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. 2006 Jun;1(2):117–123. doi: 10.1007/BF02829953

Association of leptin genetic polymorphism -2548 G/A with gestational diabetes mellitus

Julie Anna Bienertová Vaškú 1,, Anna Vaškú 1, Zuzana Dostálová 3, Petr Bienert 1
PMCID: PMC3454683  PMID: 18850205

Abstract

The aim of this study was to investigate possible associations of -2548 G/A polymorphism in leptin gene promoter and pregnancy-associated diseases with abnormal fetal growth such as preeclampsia and gestational diabetes. The study was also focused on whether it is rather maternal or fetal variants that determines the pathological growth status. Peripheral or cord blood samples obtained from 49 preeclamptic women and their 39 newborns, 53 healthy controls and their 53 healthy newborns and 48 patients with gestational diabetes mellitus were evaluated for leptin gene (LEP) locus -2548 genotypes. The significantly higher risk for gestational diabetes mellitus was observed in the presence of an allele (AA and AG genotypes) against carriers of GGgenotype(OR=2.84, 95%CI1.14–7.07,p=0.02). Thereisa significant risk of diabetes mellitus associated to A allele (OR=1.79, 95%CI 1.02–3.14, p=0.03). Furthermore, evaluations of preeclamptic patients’ data revealed a significant association of genotype distribution and delivery and spontaneous abortion rate, where the GG carriers performed the highest pregnancy rate while the AG carriers performed the lowest spontaneous abortion rate. Our results support the hypothesis for -2548 G/A leptin gene polymorphism involvement in ethiopathogenesis of pregnancy-associated diseases with abnormal fetal growth, especially gestational diabetes mellitus.

