Title |
Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis
|
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Published in |
Blood, April 2018
|
DOI | 10.1182/blood-2017-11-814608 |
Pubmed ID | |
Authors |
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, 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 E Kay, Karin E Smedby, Sonja I Berndt, James R Cerhan, Neil Caporaso, Susan L Slager |
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 1,499 CLLs and 2,459 controls from the InterLymph Consortium. For validation, we utilized data from 1,267 controls from Mayo Clinic and 201 CLLs, 95 MBLs, and 144 controls with FH of CLL from the GEC 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=4.4×10-94). We replicated these findings in the GEC Consortium and Mayo controls (OR=3.02, P=7.8x10-30) 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=9.8×10-16). 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 6 | 46% |
Spain | 1 | 8% |
Saudi Arabia | 1 | 8% |
Unknown | 5 | 38% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 7 | 54% |
Practitioners (doctors, other healthcare professionals) | 3 | 23% |
Science communicators (journalists, bloggers, editors) | 2 | 15% |
Scientists | 1 | 8% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 51 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 10 | 20% |
Other | 6 | 12% |
Student > Master | 6 | 12% |
Researcher | 5 | 10% |
Professor | 2 | 4% |
Other | 9 | 18% |
Unknown | 13 | 25% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 13 | 25% |
Biochemistry, Genetics and Molecular Biology | 7 | 14% |
Unspecified | 2 | 4% |
Mathematics | 2 | 4% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 4% |
Other | 6 | 12% |
Unknown | 19 | 37% |