Risk Alleles for Multiple Myeloma Susceptibility in ADME Genes

Abstract

The cause of multiple myeloma (MM) remains largely unknown. Several pieces of evidence support the involvement of genetic and multiple environmental factors (i.e., chemical agents) in MM onset. The inter-individual variability in the bioactivation, detoxification, and clearance of chemical carcinogens such as asbestos, benzene, and pesticides might increase the MM risk. This inter-individual variability can be explained by the presence of polymorphic variants in absorption, distribution, metabolism, and excretion (ADME) genes. Despite the high relevance of this issue, few studies have focused on the inter-individual variability in ADME genes in MM risk. To identify new MM susceptibility loci, we performed an extended candidate gene approach by comparing high-throughput genotyping data of 1936 markers in 231 ADME genes on 64 MM patients and 59 controls from the CEU population. Differences in genotype and allele frequencies were validated using an internal control group of 35 non-cancer samples from the same geographic area as the patient group. We detected an association between MM risk and ADH1B rs1229984 (OR = 3.78; 95% CI, 1.18–12.13; p = 0.0282), PPARD rs6937483 (OR = 3.27; 95% CI, 1.01–10.56; p = 0.0479), SLC28A1 rs8187737 (OR = 11.33; 95% CI, 1.43–89.59; p = 0.005), SLC28A2 rs1060896 (OR = 6.58; 95% CI, 1.42–30.43; p = 0.0072), SLC29A1 rs8187630 (OR = 3.27; 95% CI, 1.01–10.56; p = 0.0479), and ALDH3A2 rs72547554 (OR = 2.46; 95% CI, 0.64–9.40; p = 0.0293). The prognostic value of these genes in MM was investigated in two public datasets showing that shorter overall survival was associated with low expression of ADH1B and SLC28A1. In conclusion, our proof-of-concept findings provide novel insights into the genetic bases of MM susceptibility.