Interactions between SNPs affecting inflammatory response genes are associated with multiple myeloma disease risk and survival

Kaspar René Nielsen; Maria Rodrigo-Domingo; Rudi Steffensen; John Baech; Kim S Bergkvist; Liesbeth Oosterhof; Alexander Schmitz; Julie Støve Bødker; Preben Johansen; Ulla Vogel; Anette Vangsted; Karen Dybkær; Martin Bøgsted; Hans Erik Johnsen

doi:10.1080/10428194.2017.1306643

Interactions between SNPs affecting inflammatory response genes are associated with multiple myeloma disease risk and survival

Kaspar René Nielsen, Maria Rodrigo-Domingo, Rudi Steffensen, John Baech, Kim S Bergkvist, Liesbeth Oosterhof, Alexander Schmitz, Julie Støve Bødker, Preben Johansen, Ulla Vogel, Anette Vangsted, Karen Dybkær, Martin Bøgsted, Hans Erik Johnsen

Department of Clinical Medicine

8 Citations (Scopus)

Abstract

The origin of multiple myeloma depends on interactions with stromal cells in the course of normal B-cell differentiation and evolution of immunity. The concept of the present study is that genes involved in MM pathogenesis, such as immune response genes, can be identified by screening for single-nucleotide polymorphisms (SNPs) involved in the immune response and a subsequent statistical analysis that focusses on the association of SNPs, certain haplotypes or SNP-SNP interactions with MM risk and prognosis. We genotyped 348 Danish patients and 355 controls for 13 SNPs located in the TNFA, IL-4, IL-6, IL-10 and CHI3L1 gene promoters. The occurrence of single polymorphisms, haplotypes and SNP-SNP interactions were statistically analyzed for association with disease risk and outcome following high-dose therapy. Identified genes that carried SNPs or haplotypes that were identified as risk or prognostic factors were studied for expression in normal B-cell subsets and myeloma plasma cells. We observed a significantly reduced risk when harboring the TNFA-238A allele (OR = 0.51 (0.29-0.86)) and interactions between the TNFA-1031T/C * and IL-10 -3575T/A (p = .007) as well as the TNFA-308G/A * and IL-10-1082G/A (p = .008) allels. By statistical approaches, we observed association between prognosis and the TNFA-857CC genotype (HR = 2.80 (1.29-6.10)) and IL-10-1082GG + GA genotypes (HR = 1.93 (1.07-3.49)) and interactions between IL-6-174G/C and IL-10-3575T/A (p = .001) and between TNFA-308G/A and IL-4-1098T/G (p= .005). The 'risk genes' were analyzed for expression in normal B-cell subsets (N = 6) from seven healthy donors and we found TNFA and IL-6 expressed both in naïve and in memory B cells when compared to preBI, II, immature and plasma cells. The 'prognosis genes' CHI3L1, IL-6 and IL-10 were differential expressed in malignant plasma cells when comparing poor and good prognosis groups based on to the TC classification. In summary, these findings suggest that TNFA, IL-4, IL-6, IL-10 and CHI3L1 might be important players in MM pathogenesis during disease initiation and drug resistance in multiple myeloma.

Original language	English
Journal	Leukemia and Lymphoma
Volume	58
Issue number	11
Pages (from-to)	2695-2704
ISSN	1042-8194
DOIs	https://doi.org/10.1080/10428194.2017.1306643
Publication status	Published - 2 Nov 2017

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10.1080/10428194.2017.1306643

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Nielsen, K. R., Rodrigo-Domingo, M., Steffensen, R., Baech, J., Bergkvist, K. S., Oosterhof, L., Schmitz, A., Bødker, J. S., Johansen, P., Vogel, U., Vangsted, A., Dybkær, K., Bøgsted, M., & Johnsen, H. E. (2017). Interactions between SNPs affecting inflammatory response genes are associated with multiple myeloma disease risk and survival. Leukemia and Lymphoma, 58(11), 2695-2704. https://doi.org/10.1080/10428194.2017.1306643

Nielsen, KR, Rodrigo-Domingo, M, Steffensen, R, Baech, J, Bergkvist, KS, Oosterhof, L, Schmitz, A, Bødker, JS, Johansen, P, Vogel, U, Vangsted, A, Dybkær, K, Bøgsted, M & Johnsen, HE 2017, 'Interactions between SNPs affecting inflammatory response genes are associated with multiple myeloma disease risk and survival', Leukemia and Lymphoma, vol. 58, no. 11, pp. 2695-2704. https://doi.org/10.1080/10428194.2017.1306643

