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8 results on '"Norman, A.D."'

1. Do GWAS-Identified Risk Variants for Chronic Lymphocytic Leukemia Influence Overall Patient Survival and Disease Progression?

Author

Cabrera-Serrano, A.J., Sánchez-Maldonado, J.M., Horst, R, Macauda, A., García-Martín, P., Benavente, Y., Landi, S., Clay-Gilmour, A., Niazi, Y., Espinet, B., Rodríguez-Sevilla, J.J., Pérez, E.M., Maffei, R., Blanco, G., Giaccherini, M., Cerhan, J.R., Marasca, R., López-Nevot, M.Á., Chen-Liang, T., Thomsen, H., Gámez, I., Campa, D., Moreno, V., Sanjosé, S. de, Marcos-Gragera, R., García-Álvarez, M., Dierssen-Sotos, T., Jerez, A., Butrym, A., Norman, A.D., Luppi, M., Slager, S.L., Hemminki, K., Li, Y., Berndt, S.I., Casabonne, D., Alcoceba, M., Puiggros, A., Netea, M.G., Försti, A., Canzian, F., Sainz, J., Cabrera-Serrano, A.J., Sánchez-Maldonado, J.M., Horst, R, Macauda, A., García-Martín, P., Benavente, Y., Landi, S., Clay-Gilmour, A., Niazi, Y., Espinet, B., Rodríguez-Sevilla, J.J., Pérez, E.M., Maffei, R., Blanco, G., Giaccherini, M., Cerhan, J.R., Marasca, R., López-Nevot, M.Á., Chen-Liang, T., Thomsen, H., Gámez, I., Campa, D., Moreno, V., Sanjosé, S. de, Marcos-Gragera, R., García-Álvarez, M., Dierssen-Sotos, T., Jerez, A., Butrym, A., Norman, A.D., Luppi, M., Slager, S.L., Hemminki, K., Li, Y., Berndt, S.I., Casabonne, D., Alcoceba, M., Puiggros, A., Netea, M.G., Försti, A., Canzian, F., and Sainz, J.

Abstract

Contains fulltext : 292738.pdf (Publisher’s version ) (Open Access), Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults worldwide. Although genome-wide association studies (GWAS) have uncovered the germline genetic component underlying CLL susceptibility, the potential use of GWAS-identified risk variants to predict disease progression and patient survival remains unexplored. Here, we evaluated whether 41 GWAS-identified risk variants for CLL could influence overall survival (OS) and disease progression, defined as time to first treatment (TTFT) in a cohort of 1039 CLL cases ascertained through the CRuCIAL consortium. Although this is the largest study assessing the effect of GWAS-identified susceptibility variants for CLL on OS, we only found a weak association of ten single nucleotide polymorphisms (SNPs) with OS (p < 0.05) that did not remain significant after correction for multiple testing. In line with these results, polygenic risk scores (PRSs) built with these SNPs in the CRuCIAL cohort showed a modest association with OS and a low capacity to predict patient survival, with an area under the receiver operating characteristic curve (AUROC) of 0.57. Similarly, seven SNPs were associated with TTFT (p < 0.05); however, these did not reach the multiple testing significance threshold, and the meta-analysis with previous published data did not confirm any of the associations. As expected, PRSs built with these SNPs showed reduced accuracy in prediction of disease progression (AUROC = 0.62). These results suggest that susceptibility variants for CLL do not impact overall survival and disease progression in CLL patients.

