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Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis
Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA.
Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT USA;Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT USA.
NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA.
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2018 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 131, no 23, p. 2541-2551Article in journal (Refereed) Published
Abstract [en]

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 = 4.4x10(-94)). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 x 10(-30)) and observed high discrimination (c-statistic = 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 = 9.8 x10(-16)). 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.

Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY , 2018. Vol. 131, no 23, p. 2541-2551
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Hematology
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URN: urn:nbn:se:uu:diva-358155DOI: 10.1182/blood-2017-11-814608ISI: 000434789800005PubMedID: 29674426OAI: oai:DiVA.org:uu-358155DiVA, id: diva2:1268052
Funder
NIH (National Institute of Health)Swedish Cancer Society, 2009/659Swedish Cancer Society, 02 6661Available from: 2018-12-04 Created: 2018-12-04 Last updated: 2018-12-04Bibliographically approved

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Glimelius, Bengt

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