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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.

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  • Authors+Show Affiliations

    ,

    Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

    , , , , , , , , , , , , , , , , , , ,

    Source

    American journal of human genetics 91:4 2012 Oct 05 pg 621-8

    MeSH

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

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    23040493

    Citation

    Eggert, Stacey L., et al. "Genome-wide Linkage and Association Analyses Implicate FASN in Predisposition to Uterine Leiomyomata." American Journal of Human Genetics, vol. 91, no. 4, 2012, pp. 621-8.
    Eggert SL, Huyck KL, Somasundaram P, et al. Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata. Am J Hum Genet. 2012;91(4):621-8.
    Eggert, S. L., Huyck, K. L., Somasundaram, P., Kavalla, R., Stewart, E. A., Lu, A. T., ... Morton, C. C. (2012). Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata. American Journal of Human Genetics, 91(4), pp. 621-8. doi:10.1016/j.ajhg.2012.08.009.
    Eggert SL, et al. Genome-wide Linkage and Association Analyses Implicate FASN in Predisposition to Uterine Leiomyomata. Am J Hum Genet. 2012 Oct 5;91(4):621-8. PubMed PMID: 23040493.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata. AU - Eggert,Stacey L, AU - Huyck,Karen L, AU - Somasundaram,Priya, AU - Kavalla,Raghava, AU - Stewart,Elizabeth A, AU - Lu,Ake T, AU - Painter,Jodie N, AU - Montgomery,Grant W, AU - Medland,Sarah E, AU - Nyholt,Dale R, AU - Treloar,Susan A, AU - Zondervan,Krina T, AU - Heath,Andrew C, AU - Madden,Pamela A F, AU - Rose,Lynda, AU - Buring,Julie E, AU - Ridker,Paul M, AU - Chasman,Daniel I, AU - Martin,Nicholas G, AU - Cantor,Rita M, AU - Morton,Cynthia C, PY - 2012/06/29/received PY - 2012/08/06/revised PY - 2012/08/13/accepted PY - 2012/10/9/entrez PY - 2012/10/9/pubmed PY - 2013/3/19/medline SP - 621 EP - 8 JF - American journal of human genetics JO - Am. J. Hum. Genet. VL - 91 IS - 4 N2 - 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. SN - 1537-6605 UR - https://www.unboundmedicine.com/medline/citation/23040493/full_citation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(12)00421-1 DB - PRIME DP - Unbound Medicine ER -