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Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata.
Am J Hum Genet 2012; 91(4):621-8AJ

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+Show Affiliations

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -