gms | German Medical Science

MAINZ//2011: 56. GMDS-Jahrestagung und 6. DGEpi-Jahrestagung

Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e. V.
Deutsche Gesellschaft für Epidemiologie e. V.

26. - 29.09.2011 in Mainz

A genome-wide association study to identify genetic susceptibility loci that modify postmenopausal breast cancer risk associated with menopausal hormone therapy use – A four-stage design

Meeting Abstract

  • Rebecca Hein - Abteilung Epidemiologie von Krebserkrankungen, Deutsches Krebsforschungszentrum, Heidelberg
  • Dieter Flesch-Janys - Universitäres Cancer Center, Abteilung Krebsepidemiologie, klinisches Krebsregister, Universitätsklinikum Hamburg-Eppendorf, Hamburg
  • Lars Beckmann - Abteilung Epidemiologie von Krebserkrankungen, Deutsches Krebsforschungszentrum, Heidelberg
  • Per Hall - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm
  • Kamila Czene - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm
  • Douglas F. Easton - Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK
  • Norbert Dahmen - Congenics AG, Hamburg
  • Kirsten Mittelstraß - Institut für Epidemiologie, Helmholtzzentrum München, München
  • Thomas Illig - Institut für Epidemiologie, Helmholtzzentrum München, München
  • Jenny Chang-Claude - Abteilung Epidemiologie von Krebserkrankungen, Deutsches Krebsforschungszentrum, Heidelberg

Mainz//2011. 56. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 6. Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi). Mainz, 26.-29.09.2011. Düsseldorf: German Medical Science GMS Publishing House; 2011. Doc11gmds193

DOI: 10.3205/11gmds193, URN: urn:nbn:de:0183-11gmds1932

Veröffentlicht: 20. September 2011

© 2011 Hein et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Background: Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer (BC) in postmenopausal women. Few candidate gene polymorphisms studies have examined whether BC risk after HT exposure varies by individual susceptibility. To identify novel genetic loci that modify BC risk related to MHT use in postmenopausal women, we conducted a multistage genome-wide association study (GWAS). Data were evaluated with logistic regression adjusted for reference age and breast cancer risk factors.

Methods: In stage 1, we performed a case-only genome-wide association study in 776 invasive BC cases of the German case-control study MARIE. The 1220 single nucleotide polymorphisms (SNPs) showing the lowest p-values for statistical interaction with current MHT use were carried on to stage 2. In stage 2, a pooled case-control analysis including additional MARIE study subjects (1375 cases, 1974 controls) as well as 795 cases and 764 controls of a Swedish case-control study was performed. A joint p-value (Skol et al., 2006) was calculated for a combined analysis of stage 1 and 2. Fine mapping was then performed for three candidate genes harbouring the five top SNPs by assessing association with additional 33 tagging SNPs in all MARIE subjects (2380 cases, 4570 controls). Replication of the most significant interaction of the combined stages was conducted in the Breast Cancer Association Consortium (BCAC), combining results of a pooled analysis of five studies (4061 cases, 4138 controls) with the corresponding results of the NHS study (1090 cases, 1078 controls) in a meta-analysis.

Results: Stage 1 yielded 118 interactions with p-values <10-4. The lowest joint p-values of stages 1 and 2 were <6x10-6 for 5 SNPs on chromosomes 2, 7 and 18. In the fine mapping stage, we did not identify further SNPs showing stronger interaction than rs6707272 on chromosome 2 (p-value 3x10-7). This SNP did not replicate in BCAC (p-value 0.32).

Conclusions: The SNP rs6707272 is in strong LD with SNPs in the TRIP12 gene. Our inability to replicate the top interaction may indicate that it is a null result. However, the prevalence of current MHT use is remarkably higher in MARIE than other studies in BCAC (22% versus 12%), thus reducing power to detect the interaction in BCAC. Furthermore, the phenomenon known as ‘the winners curse’ may have also led to reduced power of the replication compared to the combined analysis. Therefore, our findings require replication in further independent, well-powered studies.


References

1.
Skol AD, Scott LJ, Abecasis GR, Boehnke M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet. 2006;38(2):209-13.