@article{39a348f3cf474f78b792055720b854ef,

title = "Interactions between SNPs affecting inflammatory response genes are associated with multiple myeloma disease risk and survival",

abstract = "The origin of multiple myeloma depends on interactions with stromal cells in the course of normal B-cell differentiation and evolution of immunity. The concept of the present study is that genes involved in MM pathogenesis, such as immune response genes, can be identified by screening for single-nucleotide polymorphisms (SNPs) involved in the immune response and a subsequent statistical analysis that focusses on the association of SNPs, certain haplotypes or SNP-SNP interactions with MM risk and prognosis. We genotyped 348 Danish patients and 355 controls for 13 SNPs located in the TNFA, IL-4, IL-6, IL-10 and CHI3L1 gene promoters. The occurrence of single polymorphisms, haplotypes and SNP-SNP interactions were statistically analyzed for association with disease risk and outcome following high-dose therapy. Identified genes that carried SNPs or haplotypes that were identified as risk or prognostic factors were studied for expression in normal B-cell subsets and myeloma plasma cells. We observed a significantly reduced risk when harboring the TNFA-238A allele (OR = 0.51 (0.29-0.86)) and interactions between the TNFA-1031T/C * and IL-10 -3575T/A (p = .007) as well as the TNFA-308G/A * and IL-10-1082G/A (p = .008) allels. By statistical approaches, we observed association between prognosis and the TNFA-857CC genotype (HR = 2.80 (1.29-6.10)) and IL-10-1082GG + GA genotypes (HR = 1.93 (1.07-3.49)) and interactions between IL-6-174G/C and IL-10-3575T/A (p = .001) and between TNFA-308G/A and IL-4-1098T/G (p= .005). The 'risk genes' were analyzed for expression in normal B-cell subsets (N = 6) from seven healthy donors and we found TNFA and IL-6 expressed both in na{\"i}ve and in memory B cells when compared to preBI, II, immature and plasma cells. The 'prognosis genes' CHI3L1, IL-6 and IL-10 were differential expressed in malignant plasma cells when comparing poor and good prognosis groups based on to the TC classification. In summary, these findings suggest that TNFA, IL-4, IL-6, IL-10 and CHI3L1 might be important players in MM pathogenesis during disease initiation and drug resistance in multiple myeloma.",

author = "Nielsen, {Kaspar Ren{\'e}} and Maria Rodrigo-Domingo and Rudi Steffensen and John Baech and Bergkvist, {Kim S} and Liesbeth Oosterhof and Alexander Schmitz and B{\o}dker, {Julie St{\o}ve} and Preben Johansen and Ulla Vogel and Anette Vangsted and Karen Dybk{\ae}r and Martin B{\o}gsted and Johnsen, {Hans Erik}",

year = "2017",

month = nov,

day = "2",

doi = "10.1080/10428194.2017.1306643",

language = "English",

volume = "58",

pages = "2695--2704",

journal = "Leukemia and Lymphoma",

issn = "1042-8194",

publisher = "Taylor & Francis",

number = "11",

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TY - JOUR

T1 - Interactions between SNPs affecting inflammatory response genes are associated with multiple myeloma disease risk and survival

