Type 2 Diabetes-Related Variants Influence on the Risk of Developing Multiple Myeloma: Results from the Immense Consortium

Type 2-diabetes (T2D) is thought to be a relevant risk factor for multiple myeloma (MM), but the relationship between both traits is still not well understood. Thus, we decided to conduct a population-based case-control study in a population of 1420 MM patients (705 women and 715 men) and 1858 controls (916 women and 942 men) to evaluate whether 58 genome-wide association studies (GWAS)-identified common variants for T2D influence the risk of developing MM. Logistic regression analyses showed that carriers of the KCNQ1_rs2237892T allele or CDKN2A-2B_rs2383208G/G, IGF-1_rs35767T/T and MADD_rs7944584T/T genotypes had an increased risk of MM (OR=1.32, 95%CI 1.01-1.71, P=0.039; OR=1.86, 95%CI 1.12-3.11, P=0.016; OR=2.13, 95%CI 1.35-3.37, P=0.001 and OR=1.33, 95%CI 1.06-1.67, P=0.014, respectively) whereas those carrying the KCNJ11_rs5215C, KCNJ11_rs5219T and THADA_rs7578597C alleles or the FTO_rs8050136A/A and LTA_rs1041981C/C genotypes showed a decreased risk for the disease (OR=0.85, 95%CI 0.73-0.99, P=0.38; OR=0.84, 95%CI 0.72-0.99, P=0.034; OR=0.81, 95%CI 0.68-0.98, P=0.032; OR=0.78, 95%CI 0.64-0.95, P=0.013; and OR=0.76, 95%CI 0.58-0.99, P=0.042, respectively). The associations of these T2D-related variants with an increased or decreased risk of MM were due to non-diabetogenic alleles, which suggests a non-diabetogenic mechanism underlying the effect of these variants to determine the risk of the disease. A gender-stratified analysis also revealed a significant gender effect modification for ADAM30_rs2641348, and NOTCH2_rs10923931 SNPs (P_interaction=0.001 and 0.0004 and P_het=0.19 and 0.60, respectively), which also underlies the importance of considering gender as a factor modifying the risk for MM. Men harbouring the ADAM30_rs2641348C and NOTCH2_rs10923931T alleles had a decreased risk of MM (OR=0.71, 95%CI 0.54-0.94, P=0.015 and OR=0.66, 95%CI 0.50-0.86, P=0.0019) whereas an opposite but not significant effect was observed in women. Finally, SNP-SNP interaction analysis revealed overall significant two- and three-locus interaction models to increase the risk of MM (FAM148B_rs11071657-KCNJ11_rs5219, and SLC30A8_rs13266634-KCNJ11_rs5219-FTO_rs8050136; P=0.01 and 0.001, respectively) whereas a significant four-locus model was also found to increase the risk of MM in men (FADS1_rs174550-TSPAN8_rs7961581-PROX1_rs340874-KCNJ11_rs5219, P=0.001). Although further studies in independent populations are warranted to replicate these findings, these results suggest that TD2-related variants may influence the risk of developing MM, likely through non-diabetogenic mechanisms.