Published
2023

2. Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Author

Clavero, E., Sanchez-Maldonado, J.M., Macauda, A., Horst, R. ter, Sampaio-Marques, B., Jurczyszyn, A., Clay-Gilmour, A., Stein, A., Hildebrandt, M.A., Weinhold, N., Buda, G., García-Sanz, R., Tomczak, W., Vogel, U., Jerez, A., Zawirska, D., Wątek, M., Hofmann, J.N., Landi, S., Spinelli, J.J., Butrym, A., Kumar, A., Martínez-López, J., Galimberti, S., Sarasquete, M.E., Subocz, E., Iskierka-Jażdżewska, E., Giles, G.G., Rybicka-Ramos, M., Kruszewski, M., Abildgaard, N., Verdejo, F.G., Sánchez Rovira, P., Silva Filho, M.I. da, Kadar, K., Razny, M., Cozen, W., Pelosini, M., Jurado, M., Bhatti, P., Dudzinski, M., Druzd-Sitek, A., Orciuolo, E., Li, Y., Norman, A.D., Zaucha, J.M., Reis, R.M., Markiewicz, M., Rodríguez Sevilla, J.J., Andersen, V., Jamroziak, K., Hemminki, K., Berndt, S.I., Rajkumar, V., Mazur, G., Kumar, S.K., Ludovico, P., Nagler, A., Chanock, S.J., Dumontet, C., Machiela, M.J., Varkonyi, J., Camp, N.J., Ziv, E., Vangsted, A.J., Brown, E.E., Campa, D., Vachon, C.M., Netea, M.G., Canzian, F., Försti, A., Sainz, J., Clavero, E., Sanchez-Maldonado, J.M., Macauda, A., Horst, R. ter, Sampaio-Marques, B., Jurczyszyn, A., Clay-Gilmour, A., Stein, A., Hildebrandt, M.A., Weinhold, N., Buda, G., García-Sanz, R., Tomczak, W., Vogel, U., Jerez, A., Zawirska, D., Wątek, M., Hofmann, J.N., Landi, S., Spinelli, J.J., Butrym, A., Kumar, A., Martínez-López, J., Galimberti, S., Sarasquete, M.E., Subocz, E., Iskierka-Jażdżewska, E., Giles, G.G., Rybicka-Ramos, M., Kruszewski, M., Abildgaard, N., Verdejo, F.G., Sánchez Rovira, P., Silva Filho, M.I. da, Kadar, K., Razny, M., Cozen, W., Pelosini, M., Jurado, M., Bhatti, P., Dudzinski, M., Druzd-Sitek, A., Orciuolo, E., Li, Y., Norman, A.D., Zaucha, J.M., Reis, R.M., Markiewicz, M., Rodríguez Sevilla, J.J., Andersen, V., Jamroziak, K., Hemminki, K., Berndt, S.I., Rajkumar, V., Mazur, G., Kumar, S.K., Ludovico, P., Nagler, A., Chanock, S.J., Dumontet, C., Machiela, M.J., Varkonyi, J., Camp, N.J., Ziv, E., Vangsted, A.J., Brown, E.E., Campa, D., Vachon, C.M., Netea, M.G., Canzian, F., Försti, A., and Sainz, J.

Abstract

Item does not contain fulltext, Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10(-9)) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10(-4)-5.79 × 10(-14)). Mechanistically, we found that the ULK4(rs6599175) SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10(-4)), whereas the IKBKE(rs17433804) SNP correlated with the number of transitional CD24(+)CD38(+) B cells (p = 4.8 × 10(-4)) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10(-4)). We also found that the CD46(rs1142469) SNP correlated with numbers of CD19(+) B cells, CD19(+)CD3(-) B cells, CD5(+)IgD(-) cells, IgM(-) cells, IgD(-)IgM(-) cells, and CD4(-)CD8(-) PBMCs (p = 4.9 × 10(-4)-8.6 × 10(-4)) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2A(rs2811710) SNP correlated with levels of CD4(+)EMCD45RO(+)CD27(-) cells (p = 9.3 × 10(-4)). These results s