AU - Nielsen, Kaspar René

AU - Rodrigo-Domingo, Maria

AU - Steffensen, Rudi

AU - Baech, John

AU - Bergkvist, Kim S

AU - Oosterhof, Liesbeth

AU - Schmitz, Alexander

AU - Bødker, Julie Støve

AU - Johansen, Preben

AU - Vogel, Ulla

AU - Vangsted, Anette

AU - Dybkær, Karen

AU - Bøgsted, Martin

AU - Johnsen, Hans Erik

PY - 2017/11/2

Y1 - 2017/11/2

N2 - The origin of multiple myeloma depends on interactions with stromal cells in the course of normal B-cell differentiation and evolution of immunity. The concept of the present study is that genes involved in MM pathogenesis, such as immune response genes, can be identified by screening for single-nucleotide polymorphisms (SNPs) involved in the immune response and a subsequent statistical analysis that focusses on the association of SNPs, certain haplotypes or SNP-SNP interactions with MM risk and prognosis. We genotyped 348 Danish patients and 355 controls for 13 SNPs located in the TNFA, IL-4, IL-6, IL-10 and CHI3L1 gene promoters. The occurrence of single polymorphisms, haplotypes and SNP-SNP interactions were statistically analyzed for association with disease risk and outcome following high-dose therapy. Identified genes that carried SNPs or haplotypes that were identified as risk or prognostic factors were studied for expression in normal B-cell subsets and myeloma plasma cells. We observed a significantly reduced risk when harboring the TNFA-238A allele (OR = 0.51 (0.29-0.86)) and interactions between the TNFA-1031T/C * and IL-10 -3575T/A (p = .007) as well as the TNFA-308G/A * and IL-10-1082G/A (p = .008) allels. By statistical approaches, we observed association between prognosis and the TNFA-857CC genotype (HR = 2.80 (1.29-6.10)) and IL-10-1082GG + GA genotypes (HR = 1.93 (1.07-3.49)) and interactions between IL-6-174G/C and IL-10-3575T/A (p = .001) and between TNFA-308G/A and IL-4-1098T/G (p= .005). The 'risk genes' were analyzed for expression in normal B-cell subsets (N = 6) from seven healthy donors and we found TNFA and IL-6 expressed both in naïve and in memory B cells when compared to preBI, II, immature and plasma cells. The 'prognosis genes' CHI3L1, IL-6 and IL-10 were differential expressed in malignant plasma cells when comparing poor and good prognosis groups based on to the TC classification. In summary, these findings suggest that TNFA, IL-4, IL-6, IL-10 and CHI3L1 might be important players in MM pathogenesis during disease initiation and drug resistance in multiple myeloma.

AB - The origin of multiple myeloma depends on interactions with stromal cells in the course of normal B-cell differentiation and evolution of immunity. The concept of the present study is that genes involved in MM pathogenesis, such as immune response genes, can be identified by screening for single-nucleotide polymorphisms (SNPs) involved in the immune response and a subsequent statistical analysis that focusses on the association of SNPs, certain haplotypes or SNP-SNP interactions with MM risk and prognosis. We genotyped 348 Danish patients and 355 controls for 13 SNPs located in the TNFA, IL-4, IL-6, IL-10 and CHI3L1 gene promoters. The occurrence of single polymorphisms, haplotypes and SNP-SNP interactions were statistically analyzed for association with disease risk and outcome following high-dose therapy. Identified genes that carried SNPs or haplotypes that were identified as risk or prognostic factors were studied for expression in normal B-cell subsets and myeloma plasma cells. We observed a significantly reduced risk when harboring the TNFA-238A allele (OR = 0.51 (0.29-0.86)) and interactions between the TNFA-1031T/C * and IL-10 -3575T/A (p = .007) as well as the TNFA-308G/A * and IL-10-1082G/A (p = .008) allels. By statistical approaches, we observed association between prognosis and the TNFA-857CC genotype (HR = 2.80 (1.29-6.10)) and IL-10-1082GG + GA genotypes (HR = 1.93 (1.07-3.49)) and interactions between IL-6-174G/C and IL-10-3575T/A (p = .001) and between TNFA-308G/A and IL-4-1098T/G (p= .005). The 'risk genes' were analyzed for expression in normal B-cell subsets (N = 6) from seven healthy donors and we found TNFA and IL-6 expressed both in naïve and in memory B cells when compared to preBI, II, immature and plasma cells. The 'prognosis genes' CHI3L1, IL-6 and IL-10 were differential expressed in malignant plasma cells when comparing poor and good prognosis groups based on to the TC classification. In summary, these findings suggest that TNFA, IL-4, IL-6, IL-10 and CHI3L1 might be important players in MM pathogenesis during disease initiation and drug resistance in multiple myeloma.

U2 - 10.1080/10428194.2017.1306643

DO - 10.1080/10428194.2017.1306643

M3 - Journal article

C2 - 28393658

SN - 1042-8194

VL - 58

SP - 2695

EP - 2704

JO - Leukemia and Lymphoma

JF - Leukemia and Lymphoma

IS - 11

ER -

Interactions between SNPs affecting inflammatory response genes are associated with multiple myeloma disease risk and survival

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