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. 2012 Jun;20(6):682-9.
doi: 10.1038/ejhg.2011.273. Epub 2012 Jan 18.

A two-stage association study identifies methyl-CpG-binding domain protein 2 gene polymorphisms as candidates for breast cancer susceptibility

Yadav Sapkota  1 , Paula Robson, Raymond Lai, Carol E Cass, John R Mackey, Sambasivarao Damaraju
Affiliations

A two-stage association study identifies methyl-CpG-binding domain protein 2 gene polymorphisms as candidates for breast cancer susceptibility

Yadav Sapkota et al. Eur J Hum Genet. 2012 Jun.

Abstract

Genome-wide association studies for breast cancer have identified over 40 single-nucleotide polymorphisms (SNPs), a subset of which remains statistically significant after genome-wide correction. Improved strategies for mining of genome-wide association data have been suggested to address heritable component of genetic risk in breast cancer. In this study, we attempted a two-stage association design using markers from a genome-wide study (stage 1, Affymetrix Human SNP 6.0 array, cases=302, controls=321). We restricted our analysis to DNA repair/modifications/metabolism pathway related gene polymorphisms for their obvious role in carcinogenesis in general and for their known protein-protein interactions vis-à-vis, potential epistatic effects. We selected 22 SNPs based on linkage disequilibrium patterns and high statistical significance. Genotyping assays in an independent replication study of 1178 cases and 1314 controls were attempted using Sequenom iPLEX Gold platform (stage 2). Six SNPs (rs8094493, rs4041245, rs7614, rs13250873, rs1556459 and rs2297381) showed consistent and statistically significant associations with breast cancer risk in both stages, with allelic odds ratios (and P-values) of 0.85 (0.0021), 0.86 (0.0026), 0.86 (0.0041), 1.17 (0.0043), 1.20 (0.0103) and 1.13 (0.0154), respectively, in combined analysis (N=3115). Of these, three polymorphisms were located in methyl-CpG-binding domain protein 2 gene regions and were in strong linkage disequilibrium. The remaining three SNPs were in proximity to RAD21 homolog (S. pombe), O-6-methylguanine-DNA methyltransferase and RNA polymerase II-associated protein 1. The identified markers may be relevant to breast cancer susceptibility in populations if these findings are confirmed in independent cohorts.

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Figures

Figure 1
Figure 1
Pairwise LD profiles between SNPs from MBD2 gene region. (a) LD profile of whole MBD2 isoform 1 spanning ∼70.58 kbp. The gene is in reverse orientation (3′–5′) on chromosome 18q arm. Five SNPs (three from our study that shown in black and two from Zhu et al that are shown in red) in MBD2 gene regions are shown based on their relative position on HapMap CEU data set (phase 1 and 2-full data set). LD blocks were defined using ‘CI' method as explained by Gabriel et al. D′ values are given for LD between the markers. The darker the cell, the greater the D′ value between the SNPs. (b) LD profile for three MBD2 SNPs from our study based on our study population.
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