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

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

Distinct QTLs are linked to cardiac left ventricular mass in a sex-specific manner in a normotensive inbred rat intercross

Genetic mapping of the progeny of an F2 intercross between WKY and WKHA rats had previously allowed us to detect male-specific linkage between locus Cm24 and left ventricular mass index (LVMI). By further expanding that analysis, we detected additional loci that were all linked to LVMI in a sexspecific manner despite their autosomal location. In males, we detected one additional locus (Lvm8) on Chromosome 5 (LOD = 3.4), the two loci Lvm13 (LOD = 4.5) and Lvm9 (LOD = 2.8) on Chromosome 17, and locus Lvm10 (LOD = 4.2) on Chromosome 12. The locus Lvm13 had the same boundaries as locus Cm26 previously reported by others using a different cross. None of these loci showed linkage to LVM in females. In contrast, we identified in females the novel locus Lvm11 on Chromosome 15 (LOD = 2.8) and locus Lvm12 (LOD = 2.7) that had the same boundaries on Chromosome 3 as locus Cm25 detected previously by others using a cross of other normotensive strains. In prepubertal males, there were no differences in the width of cardiomyocytes from WKY and WKHA rats, but cardiomyocytes from WKHA became progressively wider than that of WKY as sexual maturation progressed. Altogether, these results provide evidence that distinct genes may influence LVMI of rats in a sexdependent manner, maybe by involving sex-specific interactions of sex steroids with particular genes involved in the determination of LVMI and/or cardiomyocyte width.Bastien Llamas, Zhibin Jiang, Marie-Line Rainville, Sylvie Picard and Christian F. Descheppe