Association of leptin G2548A and leptin receptor Q223R polymorphisms and their serum levels with infertility and recurrent pregnancy loss in Iranian women with polycystic ovary syndrome

Abstract

Background Adipokine leptin plays a crucial role in metabolic and reproductive functions. Leptin receptor has a soluble form that binds to leptin, thus modulating its level in the circulation. It has been indicated that the levels of leptin and leptin receptor and also LEP rs7799039 and LEPR rs1137101 polymorphisms are associated with metabolic disorders. In the present study, we assessed the levels of leptin and soluble leptin receptor (sOB-R), and also the frequency of rs7799039 and rs1137101 polymorphisms in healthy fertile women and patients with polycystic ovary syndrome (PCOS), inclusive of PCOS-infertile and PCOS-recurrent pregnancy loss (RPL) subjects. Methods A total of 324 PCOS patients- including 199 infertile cases and 125 patients with a history of RPL- and 144 healthy controls were enrolled in this study. Biochemical parameters and plasma leptin and sOB-R levels were measured by ELISA and the genotypes of rs7799039 and rs1137101 polymorphisms were determined using PCR- RFLP. Results Plasma leptin and sOB-R levels were significantly higher and lower in PCOS, PCOS-infertile and PCOS RPL groups, respectively. The GG genotype frequencies of rs7799039 and rs1137101 polymorphisms were significantly different between PCOS-infertile women and non-PCOS subjects (P = 0.043, OR = 0.47, 95% CI = 0.22–0.97, and P = 0.01, OR = 0.31, 95% CI = 0.12–0.75, respectively). Increased LEP levels were associated with the risk of PCOS and RPL in women with PCOS (P = 0.039, OR = 1.203, 95%CI = [1.009–1.435] and P = 0.012, OR = 1.267, 95% CI = [1.054–1.522], respectively). Conclusion Polymorphisms rs7799039 and rs1137101 and circulating leptin and sOB-R levels were associated with infertility in Iranian women with PCOS. Further studies are needed to reveal the role of leptin in PCOS pathogenesis.

Progress of Adipokines in the Female Reproductive System: A Focus on Polycystic Ovary Syndrome

“…Studies have shown that Leptin enhanced the expression of aromatase genes by activating classic signal transduction pathways MAPK and PI3K, whereas this phenomenon was significantly attenuated in granulosa cells of PCOS patients, together with significantly increased plasma Leptin and decreased soluble Leptin receptor (s OB-R) in PCOS patients ( 80 ). This may suggest that Leptin resistance in PCOS patients may be possibly mediated by Sam68, an RNA-binding protein that is widely expressed in the body and has signaling functions ( 81 ).…”

-2548G>A LEP Polymorphism Is Positively Associated with Increased Leptin and Glucose Levels in Obese Saudi Patients Irrespective of Blood Pressure Status

“…A common variant of the -2548G>A (rs7799039) leptin promoter results in the transition substitution of guanine to adenine at nucleotide position -2548 upstream of the ATG start site [ 15 ]. This variant has previously been reported to be association with elevated serum leptin levels, metabolic syndrome, hypertension and obesity [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. On the other hand, there is conflicting information relating to these associations with some studies reporting a positive correlation and some reporting a negative correlation.…”

The Identification of Key Genes and Biological Pathways in Polycystic Ovary Syndrome and its Complications by Next Generation Squancing (NGS) and Bioinformatics Analysis

“…Tshori et al [161], Cheng et al [162], Nowzari et al [163], Choi et al [164], Ji et al [165], Huang et al [166], Zhai et al [167], Schiattarella et al [168], Brodehl et al [169], Wu et al [170], Zhao et al [171], Ujihara et al [172], Tan et al [173], Gittleman et al [174], Chen et al [175], Layrisse et al [176], Nakayama et al [177], Zhang et al [178], Vadvalkar et al [179], Burdon et al [180], Steffen et al [181], Ye et al [182], Tao et al [183] and Li et al [184] reported that PLA2G5, CASP1, TNNT2, FOXP3, DRD4, NEURL1, TIMP4, SOCS1, CD74, PLK1, ATF5, GATA6, IRF7, FOXC2, IRF9, FHOD3, BGN (biglycan), CACNA1H, FBLN2, ADAMTS8, COL1A1, POSTN (periostin), VARS2, SOD3, ADAMTS13, FABP5, ADAM23, COL1A2, MST1, ENDOG (endonuclease G), NKX2-6, MYOCD (myocardin), CES1, CYP19A1, PKP2, CD36, SALL1, ARG1, MSR1, S1PR1, OXTR (oxytocin receptor), MITF (melanocyte inducing transcription factor), MSX2, LEPR (leptin receptor), CDH13, PRKCH (protein kinase C eta), AR (androgen receptor), DKK3, FOXO1, CRYAB (crystallin alpha B), B2M, WWP1, FKTN (fukutin), PIK3C2A, KLKB1, CHRNA5, HLA-C, ARRDC4, KCNE3, MPC2, EPHX2, C2, IKZF2, ZBTB20 and RCN2 expressions might be regarded as an indicator of susceptibility to cardiovascular problems. CASP1 [185], FOXP3 [186], SOCS1 [187], GATA6 [188], IRF7 [189], POSTN (periostin) [190], CYP19A1 [191], CD36 [192], LYN (LYN proto-oncogene, Src family tyrosine kinase) [193], CD4 [194], LEPR (leptin receptor) [195], AR (androgen receptor) [196], FOXO1 [197] and PON2 [198] are a potential biomarkers for the detection and prognosis of PCOS. Udjus et al [199] Benjafield et al [200], Shetty et al [58], Kassan et al [201], Wetzl et al [202], Le Hiress et al [203], Pal-Ghosh et al [204], Niu, [205], Fan et al [206], Deng et al [207], Chen et al [208], Sardo et al [209], Seidel et al [210], Zhu et al [211], Omura et al [212], Hu et al [213], Castoldi et al [214], Yoshida et al [215], Palao et al [216…”