Large Scale Evaluation of Genetic Variation and the Risk of Multiple Myeloma.

Genetic factors are thought to influence susceptibility to multiple myeloma, but most published studies to date have been small and limited in scope. To identify genetic polymorphisms associated with myeloma risk, we conducted a case-control study of 976 Caucasian myeloma cases enrolled from clinical trials as part of the International Myeloma Foundation’s Bank On A Cure® initiative and 3692 Caucasian controls from the three cohorts [Nurses’ Health Study (NHS), Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and 1958 British Birth Cohort (BC58)] with genome-wide scan data. A candidate gene approach was taken with a preference given to single nucleotide polymorphisms (SNPs) in coding or regulatory regions. A total of 1097 SNPs with a minor allele frequency ≥1% were genotyped in the cases and at least one control population. In order to increase our statistical power, SNPs not genotyped in NHS and PLCO were imputed from the genome scan with MACH using the HapMap CEU population as a referent and included in the analysis if the quality control r² was high (r² ≥0.9). Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusting for age, sex, and country as appropriate. We found 26 loci to be associated with myeloma risk with P < 0.01. Of particular interest, we observed an increased risk of myeloma with variants in two genes involved in the metabolism of pyrimidines, DPYD and MTHFR. An increased risk of myeloma was found with two independent SNPs, rs1023244 and rs1399291, in DPYD (OR_perGallele = 1.43, 95% CI: 1.16–1.76, P = 0.0008 and OR_perTallele = 1.18, 95% CI: 1.06–1.31, P = 0.003, respectively) and with the MTHFR high activity 677C allele (rs1801133, OR_{perC allele} = 1.18, 95% CI: 1.05–1.33, P = 0.006). We also observed significant associations for nonsynonymous SNPs in genes involved in cell cycle checkpoint regulation (ATR, P = 0.009; ZAK, P = 0.007) and the DNA damage bypass pathway (REV3L, P = 0.008), suggesting that alterations in DNA damage mediation may modulate myeloma susceptibility. In conclusion, this large study found SNPs in several pathways, including pyrimidine metabolism and DNA damage mediation, to be associated with myeloma risk. Additional studies are needed to replicate these findings and to further explore genetic variation in these regions.