The 7p15.3 (rs4487645) association for multiple myeloma shows strong allele-specific regulation of the MYC-interacting gene CDCA7L in malignant plasma cells

Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) at 7 loci influencing multiple myeloma (MM) risk. We generated expression quantitative trait loci (eQTL) data on malignant plasma cells on 848 patients to fine map the risk loci associations and gain insight into their functional basis. At 7p15.3 the strongest association with MM risk is provided by rs4487645, which is associated with allele-specific cis-regulation of the MYC-interacting gene CDCA7L with P-value=4.1x10-25. rs4487645 resides within intron 80 of DNAH11 and only 47 kb upstream of the transcription start site of CDCA7L. rs4487645 maps within a binding site for interferon regulatory factor 4 (IRF4) in a strong enhancer element upstream of CDCA7L. IRF4 is a critical transcrip-tional regulator in B-cell development. Since rs4487645 represents the strongest signal for MM at 7p15.3 the data are compatible with increased expression of CDCA7L being the functional basis of the 7p15.3 association exerting its effects through an extended pathway involving IRF4