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.

Fine Mapping of the Body Fat QTL on Human Chromosome 1q43

“…Furthermore, because obesity is associated with fibroids, albeit in a complex relationship (inverse J-shaped association peaking in the overweight category) [ 14 , 37 ], models for the observed co-localization of reproduction- and body composition-related traits and diseases to chromosome 1q43 have been proposed [ 38 ]; these were i) presence of a pleiotropic adiposity gene affecting the risk for fibroids through changes to steroid bioavailability as a result of decreasing serum level of sex hormone-binding globulin, a regulation of which has been linked to a QTL locus in the RGS7 region [ 39 ], ii) LD between variants in two distinct genes with independent influences on obesity and fibroids, and iii) coordinated expression of major reproductive and metabolic genes influencing thrifty correlated phenotypes. Our recent fine mapping of the fibroid locus on 1q43 close to a long non-coding RNA (lncRNA) locus located between RGS7 and FH (fumarate hydratase) [ 16 ], and the report of co-regulated expressions of the same lncRNA and RGS7 in fibroids [ 40 ] are potentially consistent with the hypothesis of a pleiotropic RGS7 .…”

“…Several factors might have improved the power of our study to detect associations with RGS7 . First, we used a dense set of multi-population tag SNPs selected in a two-stage next-generation sequencing and genotyping study [ 13 , 16 ]; thus most of the genetic variation in the studied region in these populations is predicted to be captured by our SNP selection. Second, because all the studied individuals are randomly-selected premenopausal women in the 35–51 years range of age; the higher correlation between BMI and body fat among women compared to men [ 21 ] likely improved the power to detect the association with the correlated body fat QTL reported in QFS.…”

“…The present study was motivated by previous observations suggesting a role for this genomic region in the development of obesity and uterine leiomyoma (fibroid tumors) [ 7 , 13 , 16 , 35 , 36 ]. Furthermore, because obesity is associated with fibroids, albeit in a complex relationship (inverse J-shaped association peaking in the overweight category) [ 14 , 37 ], models for the observed co-localization of reproduction- and body composition-related traits and diseases to chromosome 1q43 have been proposed [ 38 ]; these were i) presence of a pleiotropic adiposity gene affecting the risk for fibroids through changes to steroid bioavailability as a result of decreasing serum level of sex hormone-binding globulin, a regulation of which has been linked to a QTL locus in the RGS7 region [ 39 ], ii) LD between variants in two distinct genes with independent influences on obesity and fibroids, and iii) coordinated expression of major reproductive and metabolic genes influencing thrifty correlated phenotypes.…”

“…Genotyping. Genotype data were available for a combined set of 1,902 quality control-filtered SNPs typed previously in a two-stage genetic association study [ 13 , 16 ]. Illumina® iSelect and Illumina®GoldenGate platforms (Illumina Inc., San Diego, CA) were used for SNP genotyping in the two-stage study.…”

Variants of Fumarate Hydratase Gene in Uterine Disorders: A Clinical Trial

“…Studies proposed that variants in FH or related genes may also predispose to UL; however, it is uncommon in nonsyndromic UL or fibroids. 20 Aissani reported FH mutations in 9 out of the 18 HLRCC-related UL cases and determined two missense mutations in FH in only two nonsyndromic UL cases and one control. 20 The detection rate of FH deficiency by immunohistochemistry was 1.6% in nonatypical UL, 1.8% in cellular UL, 37.3% in atypical leiomyomas, and none in the leiomyosarcomas.…”