Published
2023

3. Identification of novel genetic loci for risk of multiple myeloma by functional annotation.

Author

Macauda, A., Briem, K., Clay-Gilmour, A., Cozen, W., Försti, A., Giaccherini, M., Corradi, C., Sainz, J., Niazi, Y., Horst, R. ter, Li, Y., Netea, M.G., Vogel, U., Hemminki, K., Slager, S.L., Varkonyi, J., Andersen, V., Iskierka-Jazdzewska, E., Mártinez-Lopez, J., Zaucha, J., Camp, N.J., Rajkumar, S.V., Druzd-Sitek, A., Bhatti, P., Chanock, S.J., Kumar, S.K., Subocz, E., Mazur, G., Landi, S., Machiela, M.J., Jerez, A., Norman, A.D., Hildebrandt, M.A., Kadar, K., Berndt, S.I., Ziv, E., Buda, G., Nagler, A., Dumontet, C., Raźny, M., Watek, M., Butrym, A., Grzasko, N., Dudzinski, M., Rybicka-Ramos, M., Matera, E.L., García-Sanz, R., Goldschmidt, H., Jamroziak, K., Jurczyszyn, A., Clavero, E., Giles, G.G., Pelosini, M., Zawirska, D., Kruszewski, M., Marques, H., Haastrup, E., Sánchez-Maldonado, J.M., Bertsch, U., Rymko, M., Raab, M.S., Brown, E.E., Hofmann, J.N., Vachon, C., Campa, D., Canzian, F., Macauda, A., Briem, K., Clay-Gilmour, A., Cozen, W., Försti, A., Giaccherini, M., Corradi, C., Sainz, J., Niazi, Y., Horst, R. ter, Li, Y., Netea, M.G., Vogel, U., Hemminki, K., Slager, S.L., Varkonyi, J., Andersen, V., Iskierka-Jazdzewska, E., Mártinez-Lopez, J., Zaucha, J., Camp, N.J., Rajkumar, S.V., Druzd-Sitek, A., Bhatti, P., Chanock, S.J., Kumar, S.K., Subocz, E., Mazur, G., Landi, S., Machiela, M.J., Jerez, A., Norman, A.D., Hildebrandt, M.A., Kadar, K., Berndt, S.I., Ziv, E., Buda, G., Nagler, A., Dumontet, C., Raźny, M., Watek, M., Butrym, A., Grzasko, N., Dudzinski, M., Rybicka-Ramos, M., Matera, E.L., García-Sanz, R., Goldschmidt, H., Jamroziak, K., Jurczyszyn, A., Clavero, E., Giles, G.G., Pelosini, M., Zawirska, D., Kruszewski, M., Marques, H., Haastrup, E., Sánchez-Maldonado, J.M., Bertsch, U., Rymko, M., Raab, M.S., Brown, E.E., Hofmann, J.N., Vachon, C., Campa, D., and Canzian, F.

Abstract

Contains fulltext : 299996.pdf (Publisher’s version ) (Open Access), 01 november 2023

Published
2023

4. Validation and functional characterization of GWAS-identified variants for chronic lymphocytic leukemia: a CRuCIAL study

Author

García-Martín, P., Díez, A.M., Maldonado, J.M.S., Serrano, A.J.C., Horst, R. ter, Benavente, Y., Landi, S., Macauda, A., Clay-Gilmour, A., Hernández-Mohedo, F., Niazi, Y., González-Sierra, P., Espinet, B., Rodríguez-Sevilla, J.J., Maffei, R., Blanco, G., Giaccherini, M., Puiggros, A., Cerhan, J., Marasca, R., Cañadas-Garre, M., López-Nevot, M., Chen-Liang, T., Thomsen, H., Gámez, I., Moreno, V., Marcos-Gragera, R., García-Álvarez, M., Llorca, J., Jerez, A., Berndt, S., Butrym, A., Norman, A.D., Casabonne, D., Luppi, M., Slager, S.L., Hemminki, K., Li, Y., Alcoceba, M., Campa, D., Canzian, F., Sanjosé, S. de, Försti, A., Netea, M.G., Jurado, M., Sainz, J., García-Martín, P., Díez, A.M., Maldonado, J.M.S., Serrano, A.J.C., Horst, R. ter, Benavente, Y., Landi, S., Macauda, A., Clay-Gilmour, A., Hernández-Mohedo, F., Niazi, Y., González-Sierra, P., Espinet, B., Rodríguez-Sevilla, J.J., Maffei, R., Blanco, G., Giaccherini, M., Puiggros, A., Cerhan, J., Marasca, R., Cañadas-Garre, M., López-Nevot, M., Chen-Liang, T., Thomsen, H., Gámez, I., Moreno, V., Marcos-Gragera, R., García-Álvarez, M., Llorca, J., Jerez, A., Berndt, S., Butrym, A., Norman, A.D., Casabonne, D., Luppi, M., Slager, S.L., Hemminki, K., Li, Y., Alcoceba, M., Campa, D., Canzian, F., Sanjosé, S. de, Försti, A., Netea, M.G., Jurado, M., and Sainz, J.

