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

Am J Hum Genet. 2012 Oct 5;91(4):621-8. doi: 10.1016/j.ajhg.2012.08.009.

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Cohort Studies
  • Fatty Acid Synthase, Type I / genetics*
  • Female
  • Genetic Linkage*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study / methods*
  • Genotype
  • Humans
  • Hysterectomy / methods
  • Leiomyoma / genetics*
  • Leiomyoma / surgery
  • Linkage Disequilibrium
  • Lod Score
  • Monocarboxylic Acid Transporters / genetics
  • Polymorphism, Single Nucleotide
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Siblings
  • Uterine Neoplasms / genetics*
  • Uterine Neoplasms / surgery

Substances

  • Monocarboxylic Acid Transporters
  • RNA, Messenger
  • SLC16A3 protein, human
  • FASN protein, human
  • Fatty Acid Synthase, Type I