of RAI or CD3EAP could be related to NF-κB availability.

AB - The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor κB (NF-κB). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated with interferon-α (INF-α) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NFКB1. By linkage disequilibrium mapping, we found that variant alleles of several polymorphisms in a sub-region of 19q13.3 spanning the regions RAI-intron1-1 to RAI intron1-3 and the region exon1 to exon3-6 in CD3EAP were associated with prolonged time-to-treatment failure (TTF; p = 0.003) and overall survival (OS; p = 0.02). Haplotype analyses revealed that none of the haplotypes were more strongly associated to TTF or OS than the two strongly linked SNPs, RAI-intron1-1 (rs4572514) and CD3EAP G-21A (rs967591). The association of RAI-intron1-1 and CD3EAP G-21A with TTF was independent of NFKB1-94 ins/del, but homozygous ins-allele carriers which were also variant allele carriers of RAI-intron1-1 or CD3EAP G-21A had the longest OS. Among patients treated with INF-α or thalidomide, no effect was seen in relation to genotype. Our results indicate that polymorphism in RAI and CD3EAP are associated with outcome of myeloma patients treated with HDT. Combination analyses with the functional polymorphism in NFKB1 suggest that a possibly functional effect of RAI or CD3EAP could be related to NF-κB availability.

U2 - 10.1007/s00277-010-1105-z

DO - 10.1007/s00277-010-1105-z

M3 - Journal article

C2 - 21046104

VL - 90

SP - 675

EP - 684

JO - Annals of Hematology

JF - Annals of Hematology

SN - 0939-5555

IS - 6

ER -