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

Stacey L. Eggert, Karen L. Huyck, Priya Somasundaram, Raghava Kavalla, Elizabeth A. Stewart, Ake T. Lu, Jodie N. Painter, Grant W. Montgomery, Sarah E. Medland, Dale R. Nyholt, Susan A. Treloar, Krina T. Zondervan, Andrew C. Heath, Pamela A.F. Madden, Lynda Rose, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Nicholas G. Martin, Rita M. CantorCynthia C. Morton

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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 × 10-8) 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.

Original languageEnglish
Pages (from-to)621-628
Number of pages8
JournalAmerican journal of human genetics
Volume91
Issue number4
DOIs
StatePublished - Oct 5 2012

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