Type 2 diabetes-related variants influence the risk of developing multiple myeloma: results from the IMMEnSE consortium

Abstract

Type 2 diabetes (T2D) has been suggested to be a risk factor for multiple myeloma (MM), but the relationship between the two traits is still not well understood. The aims of this study were to evaluate whether 58 genome-wide-association-studies (GWAS)-identified common variants for T2D influence the risk of developing MM and to determine whether predictive models built with these variants might help to predict the disease risk. We conducted a case-control study including 1420 MM patients and 1858 controls ascertained through the International Multiple Myeloma (IMMEnSE) consortium. Subjects carrying the KCNQ1 rs2237892T allele or the CDKN2A-2B rs2383208G/G , IGF1 rs35767T/T and MADD rs7944584T/T genotypes had a significantly increased risk of MM (odds ratio (OR)Z1.32-2.13) whereas those carrying the KCNJ11 rs5215C , KCNJ11 rs5219T and THADA rs7578597C alleles or the FTO rs8050136A/A and LTA rs1041981C/C genotypes showed a significantly decreased risk of developing the disease (ORZ0.76-0.85). Interestingly, a prediction model including those T2D-related variants associated with the risk of MM showed a significantly improved discriminatory ability to predict the disease when compared to a model without genetic information (area under the curve (AUC)Z0.645 vs AUCZ0.629; PZ4.05! 10 K06). A gender-stratified analysis also revealed a significant gender effect modification for ADAM30 rs2641348 and NOTCH2 rs10923931 variants (P interaction Z0.001 and 0.0004, respectively). Men carrying the ADAM30 rs2641348C and NOTCH2 rs10923931T alleles had a significantly decreased risk of MM whereas an opposite but not significant effect was observed in women (OR M Z0.71 and OR M Z0.66 vs OR W Z1.22 and OR W Z1.15, respectively). These results suggest that TD2-related variants may influence the risk of developing MM and their genotyping might help to improve MM risk prediction models.

XRCC1‐mediated DNA repair is associated with progression‐free survival of multiple myeloma patients after autologous stem cell transplant

“…We also failed to investigate melphalan‐induced DNA damage in PBMCs. Second, as discussed earlier, a considerable number of SNPs in diverse DNA repair genes and non‐DNA repair genes could be directly/indirectly associated with the clinical outcomes of ASCT‐HDM therapy, and some of these SNPs are associated with each other due to linkage equilibrium or other mechanisms, which requires meta‐analyses and more extensive analyses in large cohorts of MM patients in controlled clinical trials to separate the “confounded” contributions of each specific SNP to response to HDM . Third, although previous studies have demonstrated that melphalan‐induced molecular changes in PBMCs are associated with those observed in matched malignant BMPCs, evaluating how rs25487 impacts XRCC1 functioning in DNA repair in patient‐matched malignant BMPCs is an important next step.…”

“…One of the postulated mechanisms of resistance to melphalan‐induced DNA damage is the ability of myeloma cells to excise melphalan monoadducts and ICLs through DNA repair, which involves four major DNA repair mechanisms (namely, BER, NER, SSBR, and DSBR) . Due to the complicated nature of these major DNA repair pathways, a number of genetic alterations could have a bearing on the capacity to repair melphalan monoadducts and ICLs in a patient's PBMC and BMPC cells (Table S1) . As such, response to melphalan in MM patients would be multifactorial.…”

“…[5][6][7][8][9] Due to the complicated nature of these major DNA repair pathways, a number of genetic alterations could have a bearing on the capacity to repair melphalan monoadducts and ICLs in a patient's PBMC and BMPC cells (Table S1). 10,[38][39][40][41][42] As such, response to melphalan in MM patients would be multifactorial.…”

“…In addition to XRCC1 rs25487, a number of SNPs in DNA repair genes have been reported to be associated clinical outcomes (including biochemical response to melphalan, PFS, OS, and the occurrence of severe mucositis) in MM patients with ASCT-HDM (Tables 2, S1, and S2). [38][39][40][41][42] For example, CD3EAP rs967591, BRCA1 rs799919, ERCC1…”

Identification of miRSNPs associated with the risk of multiple myeloma

“…TCF19 was found to be involved in cell cycle progression and proliferation in the pancreatic β‐cell and it plays a role in the pathogenesis of diabetes . Type 2 diabetes has been frequently associated with MM and it is thought to influence the myelomagenesis through hyperglycemia and insulin‐dependent and ‐independent mechanisms . Moreover, rs1419881 is in linkage disequilibrium ( r 2 = 0.82) with the SNP rs3130453 which is located in the gene CCHCR , also known as HCR (Supporting Information Table S2).…”