The LEPR (853A>G and 511A>G) Transitions may Enhance Idiopathic Recurrent Miscarriage: Evidences Based on Case-control and in silico Studies

Journal of Cell and Molecular Research

مقاله 4، دوره 11، شماره 1 - شماره پیاپی 21، آذر 2019، صفحه 23-36   

نوع مقاله: Research Articles

شناسه دیجیتال (DOI): 10.22067/jcmr.v11i1.81426

نویسندگان

Abasalt Hosseinzadeh Colagar^* ؛ Masomeh Salehi-Doon

University of Mazandaran, Babolsar, Iran

چکیده

Previous studies in human leptin receptor protein (LEPR) signaling are important in the establishment of fetal growth. Idiopathic recurrent miscarriage (IRM) may be the result of abnormal placental and fetal development. Thus single nucleotide polymorphisms (SNPs) of LEPR might be associated with IRM. In our case-control study, which conducted from 2017 to 2018 at the Milad Sari Genetic Detection Center and Razi Hospital (Ghaemshahr, Iran), 140 samples, including 70 cases with history of three or more IRM as before the 22nd week of gestation, and 70 controls with at least two live births and no history of pathologic pregnancies during reproductive period were studied. Polymorphisms of maternal LEPR 853A>G and 511A>G were assessed by PCR-RFLP and SSCP, respectively. Results showed that 853A>G SNP, contained frequent genotype AG (p= 0.002; OR= 0.391; 95% CI= 0.154-0.664) and G allele (p= 0.003; OR= 0.125; 95% CI= 0.032–0.489), revealed a significant protective association with IRM. Primary screening of 511A>G showed that 63 case-samples were AG genotype. PCR directed sequence showed this SNP contained frequent genotype for AG (p= 0.001; OR= 0.57; 95% CI= 0.22-0.147) and G allele (p= 0.006; OR= 0.34; 95% CI= 0.008–0.149), revealed a significant protective association with IRM. Based on our findings, LEPR (853A>G and 511A>G) gene transitions not only might enhance IRM but also could be useful genetic markers in susceptibility and severity of recurrent miscarriage.

کلیدواژه‌ها

LEPR gene؛ obesity؛ recurrent miscarriage

مراجع

Adzhubei I., Jordan D. M. and Sunyaev S. R. (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Current Protocols in Human Genetics 120:301-333.

Aftabi Y., Colagar A. H. and Mehrnejad F. (2016) An in silico approach to investigate the source of the controversial interpretations about the phenotypic results of the human AhR-gene G1661A polymorphism. Journal of Theoretical Biology 393:1-15.

AlShaikh F. S., Finan R. R., Almawi A. W., Mustafa F. E. and Almawi W. Y. (2011) Association of the R67X and W303X non-sense polymorphisms in the protein Z-dependent protease inhibitor gene with idiopathic recurrent miscarriage. Molecular Human Reproduction 18(3):156-160.

Alshaker H., Sacco K., Alfraidi A., Muhammad A., Winkler M. and Pchejetski D. (2015) Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma. Oncotarget 6(34):35556.

Bartha T., Sayed-Ahmed A. and Rudas P. (2005) Expression of leptin and its receptors in various tissues of ruminants. Domestic Animal Endocrinology 29(1):193-202.

Baumann H., Morella K. K., White D. W., Dembski M., Bailon P. S., Kim H. and Tartaglia L. A. (1996) The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proceedings of the National Academy of Sciences 93(16):8374-8378.

Bhandari S., Ganguly I., Bhandari M., Agarwal P., Singh A., Gupta N. and Mishra A. (2016) Effect of sleeve gastrectomy bariatric surgery-induced weight loss on serum AMH levels in reproductive aged women. Gynecological Endocrinology 32(10):799-802.

Bromberg Y. and Rost B. (2007) SNAP: predict effect of non-synonymous polymorphisms on function. Nucleic Acids Research 35(11):3823-3835.

Chatr-Aryamontri A., Breitkreutz B. J., Oughtred R., Boucher L., Heinicke S., Chen D. and Reguly T. (2014) The BioGRID interaction database: 2015 update. Nucleic Acids Research 43(D1):D470-D478.

