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Semin Reprod Med 2016; 34(04): 235-241
DOI: 10.1055/s-0036-1585401
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Genetic Association Studies in Uterine Fibroids: Risk Alleles Presage the Path to Personalized Therapies

C. Scott Gallagher
1   Department of Genetics, Harvard Medical School, Boston, Massachusetts
,
Cynthia C. Morton
2   Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts
3   Department of Pathology, Harvard Medical School, Boston, Massachusetts
4   Broad Institute of MIT and Harvard, Cambridge, Massachusetts
5   Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
› Author Affiliations
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Publication History

Publication Date:
11 August 2016 (online)

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Abstract

Uterine leiomyoma (UL) is the most common tumor of the female reproductive system. Epidemiological analyses, including familial aggregation, twin studies, and racial discrepancies in disease prevalence and morbidity, indicated genetic factors influence risk for developing UL. Genome-wide association studies (GWASs) are a powerful method for identifying genetic variants that are associated with elevated risk for a common, complex disease. To date, three genome-wide scans for UL have been performed: a GWAS in Japanese women, a genome-wide linkage and association study in women of European decent, and an admixture-based analysis in African American women. Results from each of the three genome-wide scans performed have had varying success in identifying unique loci associated with predisposition to developing UL. Here, we address the evidence for a genetic basis for UL risk, discuss genetic association studies and their results, and identify challenges and future directions for UL GWAS analyses.

