Linkage disequilibrium mapping of a breast cancer susceptibility locus near RAI/PPP1R13L/iASPP

Bjørn A Nexø¹ , Ulla Vogel² , Anja Olsen³ , Mette Nyegaard¹ , Zuzanna Bukowy¹^,4 , Eszter Rockenbauer¹^,2^,5 , Xiuqing Zhang¹^,6 , Cemile Koca¹ , Mette Mains¹ , Bettina Hansen¹ , Anne Hedemand¹ , Anette Kjeldgaard¹ , Magdalena J Laska¹^,7 , Ole Raaschou-Nielsen³ , Søren Cold⁸ , Kim Overvad⁹ , Anne Tjønneland³ , Lars Bolund¹^,6 and Anders D Børglum¹

¹Institute of Human Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark

²National Research Centre for the Working Environment, DK-2100 Copenhagen O, Denmark, Institute for Science, Systems and Models, University of Roskilde, DK-4000 Roskilde. and National Food Institute, Technical University of Denmark, Denmark

³Institute of Cancer Epidemiology, The Danish Cancer Society, DK-2100 Copenhagen O, Denmark

⁴Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warshawa, Poland

⁵Department of Forensic Genetics, Institute of Forensic Medicine, University of Copenhagen, DK-2100 Copenhagen O, Denmark

⁶Beijing Genomics Institute, Beijing, PR China

⁷Institute of Embryology and Histology, University of Silesia, Poland

⁸Odense University Hospital, DK-5000 Odensek, Denmark

⁹Department of Clinical Epidemiology, Aalborg Hospital and Aarhus University Hospital, DK-9000 Aalborg, Denmark

author email corresponding author email

BMC Medical Genetics 2008, 9:56doi:10.1186/1471-2350-9-56


Published:	27 June 2008

Abstract

Background

Previous results have suggested an association of the region of 19q13.3 with several forms of cancer. In the present study, we investigated 27 public markers within a previously identified 69 kb stretch of chromosome 19q for association with breast cancer by using linkage disequilibrium mapping. The study groups included 434 postmenopausal breast cancer cases and an identical number of individually matched controls.

Methods and Results

Studying one marker at a time, we found a region spanning the gene RAI (alias PPP1R13L or iASPP) and the 5' portion of XPD to be associated with this cancer. The region corresponds to a haplotype block, in which there seems to be very limited recombination in the Danish population. Studying combinations of markers, we found that two to four neighboring markers gave the most consistent and strongest result. The haplotypes with strongest association with cancers were located in the gene RAI and just 3' to the gene. Coinciding peaks were seen in the region of RAI in groups of women of different age.

In a follow-up to these results we sequenced 10 cases and 10 controls in a 44 kb region spanning the peaks of association. This revealed 106 polymorphisms, many of which were not in the public databases. We tested an additional 44 of these for association with disease and found a new tandem repeat marker, called RAI-3'd1, located downstream of the transcribed region of RAI, which was more strongly associated with breast cancer than any other marker we have tested (RR = 2.44 (1.41–4.23, p = 0.0008, all cases; RR = 6.29 (1.49–26.6), p = 0.01, cases up to 55 years of age).

Conclusion

We expect the marker RAI-3'd1 to be (part of) the cause for the association of the chromosome 19q13.3 region's association with cancer.