Skip to main content

Advertisement

SpringerLink
Log in

Uterine leiomyomata and decreased height: a common HMGA2 predisposition allele

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Uterine leiomyomata (UL) are the most common female pelvic tumors and the primary indication for hysterectomy in the United States. We assessed genetic liability for UL by a known embryonic proliferation modulator, HMGA2, in 248 families ascertained through medical record-confirmed affected sister-pairs. Using a (TC) n repeat in the 5′ UTR and 17 SNPs spanning HMGA2, permutation-based association tests identified a significant increase in transmission of a single TC repeat allele (TC227) with UL (allele-specific P = 0.00005, multiple testing corrected min-P = 0.0049). The hypothesis that TC227 is a pathogenic variant is supported by a trend towards higher HMGA2 expression in TC227 allele-positive compared with non-TC227 UL tissue as well as by absence of culpable exonic sequence variants. HMGA2 has also been suggested recently by three genome-wide SNP studies to influence human height variation, and our examination of the affected sister-pair families revealed a significant association of TC227 with decreased height (allele-specific P = 0.00033, multiple testing corrected min-P = 0.016). Diminished stature and elevated risk of UL development have both been correlated with an earlier age of menarche, which may be the biological mechanism for TC227 effects as a tendency of women with TC227 to have an earlier onset of menarche was identified in our study population. These results indicate HMGA2 has a role in two growth-related phenotypes, UL predisposition and height, of which the former may affect future medical management decisions for many women.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abecasis GR, Cookson WO (2000) GOLD—graphical overview of linkage disequilibrium. Bioinformatics 16:182–183

    Article  PubMed  CAS  Google Scholar 

  • Borrmann L, Seebeck B, Rogalla P, Bullerdiek J (2003) Human HMGA2 promoter is coregulated by a polymorphic dinucleotide (TC)-repeat. Oncogene 22:756–760

    Article  PubMed  CAS  Google Scholar 

  • Buttram VC Jr, Reiter RC (1981) Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 36:433–445

    PubMed  Google Scholar 

  • Chiba-Falek O, Nussbaum RL (2001) Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet 10:3101–3109

    Article  PubMed  CAS  Google Scholar 

  • Cramer SF, Patel A (1990) The frequency of uterine leiomyomas. Am J Clin Pathol 94:435–438

    PubMed  CAS  Google Scholar 

  • Flynn M, Jamison M, Datta S, Myers E (2006) Health care resource use for uterine fibroid tumors in the United States. Am J Obstet Gynecol 195:955–964

    Article  PubMed  Google Scholar 

  • Gattas GJ, Quade BJ, Nowak RA, Morton CC (1999) HMGIC expression in human adult and fetal tissues and in uterine leiomyomata. Genes Chromosomes Cancer 25:316–322

    Article  PubMed  CAS  Google Scholar 

  • Gross KL, Neskey DM, Manchanda N, Weremowicz S, Kleinman MS, Nowak RA, Ligon AH, Rogalla P, Drechsler K, Bullerdiek J, Morton CC (2003) HMGA2 expression in uterine leiomyomata and myometrium: quantitative analysis and tissue culture studies. Genes Chromosomes Cancer 38:68–79

    Article  PubMed  CAS  Google Scholar 

  • Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, Sulem P, Thorlacius S, Gylfason A, Steinberg S, Helgadottir A, Ingason A, Steinthorsdottir V, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Pedersen O, Aben KK, Witjes JA, Swinkels DW, den Heijer M, Franke B, Verbeek AL, Becker DM, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Gulcher J, Kiemeney LA, Kong A, Thorsteinsdottir U, Stefansson K (2008) Many sequence variants affecting diversity of adult human height. Nat Genet 40:609–615

    Article  PubMed  CAS  Google Scholar 

  • Hartmann KE, Birnbaum H, Ben-Hamadi R, Wu EQ, Farrell MH, Spalding J, Stang P (2006) Annual costs associated with diagnosis of uterine leiomyomata. Obstet Gynecol 108:930–937

    Article  PubMed  Google Scholar 

  • Hirning-Folz U, Wilda M, Rippe V, Bullerdiek J, Hameister H (1998) The expression pattern of the Hmgic gene during development. Genes Chromosomes Cancer 23:350–357

    Article  PubMed  CAS  Google Scholar 

  • Huyck KL, Panhuysen CI, Cuenco KT, Zhang J, Goldhammer H, Jones ES, Somasundaram P, Lynch AM, Harlow BL, Lee H, Stewart EA, Morton CC (2008) 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 198(168):e161–e169

    Google Scholar 

  • Ishwad CS, Shriver MD, Lassige DM, Ferrell RE (1997) The high mobility group I-C gene (HMGI-C): polymorphism and genetic localization. Hum Genet 99:103–105

