A comprehensive study of polymorphisms in the ABCB1, ABCC2, ABCG2, NR1I2 genes and lymphoma risk

Abstract

Owing to their role in controlling the efflux of toxic compounds, transporters are central players in the process of detoxification and elimination of xenobiotics, which in turn is related to cancer risk. Among these transporters, ATP-binding cassette B1/multidrug resistance 1 (ABCB1/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP) affect susceptibility to many hematopoietic malignancies. The maintenance of regulated expression of these transporters is governed through the activation of intracellular "xenosensors" like the nuclear receptor 1I2/pregnane X receptor (NR1I2/PXR). SNPs in genes encoding these regulators have also been implicated in the risk of several cancers. Using a tagging approach, we tested the hypothesis that common polymorphisms in the transporter genes ABCB1, ABCC2, ABCG2 and the regulator gene NR1I2 could be implicated in lymphoma risk. We selected 68 SNPs in the four genes, and we genotyped them in 1,481 lymphoma cases and 1,491 controls of the European case-control study (EpiLymph) using the Illumina GoldenGate™ assay technology. Carriers of the SNP rs6857600 minor allele in ABCG2 was associated with a decrease in risk of B-cell lymphoma (B-NHL) overall (p < 0.001). Furthermore, a decreased risk of chronic lymphocytic leukemia (CLL) was associated with the ABCG2 rs2231142 variant (p = 0.0004), which could be replicated in an independent population. These results suggest a role for this gene in B-NHL susceptibility, especially for CLL.

Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Copyright © 2011 UICC.

Figures

Figure 1. Association between rs2231142 (ABCG2) and CLL risk

Relative samples sizes are represented by size of symbols. Horizontal lines indicate the 95% confidence intervals for the respective allelic odds. The combined estimate is indicated by a diamond. For the Mayo-GEC population the OR calculation was based on imputed information.

Figure 2. Haplotype blocks of the ABCG2 gene

Figure 2 shoes the estimates of the correlation coefficient r2 in the ABCG2 gene, derived from the genotypes in the underlying study population in the Haploview software. The LD relationship between each pair of SNP is indicated by the values in the squares. The shading indicates the extent of LD, a greater LD is represented by darker shading. The rs1481012 and rs2231142 are in high LD (r2=0.989), and the rs2775256 is in high LD with the rs1564481 (r2=0.982).