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  • Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata.

Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata.

American journal of human genetics (2012-10-09)
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 Cantor, Cynthia C Morton
초록

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.