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Clinical Trial
. 2013;8(3):e58399.
doi: 10.1371/journal.pone.0058399. Epub 2013 Mar 14.

Multiple Hits for the Association of Uterine Fibroids on Human Chromosome 1q43

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Free PMC article
Clinical Trial

Multiple Hits for the Association of Uterine Fibroids on Human Chromosome 1q43

Brahim Aissani et al. PLoS One. .
Free PMC article

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Abstract

Uterine leiomyomas (or fibroids) are the most common tumors in women of reproductive age. Early studies of two familial cancer syndromes, the multiple cutaneous and uterine leiomyomatosis (MCUL1), and the hereditary leiomyomatosis and renal cell cancer (HLRCC), implicated FH, a gene on chromosome 1q43 encoding the tricarboxylic acid cycle fumarate hydratase enzyme. The role of this metabolic housekeeping gene in tumorigenesis is still a matter of debate and pseudo-hypoxia has been suggested as a pathological mechanism. Inactivating FH mutations have rarely been observed in the nonsyndromic and common form of fibroids; however, loss of heterozygosity across FH appeared as a significant event in the pathogenesis of a subset of these tumors. To assess the role of FH and the linked genes in nonsyndromic uterine fibroids, we explored a two-megabase interval spanning FH in the NIEHS Uterine fibroid study, a cross-sectional study of fibroids in 1152 premenopausal women. Association mapping with a dense set of single nucleotide polymorphisms revealed several peaks of association (p = 10(-2)-8.10(-5)) with the risk and/or growth of fibroids. In particular, genes encoding factors suspected (cytosolic FH) or known (EXO1 - exonuclease 1) to be involved in DNA mismatch repair emerged as candidate susceptibility genes whereas those acting in the autophagy/apoptosis (MAP1LC3C - microtubule-associated protein) or signal transduction (RGS7 - Regulator of G-protein and PLD5- Phospoholipase D) appeared to affect tumor growth. Furthermore, body mass index, a suspected confounder altered significantly but unpredictably the association with the candidate genes in the African and European American populations, suggesting the presence of a major obesity gene in the studied region. With the high potential for occult tumors in common conditions such as fibroids, validation of our data in family-based studies is needed.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Association of chromosome 1q43 single nucleotide polymorphisms with the risk of uterine leiomyomas (unadjusted models).
P-values for 2 d.f. tests from dichotomous logistic regression models adjusted for the only effect of age are reported separately for the African Americans (AA) and European Americans (EA) study groups. Because of the high correlations among the tightly linked SNPs, the p-values are not corrected for multiple testing. The placement of the genes in the gene map shown above the plot and the coordinates show below were derivedthe Human Genome assembly 19. Arrows indicate the orientation of the genes and are drawn proportionally to the size of the genes. RGS7 (regulator of Gprotein 7); FH (fumarate hydratase); KMO (kynurenine 3monooxygenase); OPN3 (opsin 3); WDR64 (WD repeat domain 64); EXO1 (exonuclease 1); MAP1LC3C (microtubuleassociated protein 1 light chain 3 gamma); PLD5 (phospholipase D family, member 5).
Figure 2
Figure 2. Association of chromosome 1q43 single nucleotide polymorphisms with the risk of uterine leiomyomas
(full models). P-values are from dichotomous logistic regression models adjusted for age, age at menarche, parity, physical activity and body mass index (BMI). BMI and physical activity were modeled as four-level variables and age at menarche and parity as two-level variables. Other details are as described in Fig. 1.
Figure 3
Figure 3. Association of chromosome 1q43 single nucleotide polymorphisms with the growth of uterine leiomyomas (affected-only design and full models).
P-values are derived from polytomous logistic regression models with adjustment for the covariates as described in Fig. 2.
Figure 4
Figure 4. Colocalization of human traits of potential relevance to uterine fibroids on human chromosome 1q43.
Genomic map of a 2 megabase-long interval spanning the fumarate hydratase (FH) gene and showing the position of specific microsatellite markers (vertical bars) and gene loci linked or associated with diseases or traits of relevance to hormone-dependent tumors such as uterine leiomyomas. QFS (Quebec family study); SHBG (sex hormone binding globulin); HERITAGE (HERITAGE family study). Other details are as described in Fig. 1.

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