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| PMID |
|
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| TITLE |
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| Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata. |
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| ABSTRACT |
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| 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. |
| Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2012/06/29 |
| revised |
2012/08/06 |
| accepted |
2012/08/13 |
| entrez |
2012/10/09 06:00 |
| pubmed |
2012/10/09 06:00 |
| medline |
2013/03/19 06:00 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Eggert SL |
|
Eggert |
Stacey L |
SL |
|
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. |
| Huyck KL |
|
Huyck |
Karen L |
KL |
|
|
| Somasundaram P |
|
Somasundaram |
Priya |
P |
|
|
| Kavalla R |
|
Kavalla |
Raghava |
R |
|
|
| Stewart EA |
|
Stewart |
Elizabeth A |
EA |
|
|
| Lu AT |
|
Lu |
Ake T |
AT |
|
|
| Painter JN |
|
Painter |
Jodie N |
JN |
|
|
| Montgomery GW |
|
Montgomery |
Grant W |
GW |
|
|
| Medland SE |
|
Medland |
Sarah E |
SE |
|
|
| Nyholt DR |
|
Nyholt |
Dale R |
DR |
|
|
| Treloar SA |
|
Treloar |
Susan A |
SA |
|
|
| Zondervan KT |
|
Zondervan |
Krina T |
KT |
|
|
| Heath AC |
|
Heath |
Andrew C |
AC |
|
|
| Madden PA |
|
Madden |
Pamela A F |
PA |
|
|
| Rose L |
|
Rose |
Lynda |
L |
|
|
| Buring JE |
|
Buring |
Julie E |
JE |
|
|
| Ridker PM |
|
Ridker |
Paul M |
PM |
|
|
| Chasman DI |
|
Chasman |
Daniel I |
DI |
|
|
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
|
| Cantor RM |
|
Cantor |
Rita M |
RM |
|
|
| Morton CC |
|
Morton |
Cynthia C |
CC |
|
|
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| INVESTIGATORS |
|
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| JOURNAL |
|
| VOLUME: 91 |
| ISSUE: 4 |
| TITLE: American journal of human genetics |
| ISOABBREVIATION: Am J Hum Genet |
| YEAR: 2012 |
| MONTH: Oct |
| DAY: 05 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1537-6605 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: Am J Hum Genet |
| COUNTRY: United States |
| ISSNLINKING: 0002-9297 |
| NLMUNIQUEID: 0370475 |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Meta-Analysis |
| Research Support, N.I.H., Extramural |
| Research Support, Non-U.S. Gov't |
|
| COMMENTS AND CORRECTIONS |
|
| REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
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|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| DA019951 |
NIDA NIH HHS |
United States |
| R01 AA007535 |
NIAAA NIH HHS |
United States |
| AA13320 |
NIAAA NIH HHS |
United States |
| HD046226 |
NICHD NIH HHS |
United States |
| AA13321 |
NIAAA NIH HHS |
United States |
| R56 DA012854 |
NIDA NIH HHS |
United States |
| AA17688 |
NIAAA NIH HHS |
United States |
| HHSN268200782096C |
NHGRI NIH HHS |
United States |
| R01 DA012854 |
NIDA NIH HHS |
United States |
| U19 HL069757 |
NHLBI NIH HHS |
United States |
| AA14041 |
NIAAA NIH HHS |
United States |
| U01 HL069757 |
NHLBI NIH HHS |
United States |
| R01 AA014041 |
NIAAA NIH HHS |
United States |
| K05 AA017688 |
NIAAA NIH HHS |
United States |
| 085235 |
Wellcome Trust |
United Kingdom |
| P50 AA011998 |
NIAAA NIH HHS |
United States |
| HL69757 |
NHLBI NIH HHS |
United States |
| R01 AA007728 |
NIAAA NIH HHS |
United States |
| R01 HL043851 |
NHLBI NIH HHS |
United States |
| DA012854 |
NIDA NIH HHS |
United States |
| R01 AA013321 |
NIAAA NIH HHS |
United States |
| HD060530 |
NICHD NIH HHS |
United States |
| CA047988 |
NCI NIH HHS |
United States |
| R01 HD060530 |
NICHD NIH HHS |
United States |
| AA07728 |
NIAAA NIH HHS |
United States |
| 090532 |
Wellcome Trust |
United Kingdom |
| AA11998 |
NIAAA NIH HHS |
United States |
| R01 CA047988 |
NCI NIH HHS |
United States |
| K08 DA019951 |
NIDA NIH HHS |
United States |
| 084766 |
Wellcome Trust |
United Kingdom |
| R37 AA007728 |
NIAAA NIH HHS |
United States |
| WT085235/Z/08/Z |
Wellcome Trust |
United Kingdom |
| R01 AA013320 |
NIAAA NIH HHS |
United States |
| R01 HD046226 |
NICHD NIH HHS |
United States |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Alleles |
|
| Cohort Studies |
|
| Fatty Acid Synthase, Type I |
genetics |
| Female |
genetics |
| Genetic Linkage |
genetics |
| Genetic Predisposition to Disease |
genetics |
| Genome-Wide Association Study |
methods |
| Genotype |
methods |
| Humans |
methods |
| Hysterectomy |
methods |
| Leiomyoma |
surgery |
| Linkage Disequilibrium |
surgery |
| Lod Score |
surgery |
| Monocarboxylic Acid Transporters |
genetics |
| Polymorphism, Single Nucleotide |
genetics |
| RNA, Messenger |
genetics |
| Siblings |
genetics |
| Symporters |
genetics |
| Uterine Neoplasms |
surgery |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| 0 |
Monocarboxylic Acid Transporters |
| 0 |
RNA, Messenger |
| 0 |
SLC16A3 protein, human |
| 0 |
Symporters |
| EC 2.3.1.85 |
FASN protein, human |
| EC 2.3.1.85 |
Fatty Acid Synthase, Type I |
|
| OTHER ID's |
|
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|
