Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Geffen Kleinstern, Nicola J. Camp, Lynn R. Goldin, Celine M Vachon, Claire M. Vajdic, Silvia De Sanjose, J. Brice Weinberg, Yolanda Benavente, Delphine Casabonne, Mark Liebow, Alexandra Nieters, Henrik Hjalgrim, Mads Melbye, Bengt Glimelius, Hans Olov Adami, Paolo Boffetta, Paul Brennan, Marc Maynadie, James McKay, Pier Luigi Cocco & 28 others Tait D. Shanafelt, Timothy G. Call, Aaron D. Norman, Curtis Hanson, Dennis Robinson, Kari G. Chaffee, Angela R. Brooks-Wilson, Alain Monnereau, Jacqueline Clavel, Martha Glenn, Karen Curtin, Lucia Conde, Paige M. Bracci, Lindsay M. Morton, Wendy Cozen, Richard K. Severson, Stephen J. Chanock, John J. Spinelli, James B. Johnston, Nathaniel Rothman, Christine F. Skibola, Jose F. Leis, Neil Elliot Kay, Karin E. Smedby, Sonja I. Berndt, James R Cerhan, Neil Caporaso, Susan L Slager

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P 5 4.4310294). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P 5 7.8 3 10230) and observed high discrimination (c-statistic 5 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P 5 9.8 310216). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH.The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL. (Blood. 2018;131(23):2541-2551).

Original languageEnglish (US)
Pages (from-to)2541-2551
Number of pages11
JournalBlood
Volume131
Issue number23
DOIs
StatePublished - Jun 7 2018

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Lymphocytosis
B-Cell Chronic Lymphocytic Leukemia
Cells
Odds Ratio
Single Nucleotide Polymorphism
Polymorphism
B-Lymphocytes
Molecular Epidemiology
Nucleotides
Statistics
B-Lymphoid Precursor Cells

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. / Kleinstern, Geffen; Camp, Nicola J.; Goldin, Lynn R.; Vachon, Celine M; Vajdic, Claire M.; De Sanjose, Silvia; Weinberg, J. Brice; Benavente, Yolanda; Casabonne, Delphine; Liebow, Mark; Nieters, Alexandra; Hjalgrim, Henrik; Melbye, Mads; Glimelius, Bengt; Adami, Hans Olov; Boffetta, Paolo; Brennan, Paul; Maynadie, Marc; McKay, James; Cocco, Pier Luigi; Shanafelt, Tait D.; Call, Timothy G.; Norman, Aaron D.; Hanson, Curtis; Robinson, Dennis; Chaffee, Kari G.; Brooks-Wilson, Angela R.; Monnereau, Alain; Clavel, Jacqueline; Glenn, Martha; Curtin, Karen; Conde, Lucia; Bracci, Paige M.; Morton, Lindsay M.; Cozen, Wendy; Severson, Richard K.; Chanock, Stephen J.; Spinelli, John J.; Johnston, James B.; Rothman, Nathaniel; Skibola, Christine F.; Leis, Jose F.; Kay, Neil Elliot; Smedby, Karin E.; Berndt, Sonja I.; Cerhan, James R; Caporaso, Neil; Slager, Susan L.

In: Blood, Vol. 131, No. 23, 07.06.2018, p. 2541-2551.

