The 4q21 variant significantly associated with UADT cancers was rs1494961 located (Table 1) 20 Mb proximal to the ADH gene cluster. There is no LD between rs1494961 and either rs1229984, rs1573496 or rs698 (r2<0.003). rs1494961 is a non-synonymous variant positioned in the HEL308 gene, a single stranded DNA-dependent ATPase and DNA helicase involved in DNA intra-strand cross-linking repair [27], although the residue involved, I306V, is not an evolutionary conserved site [28] suggesting that this alteration may not have a functional consequence. rs1494961 is in a LD region spanning approximately 90 kb, and is highly correlated (r2>0.95) with more than 20 common genetic variants. This region contains additional genes (Figure 2), notably a second DNA repair-related gene, FAM175A (or Abraxas and CCDC98), that interacts directly with the BRCT repeat region of BRCA1 [29]. That a comparable association was noted between this variant and lung cancer (p = 3×10−4) (Figure 4) suggests that the causal variant maybe relevant for cancers influenced by tobacco consumption in general.