Cheng J., Randall A. and Baldi P. (2006) Prediction of protein stability changes for single-site mutations using support vector machines. Proteins Structure Function and Bioinformatics 62(4):1125-1132.

Chin J. R., Heuser C. C., Eller A. G., Branch D. W., Nelson L. T. and Silver R. M. (2013) Leptin and leptin receptor polymorphisms and recurrent pregnancy loss. Journal of the California Perinatal Association 33(8):589.

Chou K. C. (2015) Impacts of bioinformatics to medicinal chemistry. Journal of Medicinal and Pharmaceutical Chemistry 11(3): 218-234.

Chou P. Y. and Fasman G. D. (1974) Prediction of protein conformation. Journal of Biological Chemistry 13(2):222-245.

Chung W. K., Power-Kehoe L., Chua M., Chu F., Aronne L., Huma Z. and Leibel R. L. (1997) Exonic and intronic sequence variation in the human leptin receptor gene (LEPR). Diabetic Medicine 46(9):1509.

Cleveland R. J., Gammon M. D., Long C. M., Gaudet M. M., Eng S. M., Teitelbaum S. L. and Santella R. M. (2010) Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival. Breast Cancer Research and Treatment 120(3):745-752.

Cohen A. W., Hnasko R., Schubert W. and Lisanti M. P. (2004) Role of caveolae and caveolins in health and disease. Physiological Reviews 84(4):1341-1379.

Considine R. V., Sinha M. K., Heiman M. L., Kriauciunas A., Stephens T. W., Nyce M. R., Ohannesian J. P., Marco C. C., McKee L. J. and Bauer T. L. (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. The New England Journal of Medicine 334(5):292-5.

Da Silva Santos T., Ieque A. L., de Carvalho H. C., Sell A. M., Lonardoni M. V. C., Demarchi I. G. and Teixeira J. J. V. (2017) Antiphospholipid syndrome and recurrent miscarriage: a systematic review and meta-analysis. Journal of Reproductive Immunology 85(9):141-179

David A., Razali R., Wass M. N. and Sternberg M. J. (2012) Protein-protein interaction sites are hot spots for disease associated nonsynonymous SNPs. Human Mutation 33(2):359-363.

Dias N. F., Fernandes A. E., Melo M. E. D., Reinhardt H. L., Cercato C., Villares S. M. F. and Mancini M. C. (2012) Lack of mutations in the leptin receptor gene in severely obese children. Arquivos Brasileiros de Endocrinologia & Metabologia 56(3):178-183.

Duggavathi R., Volle D. H., Mataki C., Antal M. C., Messaddeq N., Auwerx J. and Schoonjans K. (2008) Liver receptor homolog 1 is essential for ovulation. Genes & Development 22(14):1871-1876.

Fan H. Y., Liu Z., Johnson P. F. and Richards J. S. (2011) CCAAT/enhancer-binding proteins (C/EBP)-α and-β are essential for ovulation, luteinization, and the expression of key target genes. Molecular Endocrinology 25(2):253-268.

Fraga L. R., Dutra C. G., Boquett J. A., Vianna F. S. L., Gonçalves R. O., Paskulin D. D. and Schuler-Faccini L. (2014) P53 signaling pathway polymorphisms associated to recurrent pregnancy loss. Molecular Biology Reports 41(3):1871-1877.

Gasteiger E., Hoogland C., Gattiker A., Wilkins M. R., Appel R. D. and Bairoch A. (2005) Protein identification and analysis tools on the ExPASy server. In The Proteomics Protocols Handbook (pp. 571-607). Humana press

Gaus G., Funayama H., Huppertz B., Kaufmann P. and Frank H. G. (1997) Parent cells for trophoblast hybridization I: Isolation of extravillous trophoblast cells from human term chorion laeve. Placenta Journal 18:181-190.

Green M. R. and Sambrook J. (2012) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor.

Jannat Alipoor F., Asadi M. H. and Torkzadeh-Mahani M. (2017) Miat LncRNA promotes proliferation of cervical cancer cells and acts as an anti-apoptotic factor. Journal of Genetic Resources 3(2):80-86.