    Article  PubMed  CAS  Google Scholar 

  • Klotzbucher M, Wasserfall A, Fuhrmann U (1999) Misexpression of wild-type and truncated isoforms of the high-mobility group I proteins HMGI-C and HMGI(Y) in uterine leiomyomas. Am J Pathol 155:1535–1542

    PubMed  CAS  Google Scholar 

  • Kurbanova M, Koroleva AG, Sergeev AS (1989) Genetic-epidemiologic analysis of uterine myoma: assessment of repeated risk. Genetika 25:1896–1898

    PubMed  Google Scholar 

  • Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R, Aaltonen LA (2001) Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA 98:3387–3392

    Article  PubMed  CAS  Google Scholar 

  • Lee YS, Dutta A (2007) The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21:1025–1030

    Article  PubMed  CAS  Google Scholar 

  • Lepine LA, Hillis SD, Marchbanks PA, Koonin LM, Morrow B, Kieke BA, Wilcox LS (1997) Hysterectomy surveillance—United States, 1980–1993. MMWR CDC Surveill Summ 46:1–15

    PubMed  CAS  Google Scholar 

  • Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, Eyheramendy S, Voight BF, Butler JL, Guiducci C, Illig T, Hackett R, Heid IM, Jacobs KB, Lyssenko V, Uda M, Boehnke M, Chanock SJ, Groop LC, Hu FB, Isomaa B, Kraft P, Peltonen L, Salomaa V, Schlessinger D, Hunter DJ, Hayes RB, Abecasis GR, Wichmann HE, Mohlke KL, Hirschhorn JN (2008) Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 40:584–591

    Article  PubMed  CAS  Google Scholar 

  • Luoto R, Kaprio J, Rutanen EM, Taipale P, Perola M, Koskenvuo M (2000) Heritability and risk factors of uterine fibroids—the Finnish Twin Cohort study. Maturitas 37:15–26

    Article  PubMed  CAS  Google Scholar 

  • Marshall LM, Spiegelman D, Goldman MB, Manson JE, Colditz GA, Barbieri RL, Stampfer MJ, Hunter DJ (1998) A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata. Fertil Steril 70:432–439

    Article  PubMed  CAS  Google Scholar 

  • Moore SD, Herrick SR, Ince TA, Kleinman MS, Cin PD, Morton CC, Quade BJ (2004) Uterine leiomyomata with t(10;17) disrupt the histone acetyltransferase MORF. Cancer Res 64:5570–5577

    Article  PubMed  CAS  Google Scholar 

  • Okladnova O, Syagailo YV, Tranitz M, Stober G, Riederer P, Mossner R, Lesch KP (1998) A promoter-associated polymorphic repeat modulates PAX–6 expression in human brain. Biochem Biophys Res Commun 248:402–405

    Article  PubMed  CAS  Google Scholar 

  • Onland-Moret NC, Peeters PH, van Gils CH, Clavel-Chapelon F, Key T, Tjonneland A, Trichopoulou A, Kaaks R, Manjer J, Panico S, Palli D, Tehard B, Stoikidou M, Bueno-De-Mesquita HB, Boeing H, Overvad K, Lenner P, Quiros JR, Chirlaque MD, Miller AB, Khaw KT, Riboli E (2005) Age at menarche in relation to adult height: the EPIC study. Am J Epidemiol 162:623–632

    Article  PubMed  CAS  Google Scholar 

  • Perola M, Sammalisto S, Hiekkalinna T, Martin NG, Visscher PM, Montgomery GW, Benyamin B, Harris JR, Boomsma D, Willemsen G, Hottenga JJ, Christensen K, Kyvik KO, Sorensen TI, Pedersen NL, Magnusson PK, Spector TD, Widen E, Silventoinen K, Kaprio J, Palotie A, Peltonen L (2007) Combined genome scans for body stature in 6, 602 European twins: evidence for common Caucasian loci. PLoS Genet 3:e97

    Article  PubMed  CAS  Google Scholar 

  • Rabinowitz D (1997) A transmission disequilibrium test for quantitative trait loci. Hum Hered 47:342–350

    Article  PubMed  CAS  Google Scholar 

  • Rabinowitz D, Laird N (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 50:211–223

    Article  PubMed  CAS  Google Scholar 

  • Reed WB, Walker R, Horowitz R (1973) Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol 53:409–416

    PubMed  CAS  Google Scholar 

  • Rein MS, Friedman AJ, Barbieri RL, Pavelka K, Fletcher JA, Morton CC (1991) Cytogenetic abnormalities in uterine leiomyomata. Obstet Gynecol 77:923–926

