Abstract
Linkage disequilibrium-mapping studies in Caucasians have indicated anassociation of Chr19q13.3 sub-region spanning ERCC2, PPP1R13L, CD3EAP and ERCC1 with several cancers. To refine the region of association and identify potential causal variations among Asians, we performed a fine-mapping study using 32 (39) SNPs in a 71.654kb sub-region. The study included 384 Chinese lung cancer cases and 387 controls. Seven closely situated SNPs showed significant associations with lung cancer risk in five different genetic models of single-locus associations (adjusted for smoking duration). These were PPP1R13L rs1970764 [OR (95% CI) = 1.58 (1.09-2.29), P = 0.014] in a recessive model and PPP1R13L rs1005165 [OR (95% CI) = 1.25 (1.01-1.54), P = 0.036], CD3EAP rs967591 [OR (95% CI) = 1.40 (1.13-1.75), P = 0.0023], rs735482 [OR (95% CI) = 1.29 (1.03-1.61), P = 0.026], rs1007616 [OR (95% CI) = 0.78 (0.61-1.00), P = 0.046], and rs62109563 [OR (95% CI) = 1.28 (1.03-1.59), P = 0.024] in a log-additive model and ERCC1 rs3212965 [OR (95% CI) = 0.70 (0.52-0.94), P = 0.019] in an over-dominant model. Six-haplotype blocks were determined in the sub-region. Using an alternative approach where we performed a haplotype analysis of all significant polymorphisms, rs1970764 was found to be most consistently associated with lung cancer risk. The combined data suggest that the sub-region with the strongest association to lung cancer susceptibility might locate to the 23.173kb from PPP1R13L intron8 rs1970764 to rs62109563 3′ to CD3EAP. Limited risk loci and span on lung cancer in this sub-region are initially defined among Asians.
Highlights
The candidate sub-region of chromosome 19q13.3 includes four genes
Fine-mapping studies enable us to narrow down the set of candidate causal polymorphisms
This study is an elaboration of our previous association analysis with lung cancer including 18 tag single nucleotide polymorphisms (SNP) and 14 non-tag SNPs
Summary
The candidate sub-region of chromosome 19q13.3 includes four genes. From 3'→5', they are ERCC2/XPD (excision repair cross-complementing rodent repair deficiency, complementation group 2/ xeroderma pigmentosum complementary group D), PPP1R13L/IASPP/RAI [protein phosphatase 1, regulatory (inhibitor) subunit 13 like/Inhibitory member of the ASPP family/RelA-associated inhibitor], CD3EAP/ASE-1 [CD3e molecule, epsilon-associated protein/ antisense to ERCC1)], and ERCC1 (excision repair crosscomplementing rodent repair deficiency, complementation group 1) (Figure 1). The candidate sub-region of chromosome 19q13.3 includes four genes. From 3'→5', they are ERCC2/XPD (excision repair cross-complementing rodent repair deficiency, complementation group 2/ xeroderma pigmentosum complementary group D), PPP1R13L/IASPP/RAI [protein phosphatase 1, regulatory (inhibitor) subunit 13 like/Inhibitory member of the ASPP family/RelA-associated inhibitor], CD3EAP/. ASE-1 [CD3e molecule, epsilon-associated protein/ antisense to ERCC1)], and ERCC1 (excision repair crosscomplementing rodent repair deficiency, complementation group 1) (Figure 1). ERCC2 and ERCC1 are involved in DNA repair while PPP1R13L and CD3EAP participate in apoptosis and rRNA transcription, respectively [1, 2]. Determined changes in activity of any of the four genes may play vital roles in carcinogenesis. Lung cancer is a leading cause of death worldwide [3].
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