Abstract

Contains fulltext : 251927.pdf (Publisher’s version ) (Open Access)

Published
2022

5. Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Author

Vachon C.M., Canzian F., Campa D., Watek M., Jurczyszyn A., Brown E.E., Berndt S., Butrym A., Norman A.D., Gemignani F., Slager S.L., Macauda A., Piredda C., Clay-Gilmour A.I., Sainz J., Buda G., Markiewicz M., Barington T., Ziv E., Hildebrandt M.A.T., Belachew A.A., Varkonyi J., Prejzner W., Druzd-Sitek A., Spinelli J., Andersen N.F., Hofmann J.N., Dudzinski M., Martinez-Lopez J., Iskierka-Jazdzewska E., Milne R.L., Mazur G., Giles G.G., Ebbesen L.H., Rymko M., Jamroziak K., Subocz E., Reis R.M., Garcia-Sanz R., Suska A., Haastrup E.K., Zawirska D., Grzasko N., Vangsted A.J., Dumontet C., Kruszewski M., Dutka M., Camp N.J., Waller R.G., Tomczak W., Pelosini M., Razny M., Marques H., Abildgaard N., Vachon C.M., Canzian F., Campa D., Watek M., Jurczyszyn A., Brown E.E., Berndt S., Butrym A., Norman A.D., Gemignani F., Slager S.L., Macauda A., Piredda C., Clay-Gilmour A.I., Sainz J., Buda G., Markiewicz M., Barington T., Ziv E., Hildebrandt M.A.T., Belachew A.A., Varkonyi J., Prejzner W., Druzd-Sitek A., Spinelli J., Andersen N.F., Hofmann J.N., Dudzinski M., Martinez-Lopez J., Iskierka-Jazdzewska E., Milne R.L., Mazur G., Giles G.G., Ebbesen L.H., Rymko M., Jamroziak K., Subocz E., Reis R.M., Garcia-Sanz R., Suska A., Haastrup E.K., Zawirska D., Grzasko N., Vangsted A.J., Dumontet C., Kruszewski M., Dutka M., Camp N.J., Waller R.G., Tomczak W., Pelosini M., Razny M., Marques H., and Abildgaard N.

Abstract

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P <.05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P =.007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.Copyright © 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.

