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

作者：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

来源：Blood, 2018, 131(23): 2541-2551.

DOI：10.1182/blood-2017-11-814608

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.

• 出版日期2018-6-7