    PubMed  CAS  Google Scholar 

  • Sanna S, Jackson AU, Nagaraja R, Willer CJ, Chen WM, Bonnycastle LL, Shen H, Timpson N, Lettre G, Usala G, Chines PS, Stringham HM, Scott LJ, Dei M, Lai S, Albai G, Crisponi L, Naitza S, Doheny KF, Pugh EW, Ben-Shlomo Y, Ebrahim S, Lawlor DA, Bergman RN, Watanabe RM, Uda M, Tuomilehto J, Coresh J, Hirschhorn JN, Shuldiner AR, Schlessinger D, Collins FS, Davey Smith G, Boerwinkle E, Cao A, Boehnke M, Abecasis GR, Mohlke KL (2008) Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40:198–203

    Article  PubMed  CAS  Google Scholar 

  • Searle S, Blackwell JM (1999) Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility. J Med Genet 36:295–299

    PubMed  CAS  Google Scholar 

  • Shimajiri S, Arima N, Tanimoto A, Murata Y, Hamada T, Wang KY, Sasaguri Y (1999) Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene. FEBS Lett 455:70–74

    Article  PubMed  CAS  Google Scholar 

  • Snieder H, MacGregor AJ, Spector TD (1998) Genes control the cessation of a woman’s reproductive life: a twin study of hysterectomy and age at menopause. J Clin Endocrinol Metab 83:1875–1880

    Article  PubMed  CAS  Google Scholar 

  • Stewart EA, Morton CC (2006) The genetics of uterine leiomyomata: what clinicians need to know. Obstet Gynecol 107:917–921

    PubMed  Google Scholar 

  • Treloar SA, Martin NG, Dennerstein L, Raphael B, Heath AC (1992) Pathways to hysterectomy: insights from longitudinal twin research. Am J Obstet Gynecol 167:82–88

    PubMed  CAS  Google Scholar 

  • Weedon MN, Lettre G, Freathy RM, Lindgren CM, Voight BF, Perry JR, Elliott KS, Hackett R, Guiducci C, Shields B, Zeggini E, Lango H, Lyssenko V, Timpson NJ, Burtt NP, Rayner NW, Saxena R, Ardlie K, Tobias JH, Ness AR, Ring SM, Palmer CN, Morris AD, Peltonen L, Salomaa V, Davey Smith G, Groop LC, Hattersley AT, McCarthy MI, Hirschhorn JN, Frayling TM (2007) A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet 39:1245–1250

    Article  PubMed  CAS  Google Scholar 

  • Yamada N, Yamaya M, Okinaga S, Nakayama K, Sekizawa K, Shibahara S, Sasaki H (2000) Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema. Am J Hum Genet 66:187–195

    Article  PubMed  CAS  Google Scholar 

  • Zhou X, Benson KF, Ashar HR, Chada K (1995) Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature 376:771–774

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Weining Lu for real-time PCR instruction, Rita Cantor for helpful comments on the manuscript, Efthymia Melista and Alison Brown for assistance with genotyping, and all the women and their families who participated in this study. This work was supported by NIH grants RO1HD046226 and RO1CA78895 (to CCM). JCH was supported by T32GM007748 and KLH by a Howard Hughes Medical Institute Predoctoral Fellowship in Biological Sciences.

Author information

Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, New Research Building Room 160, Boston, MA, 02115, USA

    Jennelle C. Hodge, Priya Somasundaram, Elizabeth A. Stewart & Cynthia C. Morton

  2. Harvard Medical School, Boston, MA, USA

    Jennelle C. Hodge, Elizabeth A. Stewart & Cynthia C. Morton

  3. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Jennelle C. Hodge

  4. Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA, USA

    Karen T.Cuenco & Carolien I. M. Panhuysen

  5. Department of Epidemiology, Boston University School of Medicine, Boston, MA, USA

    Karen T.Cuenco

  6. Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Karen T.Cuenco

  7. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Karen T.Cuenco

  8. Department of Pathology, University of Vermont, Burlington, VT, USA

    Karen L. Huyck

Authors
  1. Jennelle C. Hodge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen T.Cuenco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karen L. Huyck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Priya Somasundaram
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carolien I. M. Panhuysen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elizabeth A. Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cynthia C. Morton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cynthia C. Morton.

Additional information

J. C. Hodge and K. T.Cuenco are to be regarded as co-First Authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hodge, J.C., T.Cuenco, K., Huyck, K.L. et al. Uterine leiomyomata and decreased height: a common HMGA2 predisposition allele. Hum Genet 125, 257–263 (2009). https://doi.org/10.1007/s00439-008-0621-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-008-0621-6

Keywords

Search

Navigation