Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis
Menée à partir de données portant sur 41 polymorphismes à simple nucléotide détectés chez 1 499 patients atteints d'une leucémie lymphoïde chronique (LLC) et chez 2 459 témoins, puis validée à partir de données portant sur 296 patients atteints d'une LLC ou d'une lymphocytose B monoclonale et sur 1 411 témoins dont 144 avec antécédents familiaux de LLC, cette étude met en évidence une association entre un système de score, basé sur la présence de plusieurs polymorphismes à simple nucléotide, et le risque de leucémie lymphoïde chronique ou de lymphocytose B monoclonale
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.
Blood , résumé, 2017