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Horm Metab Res 2011; 43(6): 427-432
DOI: 10.1055/s-0031-1273761
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Lipin 1 Gene Polymorphisms in Polycystic Ovary Syndrome

B. Mlinar1 , P. Ferk2 , 3 , M. Pfeifer4 , K. Geršak2 , J. Marc1
  • 1Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
  • 2Department of Obstetrics and Gynaecology, University Medical Centre Ljubljana, Ljubljana, Slovenia
  • 3Present address: Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
  • 4Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia
Further Information

Publication History

received 27.09.2010

accepted 15.02.2011

Publication Date:
29 March 2011 (online)

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Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with increased prevalence of insulin resistance (IR). IR could be implicated in PCOS etiology and represents the major cause of cardiometabolic complications. The aim of present study was to investigate for the first time the association of lipin 1 gene polymorphisms with metabolic and hormonal profile in PCOS patients and controls. Into a case-control study 371 individuals were enrolled: 222 PCOS patients and 149 controls. Two lipin 1 gene polymorphisms were analyzed: rs11693809 (intron 1 SNP) and rs2716610 (intron 17 SNP) using fluorescent hydrolyzing probes. Body mass index, fasting plasma insulin and glucose along with androgen profile were measured in all subjects. Plasma lipids were measured in 93 patients and 43 controls and oral glucose test (OGTT) was performed on 68 PCOS patients. C/T heterozygotes for intron 1 SNP had significantly lower LDL-cholesterol than wild type C/C homozygotes (p=0.026) in the control group. In PCOS patients, mutated T/T homozygotes exhibited significantly lower glucose after OGTT than heterozygotes (p=0.033). Similarly, in nonobese PCOS patients, intron 1 SNP T/T homozygotes had lower HOMA-IR than heterozygotes (p=0.009). For intron 17 SNP, mutated C/T+T/T genotypes were associated with higher plasma triglycerides in controls (p=0.039). Genotype and allele frequencies were similar between PCOS patients and controls for both SNPs. Our results show that, in PCOS patients, intron 1 SNP is protective against IR and glucose intolerance suggesting that lipin 1 variation could be one of the genetic factors in cardiometabolic complications of PCOS.

