Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability
- University of Helsinki, Finland
- University of Helsinki and Helsinki University Hospital, Finland
- University of Oulu, Finland
- Oulu University Hospital, Finland
- University Of Helsinki, Finland
Abstract
Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.
Data availability
The UKBB data is available through the UK Biobank (http://www.ukbiobank.ac.uk). The NFBC data can be requested from the Northern Finland Birth Cohorts' Project Center at the Medical Faculty, University of Oulu (http://www.oulu.fi/nfbc/). The summary statistics that support the findings presented in this work are included in Supplementary Tables and Supplementary Data.
Article and author information
Author details
Funding
Terveyden Tutkimuksen Toimikunta (1250345)
- Lauri A Aaltonen
European Research Council (695727)
- Lauri A Aaltonen
Cancer Society of Finland
- Lauri A Aaltonen
Sigrid Juséliuksen Säätiö
- Lauri A Aaltonen
Jane ja Aatos Erkon Säätiö
- Lauri A Aaltonen
Luonnontieteiden ja Tekniikan Tutkimuksen Toimikunta (287665)
- Niko Välimäki
NordForsk (62721)
- Kimmo Palin
Terveyden Tutkimuksen Toimikunta (312041)
- Lauri A Aaltonen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The anonymous patient samples (65) were collected according to Finnish laws and regulations by permission of the director of the health care unit. For the rest of the patients, an informed consent was obtained. This study was conducted in accordance with the Declaration of Helsinki and approved by the Finnish National Supervisory Authority for Welfare and Health, National Institute for Health and Welfare (THL/151/5.05.00/2017), and the Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS/177/13/03/03/2016).
Copyright
© 2018, Välimäki et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability
eLife 7:e37110.
https://doi.org/10.7554/eLife.37110