Published
2021

6. Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Author

Vachon C.M., Canzian F., Campa D., Watek M., Jurczyszyn A., Brown E.E., Berndt S., Butrym A., Norman A.D., Gemignani F., Slager S.L., Macauda A., Piredda C., Clay-Gilmour A.I., Sainz J., Buda G., Markiewicz M., Barington T., Ziv E., Hildebrandt M.A.T., Belachew A.A., Varkonyi J., Prejzner W., Druzd-Sitek A., Spinelli J., Andersen N.F., Hofmann J.N., Dudzinski M., Martinez-Lopez J., Iskierka-Jazdzewska E., Milne R.L., Mazur G., Giles G.G., Ebbesen L.H., Rymko M., Jamroziak K., Subocz E., Reis R.M., Garcia-Sanz R., Suska A., Haastrup E.K., Zawirska D., Grzasko N., Vangsted A.J., Dumontet C., Kruszewski M., Dutka M., Camp N.J., Waller R.G., Tomczak W., Pelosini M., Razny M., Marques H., Abildgaard N., Vachon C.M., Canzian F., Campa D., Watek M., Jurczyszyn A., Brown E.E., Berndt S., Butrym A., Norman A.D., Gemignani F., Slager S.L., Macauda A., Piredda C., Clay-Gilmour A.I., Sainz J., Buda G., Markiewicz M., Barington T., Ziv E., Hildebrandt M.A.T., Belachew A.A., Varkonyi J., Prejzner W., Druzd-Sitek A., Spinelli J., Andersen N.F., Hofmann J.N., Dudzinski M., Martinez-Lopez J., Iskierka-Jazdzewska E., Milne R.L., Mazur G., Giles G.G., Ebbesen L.H., Rymko M., Jamroziak K., Subocz E., Reis R.M., Garcia-Sanz R., Suska A., Haastrup E.K., Zawirska D., Grzasko N., Vangsted A.J., Dumontet C., Kruszewski M., Dutka M., Camp N.J., Waller R.G., Tomczak W., Pelosini M., Razny M., Marques H., and Abildgaard N.

Abstract

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P <.05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P =.007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.Copyright © 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.

Published
2021

7. Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.

Author

Camp N.J., Milne R.L., Slager S.L., Ziv E., Vachon C.M., Clay-Gilmour A.I., Hildebrandt M.A.T., Brown E.E., Hofmann J.N., Spinelli J.J., Giles G.G., Cozen W., Bhatti P., Wu X., Waller R.G., Belachew A.A., Robinson D.P., Norman A.D., Sinnwell J.P., Berndt S.I., Rajkumar S.V., Kumar S.K., Chanock S.J., Machiela M.J., Camp N.J., Milne R.L., Slager S.L., Ziv E., Vachon C.M., Clay-Gilmour A.I., Hildebrandt M.A.T., Brown E.E., Hofmann J.N., Spinelli J.J., Giles G.G., Cozen W., Bhatti P., Wu X., Waller R.G., Belachew A.A., Robinson D.P., Norman A.D., Sinnwell J.P., Berndt S.I., Rajkumar S.V., Kumar S.K., Chanock S.J., and Machiela M.J.

Abstract

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879),we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] +/- 0.04) and 15% (SE +/- 0.11) for MM and MGUS risk, respectively, and a 55% (SE +/- 0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.Copyright © 2020 by The American Society of Hematology.

Published
2020

8. Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.

Author

Camp N.J., Milne R.L., Slager S.L., Ziv E., Vachon C.M., Clay-Gilmour A.I., Hildebrandt M.A.T., Brown E.E., Hofmann J.N., Spinelli J.J., Giles G.G., Cozen W., Bhatti P., Wu X., Waller R.G., Belachew A.A., Robinson D.P., Norman A.D., Sinnwell J.P., Berndt S.I., Rajkumar S.V., Kumar S.K., Chanock S.J., Machiela M.J., Camp N.J., Milne R.L., Slager S.L., Ziv E., Vachon C.M., Clay-Gilmour A.I., Hildebrandt M.A.T., Brown E.E., Hofmann J.N., Spinelli J.J., Giles G.G., Cozen W., Bhatti P., Wu X., Waller R.G., Belachew A.A., Robinson D.P., Norman A.D., Sinnwell J.P., Berndt S.I., Rajkumar S.V., Kumar S.K., Chanock S.J., and Machiela M.J.

Abstract

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879),we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] +/- 0.04) and 15% (SE +/- 0.11) for MM and MGUS risk, respectively, and a 55% (SE +/- 0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.Copyright © 2020 by The American Society of Hematology.

Published
2020

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