Jansson T., Ekstrand Y., Björn C., Wennergren M. and Powell T. L. (2002) Alterations in the activity of placental amino acid transporters in pregnancies complicated by diabetes. Diabetic Medicine 51(7):2214-2219.

Kar B. and Linda C. B. (2017) Genetic factors associated with recurrent pregnancy loss. American Journal of Obstetrics and Gynecology 7(6):00272.

Khosronezhad N., Hosseinzadeh Colagar A. and Jorsarayi S. G. A. (2015) C26232T mutation in Nsun7 gene and reduce sperm motility in asthenoteratospermic men. Journal of Genetic Resources 1(1):25-30.

Kolte A. M., Bernardi L. A., Christiansen O. B., Quenby S., Farquharson R. G., Goddijn M. and Stephenson M. D. (2015) ESHRE special interest group, Early Pregnancy. Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Molecular Human Reproduction 30(3):495-498.

Lashen H., Fear K. and Sturdee D. W. (2004) Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study. Molecular Human Reproduction 19(7):1644-1646.

Lea R. G., Howe D., Hannah L. T., Bonneau O., Hunter L. and Hoggard N. (2000) Placental leptin in normal, diabetic and fetal growth-retarded pregnancies. Molecular Human Reproduction 6(8):763-769.

Lu C. T., Huang K. Y., Su M. G., Lee T. Y., Bretana N. A., Chang W. C. and Huang H. D. (2013) DbPTM 3.0: an informative resource for investigating substrate site specificity and functional association of protein post-translational modifications. Nucleic Acids Research 41(D1): D295-D305.

Lydon J. P., DeMayo F. J., Funk C. R., Mani S. K., Hughes A. R., Montgomery C. A. and O'Malley B. W. (1995) Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes & Development 9(18):2266-2278.

Matthiesen L., Kalkunte S. and Sharma S. (2012) Multiple pregnancy failures: an immunological paradigm. American Journal of Reproductive Immunology 67(4):334-340.

Mehmood M. A., Sehar U. and Ahmad N. (2014) Use of bioinformatics tools in different spheres of life sciences. Journal of Data Mining in Genomics & Proteomics 5(2):1.

Messaoudi S., Hizem S., Al-Sulaiti M. A., Al-Busaidi A. S., Magdoud K., Dendana M. and Mahjoub T. (2013) Contribution of JAK2 and STAT3 variants to the genetic susceptibility of recurrent spontaneous miscarriage in a Tunisian population. Genetic Testing and Molecular Biomarkers 17(1):35-39.

Minguez P., Letunic I., Parca L. and Bork P. (2012) PTMcode: A database of known and predicted functional associations between post-translational modifications in proteins. Nucleic Acids Research 41(D1): D306-D311.

Muhlhauser I., Bender R., Bott U., Jörgens V., Grüsser M., Wagener W. and Berger M. (1996) Cigarette smoking and progression of retinopathy and nephropathy in type 1 diabetes. Diabetic Medicine 13(6):536-543.

Muller A., Wagner J., Hodžić A., Maver A., Škrlec I., Heffer M. and Peterlin B. (2016) Genetic variation in leptin and leptin receptor genes is a risk factor for idiopathic recurrent spontaneous abortion. Croatian Medical Journal 57(6):566-571.

Ng P. C. and Henikoff S. (2006) Predicting the effects of amino acid substitutions on protein function. Annual Review of Genomics and Human Genetics 7:61-80.

Nigro G., Mazzocco M., Mattia E., Di Renzo G. C., Carta G. and Anceschi M. M. (2011) Role of the infections in recurrent spontaneous abortion. The Journal of Maternal-Fetal & Neonatal Medicine 24(8):983-989.

Nouri N., Fazel-Najafabadi E., Behnam M., Nouri N., Aryani O., Ghasemi M. and Sedghi M. (2014) Use of in silico tools for classification of novel missense mutations identified in dystrophin gene in developing countries. Gene 535(2):250-254.

