Fine-mapping markers of lung cancer susceptibility in a sub-region of chromosome 19q13.3 among Chinese

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.

Keywords: Chinese; Chr19q13.3; ERCC2 and PPP1R13L and CD3EAP and ERCC1; fine-mapping; lung cancer.

Figure 1. Schematic presentations of the studied genomic region 19q13.3

Upper panel: Gene locations with HUGO gene nomenclature on the chromosome sub-region 19q13.3 are shown. The arrow length represents the extent of the gene and the arrowhead indicates the transcription direction (From: http://www.ncbi.nlm.nih.gov/)(Adopted time: 2013-10-31). The distributed extent of 39 SNPs related to ERCC2, PPP1R13L, CD3EAP and ERCC1 in current study was 71.654kb. Lower panel: D′ LD map and LD plot of 32 SNPs covering ERCC2 (SNP1~10), PPP1R13L (SNP11~19), CD3EAP (SNP20~25) and ERCC1 (SNP26~32) on chromosome 19q13.3 from this Chinese lung cancer study. SNPs in 3′ to 5′ order as indicated in Table 4. Six blocks were detected by Haploview 4.2. The criteria of block partition were based on 95% confidence interval bounds of D′ values. The digit in the boxes D′ value (e.g. 99 means 0.99; 1 means 0.01; empty boxes means 1.0). Deep red boxes designate strong evidence of LD. Light red boxes designate uninformative. White boxes designate strong evidence of recombination.

Figure 2. Association of single SNPs with lung cancer for five genetic models, adjusted by smoking duration. Data from Table 2

32 SNPs in 3′ to 5′ order on chromosome 19q13.3 as indicated in Table 4. A dotted line indicates P-value of -Log (0.05).