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.

Keywords: FH; HLRCC; PLD5; RGS7; fumarate hydratase; uterine fibroids.

Figure 1

Fine mapping of chromosome 1q43 variants associated with risk and size of uterine fibroids in the NIEHS uterine fibroid study. The plot shows the strength of association (expressed as minus log10 of P value) between 1780 quality control-filtered single nucleotide polymorphisms (SNPs) and uterine fibroid outcomes (filled diamonds: risk; empty circles: tumor size including controls as the category with the lowest level; empty triangles: tumor size in case-only design) obtained for a pooled sample (525 African American and 391 European American individuals) using logistic regression models with adjustments for covariates (age, age-at-menarche, parity, BMI and physical activity) and for SNP by race interaction term.

Figure 2

Genomic annotation of the candidate uterine leiomyoma locus on human chromosome 1q43. The genomic map shows the location of the single nucleotide polymorphism (SNP) sites at which the association with risk of uterine leiomyoma (UL) peaked in the pooled analysis (rs2341938) and meta-analysis (rs78220092) between centromeric (cen) regulator of G-protein signaling 7 (RGS7) and telomeric (tel) fumarate hydratase (FH). The map shows also the relative location of lnc-RNA TCONS_l2_00000923 containing the SNP (rs1891129) associated with UL and with FH expression in peripheral blood mononuclear cells.