title: Fine mapping of the uterine leiomyoma locus on 1q43 close to a lncRNA in the RGS7-FH interval.
abstract: Mutations in fumarate hydratase (FH) on chromosome 1q43 cause a rare cancer syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC), but are rare in nonsyndromic and common uterine leiomyoma (UL) or fibroids. Studies suggested that variants in FH or in a linked gene may also predispose to UL. We re-sequenced 2.3 Mb of DNA spanning FH in 96 UL cases and controls from the multiethnic NIEHS-uterine fibroid study, and in 18 HLRCC-associated UL probands from European families then selected 221 informative SNPs for follow-up genotyping. We report promising susceptibility associations with UL peaking at rs78220092 (P=7.0×10(-5)) in the RGS7-FH interval in African Americans. In race-combined analyses and in meta-analyses (n=916), we identified promising associations with risk peaking upstream of a non-protein coding RNA (lncRNA) locus located in the RGS7-FH interval closer to RGS7, and associations with tumor size peaking in the distal phospholipase D family, member 5 (PLD5) gene at rs2654879 (P=1.7×10(-4)). We corroborated previously reported FH mutations in nine out of the 18 HLRCC-associated UL cases and identified two missense mutations in FH in only two nonsyndromic UL cases and one control. Our fine association mapping and integration of existing gene profiling data showing upregulated expression of the lncRNA and downregulation of PLD5 in fibroids, as compared to matched myometrium, suggest a potential role of this genomic region in UL pathogenesis. While the identified variations at 1q43 represent a potential risk locus for UL, future replication analyses are required to substantiate our observation.
authors.affiliation: Department of EpidemiologyR217JDepartment of BiostatisticsSchool of Public Health, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, Alabama 35294-0022, USADepartment of Human GeneticsRadboud University Medical Center Nijmegen, Nijmegen, The NetherlandsNetherlands Cancer InstituteAmsterdam, The Netherlands baissani@uab.edu.
authors.forename: Brahim
authors.initials: B
authors.lastname: Aissani
authors.affiliation: Department of EpidemiologyR217JDepartment of BiostatisticsSchool of Public Health, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, Alabama 35294-0022, USADepartment of Human GeneticsRadboud University Medical Center Nijmegen, Nijmegen, The NetherlandsNetherlands Cancer InstituteAmsterdam, The Netherlands.
authors.forename: Kui
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of EpidemiologyR217JDepartment of BiostatisticsSchool of Public Health, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, Alabama 35294-0022, USADepartment of Human GeneticsRadboud University Medical Center Nijmegen, Nijmegen, The NetherlandsNetherlands Cancer InstituteAmsterdam, The Netherlands.
authors.forename: Arjen R
authors.initials: AR
authors.lastname: Mensenkamp
authors.affiliation: Department of EpidemiologyR217JDepartment of BiostatisticsSchool of Public Health, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, Alabama 35294-0022, USADepartment of Human GeneticsRadboud University Medical Center Nijmegen, Nijmegen, The NetherlandsNetherlands Cancer InstituteAmsterdam, The Netherlands.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Menko
authors.affiliation: Department of EpidemiologyR217JDepartment of BiostatisticsSchool of Public Health, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, Alabama 35294-0022, USADepartment of Human GeneticsRadboud University Medical Center Nijmegen, Nijmegen, The NetherlandsNetherlands Cancer InstituteAmsterdam, The Netherlands.
authors.forename: Howard W
authors.initials: HW
authors.lastname: Wiener
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D002878:Chromosomes, Human, Pair 1; D005260:Female; D005649:Fumarate Hydratase / Q000235:genetics*; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007889:Leiomyoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020710:RGS Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding; D047368:Tumor Burden; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology; D044465:White People / Q000235:genetics
chemical_list: D020710:RGS Proteins; C492039:RGS7 protein, human; D062085:RNA, Long Noncoding; D005649:Fumarate Hydratase
keywords: FH; HLRCC; PLD5; RGS7; fumarate hydratase; uterine fibroids