Research output: Contribution to journalArticle

Kleinstern, G, Camp, NJ, Goldin, LR, Vachon, CM, Vajdic, CM, De Sanjose, S, Weinberg, JB, Benavente, Y, Casabonne, D, Liebow, M, Nieters, A, Hjalgrim, H, Melbye, M, Glimelius, B, Adami, HO, Boffetta, P, Brennan, P, Maynadie, M, McKay, J, Cocco, PL, Shanafelt, TD, Call, TG, Norman, AD, Hanson, C, Robinson, D, Chaffee, KG, Brooks-Wilson, AR, Monnereau, A, Clavel, J, Glenn, M, Curtin, K, Conde, L, Bracci, PM, Morton, LM, Cozen, W, Severson, RK, Chanock, SJ, Spinelli, JJ, Johnston, JB, Rothman, N, Skibola, CF, Leis, JF, Kay, NE, Smedby, KE, Berndt, SI, Cerhan, JR, Caporaso, N & Slager, SL 2018, 'Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis', Blood, vol. 131, no. 23, pp. 2541-2551. https://doi.org/10.1182/blood-2017-11-814608
Kleinstern, Geffen ; Camp, Nicola J. ; Goldin, Lynn R. ; Vachon, Celine M ; Vajdic, Claire M. ; De Sanjose, Silvia ; Weinberg, J. Brice ; Benavente, Yolanda ; Casabonne, Delphine ; Liebow, Mark ; Nieters, Alexandra ; Hjalgrim, Henrik ; Melbye, Mads ; Glimelius, Bengt ; Adami, Hans Olov ; Boffetta, Paolo ; Brennan, Paul ; Maynadie, Marc ; McKay, James ; Cocco, Pier Luigi ; Shanafelt, Tait D. ; Call, Timothy G. ; Norman, Aaron D. ; Hanson, Curtis ; Robinson, Dennis ; Chaffee, Kari G. ; Brooks-Wilson, Angela R. ; Monnereau, Alain ; Clavel, Jacqueline ; Glenn, Martha ; Curtin, Karen ; Conde, Lucia ; Bracci, Paige M. ; Morton, Lindsay M. ; Cozen, Wendy ; Severson, Richard K. ; Chanock, Stephen J. ; Spinelli, John J. ; Johnston, James B. ; Rothman, Nathaniel ; Skibola, Christine F. ; Leis, Jose F. ; Kay, Neil Elliot ; Smedby, Karin E. ; Berndt, Sonja I. ; Cerhan, James R ; Caporaso, Neil ; Slager, Susan L. / Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. In: Blood. 2018 ; Vol. 131, No. 23. pp. 2541-2551.
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abstract = "Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P 5 4.4310294). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P 5 7.8 3 10230) and observed high discrimination (c-statistic 5 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P 5 9.8 310216). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH.The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL. (Blood. 2018;131(23):2541-2551).",
author = "Geffen Kleinstern and Camp, {Nicola J.} and Goldin, {Lynn R.} and Vachon, {Celine M} and Vajdic, {Claire M.} and {De Sanjose}, Silvia and Weinberg, {J. Brice} and Yolanda Benavente and Delphine Casabonne and Mark Liebow and Alexandra Nieters and Henrik Hjalgrim and Mads Melbye and Bengt Glimelius and Adami, {Hans Olov} and Paolo Boffetta and Paul Brennan and Marc Maynadie and James McKay and Cocco, {Pier Luigi} and Shanafelt, {Tait D.} and Call, {Timothy G.} and Norman, {Aaron D.} and Curtis Hanson and Dennis Robinson and Chaffee, {Kari G.} and Brooks-Wilson, {Angela R.} and Alain Monnereau and Jacqueline Clavel and Martha Glenn and Karen Curtin and Lucia Conde and Bracci, {Paige M.} and Morton, {Lindsay M.} and Wendy Cozen and Severson, {Richard K.} and Chanock, {Stephen J.} and Spinelli, {John J.} and Johnston, {James B.} and Nathaniel Rothman and Skibola, {Christine F.} and Leis, {Jose F.} and Kay, {Neil Elliot} and Smedby, {Karin E.} and Berndt, {Sonja I.} and Cerhan, {James R} and Neil Caporaso and Slager, {Susan L}",
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TY - JOUR

T1 - Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

AU - Kleinstern, Geffen

AU - Camp, Nicola J.

AU - Goldin, Lynn R.

AU - Vachon, Celine M

AU - Vajdic, Claire M.

AU - De Sanjose, Silvia

AU - Weinberg, J. Brice

AU - Benavente, Yolanda

AU - Casabonne, Delphine

AU - Liebow, Mark

AU - Nieters, Alexandra

AU - Hjalgrim, Henrik

AU - Melbye, Mads

AU - Glimelius, Bengt

AU - Adami, Hans Olov

AU - Boffetta, Paolo

AU - Brennan, Paul

AU - Maynadie, Marc

AU - McKay, James

AU - Cocco, Pier Luigi

AU - Shanafelt, Tait D.

AU - Call, Timothy G.

AU - Norman, Aaron D.

AU - Hanson, Curtis

AU - Robinson, Dennis

AU - Chaffee, Kari G.

AU - Brooks-Wilson, Angela R.

AU - Monnereau, Alain

AU - Clavel, Jacqueline

AU - Glenn, Martha

AU - Curtin, Karen

AU - Conde, Lucia

AU - Bracci, Paige M.

AU - Morton, Lindsay M.

AU - Cozen, Wendy

AU - Severson, Richard K.

AU - Chanock, Stephen J.

AU - Spinelli, John J.

AU - Johnston, James B.

AU - Rothman, Nathaniel

AU - Skibola, Christine F.

AU - Leis, Jose F.

AU - Kay, Neil Elliot

AU - Smedby, Karin E.

AU - Berndt, Sonja I.

AU - Cerhan, James R

AU - Caporaso, Neil

AU - Slager, Susan L

PY - 2018/6/7

Y1 - 2018/6/7

N2 - Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P 5 4.4310294). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P 5 7.8 3 10230) and observed high discrimination (c-statistic 5 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P 5 9.8 310216). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH.The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL. (Blood. 2018;131(23):2541-2551).

AB - Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P 5 4.4310294). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P 5 7.8 3 10230) and observed high discrimination (c-statistic 5 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P 5 9.8 310216). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH.The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL. (Blood. 2018;131(23):2541-2551).

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