title: Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata.
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.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Eggert
authors.forename: Karen L
authors.initials: KL
authors.lastname: Huyck
authors.forename: Priya
authors.initials: P
authors.lastname: Somasundaram
authors.forename: Raghava
authors.initials: R
authors.lastname: Kavalla
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Stewart
authors.forename: Ake T
authors.initials: AT
authors.lastname: Lu
authors.forename: Jodie N
authors.initials: JN
authors.lastname: Painter
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.forename: Susan A
authors.initials: SA
authors.lastname: Treloar
authors.forename: Krina T
authors.initials: KT
authors.lastname: Zondervan
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
authors.forename: Lynda
authors.initials: L
authors.lastname: Rose
authors.forename: Julie E
authors.initials: JE
authors.lastname: Buring
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cantor
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
mesh_terms: D000483:Alleles; D015331:Cohort Studies; D054890:Fatty Acid Synthase, Type I / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D007044:Hysterectomy / Q000379:methods; D007889:Leiomyoma / Q000235:genetics* / Q000601:surgery; D015810:Linkage Disequilibrium; D008126:Lod Score; D027501:Monocarboxylic Acid Transporters / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D035781:Siblings; D027981:Symporters; D014594:Uterine Neoplasms / Q000235:genetics* / Q000601:surgery
chemical_list: D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; C106260:SLC16A3 protein, human; D027981:Symporters; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I