Keywords

uterine leiomyomata - genetic association - complex diseases
 

  • References

  • 1 Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 2003; 188 (1) 100-107
    CrossrefPubMedGoogle Scholar
  • 2 Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990; 94 (4) 435-438
    CrossrefPubMedGoogle Scholar
  • 3 Borah BJ, Nicholson WK, Bradley L, Stewart EA. The impact of uterine leiomyomas: a national survey of affected women. Am J Obstet Gynecol 2013; 209 (4) 319.e1-319.e20
    CrossrefPubMedGoogle Scholar
  • 4 Buttram Jr VC, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 1981; 36 (4) 433-445
    PubMedGoogle Scholar
  • 5 Coronado GD, Marshall LM, Schwartz SM. Complications in pregnancy, labor, and delivery with uterine leiomyomas: a population-based study. Obstet Gynecol 2000; 95 (5) 764-769
    CrossrefPubMedGoogle Scholar
  • 6 Stewart EA. Uterine fibroids. Lancet 2001; 357 (9252) 293-298
    CrossrefPubMedGoogle Scholar
  • 7 Merrill RM. Hysterectomy surveillance in the United States, 1997 through 2005. Med Sci Monit 2008; 14 (1) CR24-CR31
    PubMedGoogle Scholar
  • 8 Merrill RM, Layman AB, Oderda G, Asche C. Risk estimates of hysterectomy and selected conditions commonly treated with hysterectomy. Ann Epidemiol 2008; 18 (3) 253-260
    CrossrefPubMedGoogle Scholar
  • 9 Fedele L, Parazzini F, Luchini L, Mezzopane R, Tozzi L, Villa L. Recurrence of fibroids after myomectomy: a transvaginal ultrasonographic study. Hum Reprod 1995; 10 (7) 1795-1796
    CrossrefPubMedGoogle Scholar
  • 10 Gross KL, Morton CC. Genetics and the development of fibroids. Clin Obstet Gynecol 2001; 44 (2) 335-349
    CrossrefPubMedGoogle Scholar
  • 11 Hodge JC, Kim TM, Dreyfuss JM , et al. Expression profiling of uterine leiomyomata cytogenetic subgroups reveals distinct signatures in matched myometrium: transcriptional profiling of the t(12;14) and evidence in support of predisposing genetic heterogeneity. Hum Mol Genet 2012; 21 (10) 2312-2329
    CrossrefPubMedGoogle Scholar
  • 12 Mäkinen N, Mehine M, Tolvanen J , et al. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science 2011; 334 (6053) 252-255
    CrossrefPubMedGoogle Scholar
  • 13 Rein MS, Powell WL, Walters FC , et al. Cytogenetic abnormalities in uterine myomas are associated with myoma size. Mol Hum Reprod 1998; 4 (1) 83-86
    CrossrefPubMedGoogle Scholar
  • 14 Meloni AM, Surti U, Contento AM, Davare J, Sandberg AA. Uterine leiomyomas: cytogenetic and histologic profile. Obstet Gynecol 1992; 80 (2) 209-217
    PubMedGoogle Scholar
  • 15 Quade BJ, Weremowicz S, Neskey DM , et al. Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15. Cancer Res 2003; 63 (6) 1351-1358
    PubMedGoogle Scholar
  • 16 Vikhlyaeva EM, Khodzhaeva ZS, Fantschenko ND. Familial predisposition to uterine leiomyomas. Int J Gynaecol Obstet 1995; 51 (2) 127-131
    CrossrefPubMedGoogle Scholar
  • 17 Sato F, Mori M, Nishi M, Kudo R, Miyake H. Familial aggregation of uterine myomas in Japanese women. J Epidemiol 2002; 12 (3) 249-253
    CrossrefPubMedGoogle Scholar
  • 18 Van Voorhis BJ, Romitti PA, Jones MP. Family history as a risk factor for development of uterine leiomyomas. Results of a pilot study. J Reprod Med 2002; 47 (8) 663-669
    PubMedGoogle Scholar
  • 19 D'Aloisio AA, Baird DD, DeRoo LA, Sandler DP. Early-life exposures and early-onset uterine leiomyomata in black women in the Sister Study. Environ Health Perspect 2012; 120 (3) 406-412
    PubMedGoogle Scholar
  • 20 Greathouse KL, Cook JD, Lin K , et al. Identification of uterine leiomyoma genes developmentally reprogrammed by neonatal exposure to diethylstilbestrol. Reprod Sci 2008; 15 (8) 765-778
    CrossrefPubMedGoogle Scholar
  • 21 Segars JH, Parrott EC, Nagel JD , et al. Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations. Hum Reprod Update 2014; 20 (3) 309-333
    CrossrefPubMedGoogle Scholar
  • 22 Treloar SA, Martin NG, Dennerstein L, Raphael B, Heath AC. Pathways to hysterectomy: insights from longitudinal twin research. Am J Obstet Gynecol 1992; 167 (1) 82-88
    CrossrefPubMedGoogle Scholar
  • 23 Luoto R, Kaprio J, Rutanen EM, Taipale P, Perola M, Koskenvuo M. Heritability and risk factors of uterine fibroids—the Finnish Twin Cohort study. Maturitas 2000; 37 (1) 15-26
    CrossrefPubMedGoogle Scholar
  • 24 Marshall LM, Spiegelman D, Barbieri RL , et al. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol 1997; 90 (6) 967-973
    CrossrefPubMedGoogle Scholar
  • 25 Faerstein E, Szklo M, Rosenshein N. Risk factors for uterine leiomyoma: a practice-based case-control study. I. African-American heritage, reproductive history, body size, and smoking. Am J Epidemiol 2001; 153 (1) 1-10
    CrossrefPubMedGoogle Scholar
  • 26 Faerstein E, Szklo M, Rosenshein NB. Risk factors for uterine leiomyoma: a practice-based case-control study. II. Atherogenic risk factors and potential sources of uterine irritation. Am J Epidemiol 2001; 153 (1) 11-19
    CrossrefPubMedGoogle Scholar
  • 27 Eltoukhi HM, Modi MN, Weston M, Armstrong AY, Stewart EA. The health disparities of uterine fibroid tumors for African American women: a public health issue. Am J Obstet Gynecol 2014; 210 (3) 194-199
    CrossrefPubMedGoogle Scholar
  • 28 Huyck KL, Panhuysen CI, Cuenco KT , et al. The impact of race as a risk factor for symptom severity and age at diagnosis of uterine leiomyomata among affected sisters. Am J Obstet Gynecol 2008; 198 (2) 168.e1-168.e9
    CrossrefPubMedGoogle Scholar
  • 29 Kjerulff KH, Langenberg P, Seidman JD, Stolley PD, Guzinski GM. Uterine leiomyomas. Racial differences in severity, symptoms and age at diagnosis. J Reprod Med 1996; 41 (7) 483-490
    PubMedGoogle Scholar
  • 30 Chen CR, Buck GM, Courey NG, Perez KM, Wactawski-Wende J. Risk factors for uterine fibroids among women undergoing tubal sterilization. Am J Epidemiol 2001; 153 (1) 20-26
    CrossrefPubMedGoogle Scholar
  • 31 Launonen V, Vierimaa O, Kiuru M , et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 2001; 98 (6) 3387-3392
    CrossrefPubMedGoogle Scholar
  • 32 Reed WB, Walker R, Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol 1973; 53 (5) 409-416
    PubMedGoogle Scholar
  • 33 Thyresson HN, Su WP. Familial cutaneous leiomyomatosis. J Am Acad Dermatol 1981; 4 (4) 430-434
    CrossrefPubMedGoogle Scholar
  • 34 Cha PC, Takahashi A, Hosono N , et al. A genome-wide association study identifies three loci associated with susceptibility to uterine fibroids. Nat Genet 2011; 43 (5) 447-450
    CrossrefPubMedGoogle Scholar
  • 35 Eggert SL, Huyck KL, Somasundaram P , et al. Genome-wide linkage and association analyses implicate FASN in predisposition to uterine leiomyomata. Am J Hum Genet 2012; 91 (4) 621-628
    CrossrefPubMedGoogle Scholar
  • 36 Wise LA, Ruiz-Narvaez EA, Palmer JR , et al. African ancestry and genetic risk for uterine leiomyomata. Am J Epidemiol 2012; 176 (12) 1159-1168
    CrossrefPubMedGoogle Scholar
  • 37 Marsh EE, Lin Z, Yin P, Milad M, Chakravarti D, Bulun SE. Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium. Fertil Steril 2008; 89 (6) 1771-1776
    CrossrefPubMedGoogle Scholar
  • 38 Kim HS, Patel K, Muldoon-Jacobs K , et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 2010; 17 (1) 41-52
    CrossrefPubMedGoogle Scholar
  • 39 Edwards TL, Hartmann KE, Velez Edwards DR. Variants in BET1L and TNRC6B associate with increasing fibroid volume and fibroid type among European Americans. Hum Genet 2013; 132 (12) 1361-1369
    CrossrefPubMedGoogle Scholar
  • 40 Edwards TL, Michels KA, Hartmann KE, Velez Edwards DR. BET1L and TNRC6B associate with uterine fibroid risk among European Americans. Hum Genet 2013; 132 (8) 943-953
    CrossrefPubMedGoogle Scholar
  • 41 Hodge JC, T. Cuenco K, Huyck KL , et al. Uterine leiomyomata and decreased height: a common HMGA2 predisposition allele. Hum Genet 2009; 125 (3) 257-263
    CrossrefPubMedGoogle Scholar
  • 42 Alli PM, Pinn ML, Jaffee EM, McFadden JM, Kuhajda FP. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene 2005; 24 (1) 39-46
    CrossrefPubMedGoogle Scholar
  • 43 Lupu R, Menendez JA. Pharmacological inhibitors of Fatty Acid Synthase (FASN)—catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents?. Curr Pharm Biotechnol 2006; 7 (6) 483-493
    CrossrefPubMedGoogle Scholar