Key Words: Gestational Diabetes Mellitus, Leptin, Polymorphism, Preeclampsia

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References

  1. Baumann H., Morella K.K., White D.W., Dembski M., Bailon P.S., Kim H., Lai C.F., Tartaglia L.A. The full-length leptin receptor has signaling capabilities of interleukin 6-type receptors. Proceedings of the National Academy of Sciences of the United States of America. 1996;16:8374–8. doi: 10.1073/pnas.93.16.8374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bi S., Gavrilova O., Gong D.W. Identification of a placental enhancer for the human leptin gene. The Journal of biological chemistry. 1997;48:30583–8. doi: 10.1074/jbc.272.48.30583. [DOI] [PubMed] [Google Scholar]
  3. Campfield L.A., Smith F.J., Guisez Y., Devos R., Burn P. Recombinant mouse OB protein; evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269:546–9. doi: 10.1126/science.7624778. [DOI] [PubMed] [Google Scholar]
  4. Clement K., Garner C., Hager J., Philippi A., LeDuc C., Carey A., Harris T.J., Jury C., Cardon L.R., Basdevant A., Démenais F., Guy-Grand B., North M., Froguel P. Indication for linkage of the human OB gene region with extreme obesity. Diabetes. 1996;5:687–90. doi: 10.2337/diabetes.45.5.687. [DOI] [PubMed] [Google Scholar]
  5. Dornhorst A., Paterson C.M., Nicholls J.S., Wadsworth J., Chiu D.C., Elkeles R.S., Johnston D.G., Beard R.W. High prevalence of gestational diabetes in women from ethnic minority groups. Diabetic Medicine. 1992;9:820–5. doi: 10.1111/j.1464-5491.1992.tb01900.x. [DOI] [PubMed] [Google Scholar]
  6. Festa A., Shnawa N, Krugluger W., Hopmeier P., Schernthaner G., Haffner S.M. Relative hypoleptinaemia in women with mild gestational diabetes mellitus. Diabetic Medicine. 1999;8:656–62. doi: 10.1046/j.1464-5491.1999.00122.x. [DOI] [PubMed] [Google Scholar]
  7. Fox C., Esparza J., Nicolson M., Bennett P.H., Schulz L.O., Valencia M.E. Plasmaleptin concentrations in Pima Indians living in drastically different environments. Diabetes Care. 1999;3:413–7. doi: 10.2337/diacare.22.3.413. [DOI] [PubMed] [Google Scholar]
  8. Golden PL., Maccagnan TJ., Pardridge W.M. Human blood-barrier leptin receptor; binding and endocytosis in isolated human brain microvessels. Journal of Clinical Investigation. 1997;1:14–8. doi: 10.1172/JCI119125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Green E.D., Maffei M., Braden V.V. The human obese (Ob) gene — RNA expression pattern and mapping on the physical, cytogenetic, and genetic maps of chromosome. Genome Research. 1995;1:5–12. doi: 10.1101/gr.5.1.5. [DOI] [PubMed] [Google Scholar]
  10. Grosfeld A., Turban S., Andre J., Cauzac M., Challier J.C., Hauguel-de Mouzon S., Guerre-Millo M. Transcriptional effect of hypoxia on placental leptin. Federation of European Biochemical Societies Letters. 2001;3:122–6. doi: 10.1016/s0014-5793(01)02673-4. [DOI] [PubMed] [Google Scholar]
  11. Halaas J.L., Gajiwala K.S., Maffei M., Cohen S.L., Chait B.T., Rabinowitz D., Lallone R.L., Burley S.K., Friedman J.M. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269:543–6. doi: 10.1126/science.7624777. [DOI] [PubMed] [Google Scholar]
  12. Hamajima N., Saito T, Matsuo K., Suzuki T., Nakamura T., Matsuura A., Okuma K., Tajima K. Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients. Journal of epidemiology. 2002;3:229–36. doi: 10.2188/jea.12.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Henson M.C., Castracane V.D. Leptin in pregnancy. Biology ofreproduction. 2000;5:1219–28. doi: 10.1095/biolreprod63.5.1219. [DOI] [PubMed] [Google Scholar]
  14. Hoffman L., Nolan C., Wilson J.D., Oats J.J., Simmons D. Gestational diabetes mellitus—management guidelines — The Australasian Diabetes in Pregnancy Society. The Medical journal of Australia. 1998;2:93–7. doi: 10.5694/j.1326-5377.1998.tb140192.x. [DOI] [PubMed] [Google Scholar]
  15. Hoffstedt J., Eriksson P., Mottagui-Tabar S., Arner P. A polymorphism in the leptin promoter region (-2548 G/A) influences gene expression and adipose tissue secretion of leptin. Hormone and metabolic research. 2002;7:355–9. doi: 10.1055/s-2002-33466. [DOI] [PubMed] [Google Scholar]
  16. Holness M.J., Munns M.J., Sugden M.C. Current concepts concerning the role of leptin in reproductive function. Molecular and cellular endocrinology. 1999;1–2:11–20. doi: 10.1016/S0303-7207(99)00126-4. [DOI] [PubMed] [Google Scholar]
  17. Jaquet D., Leger J., Levy-Marchal C., Oury J.F., Czernichow P. Ontogeny of leptin in human fetuses and newborns: effect of intrauterine growth retardation on serum leptin concentrations. The Journal of clinical endocrinology and metabolism. 1998;4:1243–6. doi: 10.1210/jc.83.4.1243. [DOI] [PubMed] [Google Scholar]
  18. Lea R.G., Howe D., Hannah L.T., Bonneau O., Hunter L., Hoggard N. Placental leptin in normal, diabetic and fetal growth-retarded pregnancies. Molecular human reproduction. 2000;8:763–9. doi: 10.1093/molehr/6.8.763. [DOI] [PubMed] [Google Scholar]
  19. Lepercq J., Cauzac M., Lahlou N., Timsit J., Girard J., Auwerx J., Hauguel-de Mouzon. Over expression of placental leptin in diabetic pregnancy: a critical role for insulin. Diabetes. 1998;5:847–50. doi: 10.2337/diabetes.47.5.847. [DOI] [PubMed] [Google Scholar]
  20. Li W.D., Reed D.R., Lee J.H., Xu W., Kilker R.L., Sodam B.R., Price R.A. Sequence variants in the 5′ flanking region of the leptin gene are associated with obesity in women. Annals of human genetics. 1999;3:227–34. doi: 10.1046/j.1469-1809.1999.6330227.x. [DOI] [PubMed] [Google Scholar]
  21. Malmstrom R., Taskinen M.R., Karonen S.L., Yki-Jarvinen H. Insulin increases plasma leptin concentrations in normal subjects and patients with NIDDM. Diabetologia. 1996;8:993–6. doi: 10.1007/BF00403921. [DOI] [PubMed] [Google Scholar]
  22. Mamma O., Betoulle D., Aubert R., Herbeth B., Siest G., Fumeron F. Association of the G-2548A polymorphism in the 5′ region of the LEP gene with overweight. Annals of human genetics. 2000;5:391–4. doi: 10.1017/s0003480000008277. [DOI] [PubMed] [Google Scholar]
  23. Masuzaki H., Ogawa Y., Sagawa N. Non-adipose tissue production of leptin: Leptin as a novel placenta-derived hormone in humans. Nature Medicine. 1997;9:l029–33. doi: 10.1038/nm0997-1029. [DOI] [PubMed] [Google Scholar]
  24. Meissner U., Ostreicher I., Allabauer I., Rascher W., Dotsch J. Synergistic effects of hypoxia and insulin are regulated by different transcriptional elements of the human leptin promoter. Biochemical and biophysical research communications. 2003;2:707–12. doi: 10.1016/S0006-291X(03)00401-7. [DOI] [PubMed] [Google Scholar]
  25. Nieters A., Becker N., Linseisen J. Polymorphisms in candidate obesity genes and their interaction with dietary intake of n-6 polyunsaturated fatty acids affect obesity risk in a sub-sample of the EPIC-Heidelberg cohort. European journal of nutrition. 2002;5:210–21. doi: 10.1007/s00394-002-0378-y. [DOI] [PubMed] [Google Scholar]
  26. Pelleymounter M.A., Cullen M.J., Baker M.B., Hecht R., Winters D., Boone T., Collins F. Effect of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269:540–3. doi: 10.1126/science.7624776. [DOI] [PubMed] [Google Scholar]
  27. Simmons D., Breier B.H. Fetal overnutrition in Polynesian pregnancies and in gestational diabetes may lead to dysregulation of the adipoinsular axis in offspring. Diabetes Care. 2002;9:1539–44. doi: 10.2337/diacare.25.9.1539. [DOI] [PubMed] [Google Scholar]
  28. Stephens T.W., Basinski M., Bristow P.K., Bue-Valleskey J.M., Burgett S.G., Craft L. The role of neuropeptide Yin the antiobesity action of the obese gene product. Nature. 1995;377:530–2. doi: 10.1038/377530a0. [DOI] [PubMed] [Google Scholar]
  29. Utriainen T., Malmstrom R., Makimattila S., Yki-Jarvinen H. Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects. Diabetes. 1996;10:1364–6. doi: 10.2337/diabetes.45.10.1364. [DOI] [PubMed] [Google Scholar]
  30. Weigle D.S., Bukowski T.R., Foster D.C., Holderman S., Kramer J.M., Lasser G. Recombinant ob protein reduces feeding and body weight in the ob/ob mouse. Journal of Clinical Investigation. 1995;4:2065–70. doi: 10.1172/JCI118254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zhang Y., Proenca R., Maffei M., Barone M., Leopold L., Friedman J.M. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–32. doi: 10.1038/372425a0. [DOI] [PubMed] [Google Scholar]

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