Key words

insulin resistance - PCOS - mutation - lipids - metabolic syndrome

References

  • 1 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis.  Endocr Rev. 1997;  18 774-800
    Google Scholar
  • 2 Unluturk U, Harmanci A, Kocaefe C, Yildiz BO. The Genetic Basis of the Polycystic Ovary Syndrome: A Literature Review Including Discussion of PPAR-gamma.  PPAR Res. 2007;  2007 49109
    Google Scholar
  • 3 Puder JJ, Varga S, Kraenzlin M, De Geyter C, Keller U, Muller B. Central fat excess in polycystic ovary syndrome: relation to low-grade inflammation and insulin resistance.  J Clin Endocrinol Metab. 2005;  90 6014-6021
    Google Scholar
  • 4 Mlinar B, Marc J, Janez A, Pfeifer M. Molecular mechanisms of insulin resistance and associated diseases.  Clin Chim Acta. 2007;  375 20-35
    Google Scholar
  • 5 Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, Perusse L, Bouchard C. The human obesity gene map: the 2005 update.  Obesity (Silver Spring). 2006;  14 529-644
    Google Scholar
  • 6 Donkor J, Sariahmetoglu M, Dewald J, Brindley DN, Reue K. Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns.  J Biol Chem. 2007;  282 3450-3457
    Google Scholar
  • 7 Peterfy M, Phan J, Xu P, Reue K. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin.  Nat Genet. 2001;  27 121-124
    Google Scholar
  • 8 Zeharia A, Shaag A, Houtkooper RH, Hindi T, de Lonlay P, Erez G, Hubert L, Saada A, de Keyzer Y, Eshel G, Vaz FM, Pines O, Elpeleg O. Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood.  Am J Hum Genet. 2008;  83 489-494
    Google Scholar
  • 9 Cao H, Hegele RA. Identification of single-nucleotide polymorphisms in the human LPIN1 gene.  J Hum Genet. 2002;  47 370-372
    Google Scholar
  • 10 Suviolahti E, Reue K, Cantor RM, Phan J, Gentile M, Naukkarinen J, Soro-Paavonen A, Oksanen L, Kaprio J, Rissanen A, Salomaa V, Kontula K, Taskinen MR, Pajukanta P, Peltonen L. Cross-species analyses implicate Lipin 1 involvement in human glucose metabolism.  Hum Mol Genet. 2006;  15 377-386
    Google Scholar
  • 11 Wiedmann S, Fischer M, Koehler M, Neureuther K, Riegger G, Doering A, Schunkert H, Hengstenberg C, Baessler A. Genetic variants within the LPIN1 gene, encoding lipin, are influencing phenotypes of the metabolic syndrome in humans.  Diabetes. 2008;  57 209-217
    Google Scholar
  • 12 Loos RJ, Rankinen T, Perusse L, Tremblay A, Despres JP, Bouchard C. Association of lipin 1 gene polymorphisms with measures of energy and glucose metabolism.  Obesity (Silver Spring). 2007;  15 2723-2732
    Google Scholar
  • 13 Reue K. The lipin family: mutations and metabolism.  Curr Opin Lipidol. 2009;  20 165-170
    Google Scholar
  • 14 Fawcett KA, Grimsey N, Loos RJ, Wheeler E, Daly A, Soos M, Semple R, Syddall H, Cooper C, Siniossoglou S, O’Rahilly S, Wareham NJ, Barroso I. Evaluating the role of LPIN1 variation in insulin resistance, body weight, and human lipodystrophy in UK Populations.  Diabetes. 2008;  57 2527-2533
    Google Scholar
  • 15 Peterfy M, Phan J, Reue K. Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis.  J Biol Chem. 2005;  280 32883-32889
    Google Scholar
  • 16 Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence Jr JC, Kelly DP. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway.  Cell Metab. 2006;  4 199-210
    Google Scholar
  • 17 Donkor J, Sparks LM, Xie H, Smith SR, Reue K. Adipose Tissue Lipin-1 Expression Is Correlated with Peroxisome Proliferator-Activated Receptor {alpha} Gene Expression and Insulin Sensitivity in Healthy Young Men.  J Clin Endocrinol Metab. 2008;  93 233-239
    Google Scholar
  • 18 Yao-Borengasser A, Rasouli N, Varma V, Miles LM, Phanavanh B, Starks TN, Phan J, Spencer HJ, McGehee Jr RE, Reue K, Kern PA 3rd. Lipin expression is attenuated in adipose tissue of insulin-resistant human subjects and increases with peroxisome proliferator-activated receptor gamma activation.  Diabetes. 2006;  55 2811-2818
    Google Scholar
  • 19 van Harmelen V, Ryden M, Sjolin E, Hoffstedt J. A role of lipin in human obesity and insulin resistance: relation to adipocyte glucose transport and GLUT4 expression.  J Lipid Res. 2007;  48 201-206
    Google Scholar
  • 20 Mlinar B, Pfeifer M, Vrtacnik-Bokal E, Jensterle M, Marc J. Decreased lipin 1 beta expression in visceral adipose tissue is associated with insulin resistance in polycystic ovary syndrome.  Eur J Endocrinol. 2008;  159 833-839
    Google Scholar
  • 21 Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach.. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR (eds).Polycystic ovary syndrome Boston, MA: Blackwell Scientific Publications; 1992: 377-384
    Google Scholar
  • 22 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
    Google Scholar
  • 23 den Dunnen JT, Antonarakis SE. Nomenclature for the description of human sequence variations.  Hum Genet. 2001;  109 121-124
    Google Scholar
  • 24 Zhao JH. 2LD, GENECOUNTING and HAP: computer programs for linkage disequilibrium analysis.  Bioinformatics. 2004;  20 1325-1326
    Google Scholar
  • 25 Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data.  Am J Hum Genet. 2001;  68 978-989
    Google Scholar
  • 26 Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLINK: a tool set for whole-genome association and population-based linkage analyses.  Am J Hum Genet. 2007;  81 559-575
    Google Scholar
  • 27 Ong KL, Leung RY, Wong LY, Cherny SS, Sham PC, Lam TH, Lam KS, Cheung BM. Association of a polymorphism in the lipin 1 gene with systolic blood pressure in men.  Am J Hypertens. 2008;  21 539-545
    Google Scholar
  • 28 Bou Khalil M, Blais A, Figeys D, Yao Z. Lipin – The bridge between hepatic glycerolipid biosynthesis and lipoprotein metabolism.  Biochim Biophys Acta. 2010;  1801 1249-1259
    Google Scholar
  • 29 Bou Khalil M, Sundaram M, Zhang HY, Links PH, Raven JF, Manmontri B, Sariahmetoglu M, Tran K, Reue K, Brindley DN, Yao Z. The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL.  J Lipid Res. 2009;  50 47-58
    Google Scholar
  • 30 Rhee J, Ge H, Yang W, Fan M, Handschin C, Cooper M, Lin J, Li C, Spiegelman BM. Partnership of PGC-1alpha and HNF4alpha in the regulation of lipoprotein metabolism.  J Biol Chem. 2006;  281 14683-14690
    Google Scholar
  • 31 Michot C, Hubert L, Brivet M, De Meirleir L, Valayannopoulos V, Muller-Felber W, Venkateswaran R, Ogier H, Desguerre I, Altuzarra C, Thompson E, Smitka M, Huebner A, Husson M, Horvath R, Chinnery P, Vaz FM, Munnich A, Elpeleg O, Delahodde A, de Keyzer Y, de Lonlay P. LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.  Hum Mutat. 2010;  31 E1564-E1573
    Google Scholar
  • 32 Liu L, Shi X, Choi CS, Shulman GI, Klaus K, Nair KS, Schwartz GJ, Zhang Y, Goldberg IJ, Yu YH. Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1.  Diabetes. 2009;  58 2516-2524
    Google Scholar

Correspondence

B. Mlinar

Department of Clinical

Biochemistry

Faculty of Pharmacy

University of Ljubljana

Aškerčeva 7

1000 Ljubljana

Slovenia

Phone: +386/1/4769 630

Fax: +386/1/4258 031

Email: barbara.mlinar@ffa.uni-lj.si