Genome-wide linkage and association analyses implicate FASN in predisposition to uterine leiomyomata

Eggert, Stacey L., Huyck, Karen L., Somasundaram, Priya, Kavalla, Raghava, Stewart, Elizabeth A., Lu, Ake T., Painter, Jodie N., Montgomery, Grant W., Medland, Sarah E., Nyholt, Dale R., Treloar, Susan A., Zondervan, Krina T., Heath, Andrew C., Madden, Pamela A. F., Rose, Lynda, Buring, Julie E., Ridker, Paul M., Chasman, Daniel I., Martin, Nicholas G., Cantor, Rita M. and Morton, Cynthia C. (2012) Genome-wide linkage and association analyses implicate FASN in predisposition to uterine leiomyomata. American Journal of Human Genetics, 91 4: 621-628. doi:10.1016/j.ajhg.2012.08.009


Author Eggert, Stacey L.
Huyck, Karen L.
Somasundaram, Priya
Kavalla, Raghava
Stewart, Elizabeth A.
Lu, Ake T.
Painter, Jodie N.
Montgomery, Grant W.
Medland, Sarah E.
Nyholt, Dale R.
Treloar, Susan A.
Zondervan, Krina T.
Heath, Andrew C.
Madden, Pamela A. F.
Rose, Lynda
Buring, Julie E.
Ridker, Paul M.
Chasman, Daniel I.
Martin, Nicholas G.
Cantor, Rita M.
Morton, Cynthia C.
Title Genome-wide linkage and association analyses implicate FASN in predisposition to uterine leiomyomata
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2012-10-05
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2012.08.009
Open Access Status
Volume 91
Issue 4
Start page 621
End page 628
Total pages 8
Place of publication Cambridge, MA, United States
Publisher Cell Press
Collection year 2013
Language eng
Formatted abstract
Uterine leiomyomata (UL), the most prevalent pelvic tumors in women of reproductive age, pose a major public health problem given their high frequency, associated morbidities, and most common indication for hysterectomies. A genetic component to UL predisposition is supported by analyses of ethnic predisposition, twin studies, and familial aggregation. A genome-wide SNP linkage panel was genotyped and analyzed in 261 white UL-affected sister-pair families from the Finding Genes for Fibroids study. Two significant linkage regions were detected in 10p11 (LOD = 4.15) and 3p21 (LOD = 3.73), and five additional linkage regions were identified with LOD scores > 2.00 in 2q37, 5p13, 11p15, 12q14, and 17q25. Genome-wide association studies were performed in two independent cohorts of white women, and a meta-analysis was conducted. One SNP (rs4247357) was identified with a p value (p = 3.05 × 108) that reached genome-wide significance (odds ratio = 1.299). The candidate SNP is under a linkage peak and in a block of linkage disequilibrium in 17q25.3, which spans fatty acid synthase (FASN), coiled-coil-domain-containing 57 (CCDC57), and solute-carrier family 16, member 3 (SLC16A3). By tissue microarray immunohistochemistry, we found elevated (3-fold) FAS levels in UL-affected tissue compared to matched myometrial tissue. FAS transcripts and/or protein levels are upregulated in various neoplasms and implicated in tumor cell survival. FASN represents the initial UL risk allele identified in white women by a genome-wide, unbiased approach and opens a path to management and potential therapeutic intervention.
Keyword Fatty-acid synthase
Prostate-cancer
Pharmacological inhibitors
Cytogenetic abnormalities
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2013 Collection
Centre for Military and Veterans' Health Publications
 
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