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Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk.

ABSTRACT: Breast cancer risk is a polygenic trait. To identify breast cancer modifier alleles that have a high population frequency and low penetrance we used a comparative genomics approach. Quantitative trait loci (QTL) were initially identified by linkage analysis in a rat mammary carcinogenesis model followed by verification in congenic rats carrying the specific QTL allele under study. The Mcs5a locus was identified by fine-mapping Mcs5 in a congenic model. Here we characterize the Mcs5a locus, which when homozygous for the Wky allele, reduces mammary cancer risk by 50%. The Mcs5a locus is a compound QTL with at least two noncoding interacting elements: Mcs5a1 and Mcs5a2. The resistance phenotype is only observed in rats carrying at least one copy of the Wky allele of each element on the same chromosome. Mcs5a1 is located within the ubiquitin ligase Fbxo10, whereas Mcs5a2 includes the 5' portion of Frmpd1. Resistant congenic rats show a down-regulation of Fbxo10 in the thymus and an up-regulation of Frmpd1 in the spleen. The association of the Mcs5a1 and Mcs5a2 human orthologs with breast cancer was tested in two population-based breast cancer case-control studies (approximately 12,000 women). The minor alleles of rs6476643 (MCS5A1) and rs2182317 (MCS5A2) were independently associated with breast cancer risk. The minor allele of rs6476643 increases risk, whereas the rs2182317 minor allele decreases risk. Both alleles have a high population frequency and a low penetrance toward breast cancer risk.

SUBMITTER: Samuelson DJ

PROVIDER: S-EPMC1847458 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk.

Samuelson David J DJ Hesselson Stephanie E SE Aperavich Beth A BA Zan Yunhong Y Haag Jill D JD Trentham-Dietz Amy A Hampton John M JM Mau Bob B Chen Kai-Shun KS Baynes Caroline C Khaw Kay-Tee KT Luben Robert R Perkins Barbara B Shah Mitul M Pharoah Paul D PD Dunning Alison M AM Easton Doug F DF Ponder Bruce A BA Gould Michael N MN

Proceedings of the National Academy of Sciences of the United States of America 20070402 15

Breast cancer risk is a polygenic trait. To identify breast cancer modifier alleles that have a high population frequency and low penetrance we used a comparative genomics approach. Quantitative trait loci (QTL) were initially identified by linkage analysis in a rat mammary carcinogenesis model followed by verification in congenic rats carrying the specific QTL allele under study. The Mcs5a locus was identified by fine-mapping Mcs5 in a congenic model. Here we characterize the Mcs5a locus, which ...[more]

PMID: 17404222

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Project description:Genetic dissection of the S rat genome has provided strong evidence for the presence of two interacting blood pressure (BP) quantitative trait loci (QTLs), termed QTL1 and QTL2, on rat chromosome 5. However, the identities of the underlying interacting genetic factors remain unknown. Further experiments targeted to identify the interacting genetic factors by the substitution mapping approach alone are difficult because of the interdependency of natural recombinations to occur at the two QTLs. We hypothesized that the interacting genetic factors underlying these two QTLs may interact at the level of gene transcription and thereby represent expression QTLs (eQTLs). To detect these interacting eQTLs, a custom QTL chip containing the annotated genes within QTL1 and QTL2 was developed and used to conduct a transcriptional profiling study of S and two congenic strains that retain either one or both the QTLs. The results uncovered an interaction between two transcription factors, DMRTA2 and NFIA. Further, the âbiological signatureâ elicited by these two transcription factors was differential between the congenic strain that retained LEW alleles at both QTL1 and 2 compared to the congenic strain that retained LEW alleles at QTL1 alone. A network of transcription factors potentially affecting BP could be traced, lending support to our hypothesis. Pairs of Cy5 and Cy3 labeled targets were co-hybridized onto either a custom long oligonucleotide microarray for the interrogation of 231 genes encompassed by QTL1 and QTL2, or a TIGR rat cDNA array consisting of 26,401 probe elements representing 20,465 unique non-QTL genes. A âflip-dyeâ or âbalanced blockâ design was used as the experimental method of choice to account for potential dye-bias labeling effects. Six âbalanced blockâ normalized files are submitted for the long oligonucleotide array interrogating the hearts from S versus S.LEW(5)x6x9 animals, fourteen âflip-dyeâ hybridizations are submitted for the cDNA array interrogating the hearts from S versus S.LEW(5)x6x9 animals, and twelve âflip-dyeâ hybridizations are submitted for the cDNA array interrogating the hearts from S versus S.LEW(5)x6x11 animals. GPR and MEV files cannot be located.

Dataset Information

Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk.

Publications

Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk.

Similar Datasets

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