期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 91, 期 4, 页码 621-628出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2012.08.009
关键词
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资金
- National Institute of Child Health & Human Development [HD046226, HD060530]
- National Heart, Lung, and Blood Institute [HL043851, HL69757]
- National Cancer Institute [CA047988]
- Donald W. Reynolds Foundation
- Fondation Leducq
- Amgen
- NIH [AA07535, AA07728, AA13320, AA13321, AA14041, AA11998, AA17688, DA012854, DA019951, HHSN268200782096C]
- Australian National Health and Medical Research Council [339462, 389927, 389938, 442981, 443036, 496739]
- 5th Framework Programme (FP-5) GenomEUtwin Project [QLG2-CT-2002-01254]
- Wellcome Trust [WT085235/Z/08/Z]
- Cooperative Research Centre for Discovery of Genes for Common Human Diseases, Cerylid Biosciences (Melbourne)
- National Health and Medical Research Council
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 x 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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