Pang L., Wei Z., Li O., Huang R., Qin J., Chen H. and Chen Z. J. (2013) An increase in vascular endothelial growth factor (VEGF) and VEGF soluble receptor-1 (sFlt-1) are associated with early recurrent spontaneous abortion. PLoS One 8(9): e75759.

Radivojac P., Vacic V., Haynes C., Cocklin R. R., Mohan A., Heyen J. W. and Iakoucheva L. M. (2010) Identification, analysis, and prediction of protein ubiquitination sites. Structure Function and Bioinformatics; 78(2):365-380.

Ramirez M. (2017) Psychology of the Americas: mestizo perspectives on personality and mental health: Volume 126 of Pergamon general psychology series (Goldstein A. P., ed), Elsevier Science.

Riestra P., Garcia-Anguita A., Torres-Cantero A., Bayonas M. J., De Oya M. and Garces C. (2011) Association of the Q223R polymorphism with age at menarche in the leptin receptor gene in humans. Biology of Reproduction 84(4):752-755.

Sabarinathan R., Tafer H., Seemann S. E., Hofacker I. L., Stadler P. F. and Gorodkin J. (2013) The RNAsnp web server: predicting SNP effects on local RNA secondary structure. Nucleic Acids Research 41(W1): W475-W479.

Sagawa N., Yura S., Itoh H., Kakui K., Takemura M., Nuamah M. A. and Fujii S. (2002) Possible role of placental leptin in pregnancy. Endocrine Research Journal 19(1):65-71.

Shahsavari S., Noormohammadi Z. and Karizi S. Z. (2015) Association of kinase insert domain containing receptor (KDR) gene polymorphism/haplotypes with recurrent spontaneous abortion and genetic structure. International Journal of Reproductive Biomedicine 13(12):755.

Shin B., Gunawan O., Zhu Y., Bojarczuk N. A., Chey S. J. and Guha S. (2013) Thin film solar cell with 8.4% power conversion efficiency using an earth‐abundant Cu2ZnSnS4 absorber. Progress in Photovoltaics. European Journal of Obstetrics & Gynecology. Obstetrics & Gynecology and Reproductive Biology 21(1):72-76.

Silver R. M., Branch D. W., Goldenberg R., Iams J. D. and Klebanoff M. A. (2011) Nomenclature for pregnancy outcomes: time for a change. American Journal of Obstetrics and Gynecology 118(6):1402-1408.

Sterneck E., Tessarollo L. and Johnson P. F. (1997) An essential role for C/EBPβ in female reproduction. Genes & Development 11(17): 2153-2162.

Su M. T., Lin S. H. and Chen Y. C. (2011) Association of sex hormone receptor gene polymorphisms with recurrent pregnancy loss: a systematic review and meta-analysis. Fertility and Sterility 96(6):1435-1444.

Unkila-Kallio L., Andersson S., Koistinen H. A., Karonen S. L., Ylikorkala O. and Tiitinen A. (2001) Leptin during assisted reproductive cycles: the effect of ovarian stimulation and of very early pregnancy. Molecular Human Reproduction 16(4):657-662.

Unsal M., Kara N., Karakus N., Tural S. and Elbistan M. (2014) Effects of leptin and leptin receptor gene polymorphisms on lung cancer. Tumor Biology 35(10):10231-10236.

Wang L., Gao P., Zhang M., Huang Z., Zhang D., Deng Q. and Zhou M. (2013) Prevalence and ethnic pattern of diabetes and prediabetes in China in. Journal of the American Medical Association 317(24):2515-2523.

Yan J., Saravelos S. H., Ma N., Ma C., Chen Z. J. and Li T. C. (2012) Consecutive repeat miscarriages are likely to occur in the same gestational period. Reproductive Biomedicine Online 24(6):634-638.

Yang J., Wang Y., Wang X. Y., Zhao Y. Y., Wang J. and Zhao Y. Y. (2017) Adverse pregnancy outcomes of patients with history of first-trimester recurrent spontaneous abortion. BioMed Research International 2017: 4359424.

Zhou Y. and Rui L. (2015) Leptin signaling and leptin resistance. Frontiers of Medicine 7(2):207-222.