High leptin level and leptin receptor Lys656Asn variant are risk factors for preeclampsia

Wang, S.; Qiao, Fang; Li, Feng

doi:10.4238/2013.january.4.14

Cited by 9 publications

(9 citation statements)

References 26 publications

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“…They have poor reproductive outcomes in natural as well as assisted conception . Several LEPR SNPs were found to be associated with obesity phenotypes, insulin resistance, hypertension, renal cell carcinoma, lung cancer, dyslipidemia, pre‐eclampsia, idiopathic recurrent pregnancy loss, and decrease in ovulation and/or luteinisation resulting in various physiopathological phenotypes and diminished reproductive development in human.…”

Section: Introductionmentioning

confidence: 99%

Computational and artificial neural network based study of functional SNPs of human LEPR protein associated with reproductive function

Muruganandhan

Manian

2019

J of Cellular Biochemistry

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Genetic polymorphisms are mostly associated with inherited diseases, detecting and analyzing the biological significance of functional single‐nucleotide polymorphisms (SNPs) using wet laboratory experiments is an arduous task hence the computational analysis of putative SNPs is essential before conducting a study on a large population. SNP in the leptin receptor (LEPR) could result in the retention of intracellular signalling due to the structural and functional instability of the receptor causing abnormal reproductive function in human. In this first comprehensive computational analysis of LEPR gene mutation, we have identified and analyzed the functional consequence and structural significance of the SNPs in LEPR using recently developed several computational algorithms. Thirteen deleterious mutations such as W13C, S93G, I232R, Q307H, Y354C, E497A, Q571H, R612H, K656N, T690A, T699M V741M, and L760R were identified in the LEPR gene coding region. Backpropagation algorithm has been developed to forestall the deleterious nature of SNP and to validate the outcome of the tested computational tools. From ConSurf prediction three SNPs (Q571H, R612H, and T699M) were highly conserved on LEPR protein and the most deleterious variant R612H had one hydrogen bond abolished and severely reduced protein stability. Molecular docking suggested that the mutant (R612H) LEPR had lowest binding energy than native LEPR with the ligand molecule. Thus the energetically destructive changeover of ARG to HIS in R612H could possibly affect the LEPR protein structural stability and functional constancy due to interruption in the amino acid interactions and could result in reproductive disorders in human and increases the complication in obstetric and pregnancy outcome.

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Section: Introductionmentioning

confidence: 99%

Computational and artificial neural network based study of functional SNPs of human LEPR protein associated with reproductive function

Muruganandhan

Manian

2019

J of Cellular Biochemistry

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“…The Table 3 shows a comparison of allele frequencies of both variants c.668A>G and c.1968G>C in our studied populations and other studies from Hungary, Germany, Sri -Lanka, and China [18][19][20][21]34]. The frequency of allele G in the variant c.668A>G in our study group (26.9) was slightly lower than in the Sri-Lankan population (35.8) and much lower than in the global allele frequency (44.9), Hungarian population (42.5) and German population (57.3).…”

Section: Resultsmentioning

confidence: 93%

“…Furthermore, Wang et. al., reported a significant association of LEPR c.C1968 homozygous + LEPR c.G1968 heterozygous with preeclampsia in a Chinese population [19]. The LEPR c.1968G>C variant led to a change of G to C at nucleotide c.1968 in exon 14.…”

Section: Discussionmentioning

confidence: 93%

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Leptin receptor gene polymorphisms c.668A>G and c.1968G>C in Sudanese women with preeclampsia: a case-control study

Saad

Adam

Elzaki³

et al. 2020

BMC Med Genet

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Background: Leptin receptor gene (LEPR) variants may affect the leptin levels and act as a risk factor for preeclampsia. Two LEPR gene missense variants rs1137101 (c.668A>G) and rs1805094 (c.1968G>C) were investigated in Sudanese women with preeclampsia. Methods: A matched case-control study (122 women in each arm) was conducted in Saad Abualila Maternity Hospital in Khartoum, Sudan from May to December 2018. The cases were women with preeclampsia and the controls were healthy pregnant women. Genotyping for LEPR gene variants c.668A>G and c.1968G>C was performed using polymerase chain reaction-restriction fragment length polymorphism. Logistic regression models (adjusted for age, parity, body mass index and hemoglobin level) were conducted. Results: Genotype frequency of LEPR gene variants c.668A>G and c.1968G>C was in accordance with Hardy-Weinberg equilibrium (P > 0.05) in the controls. Allele G in LEPRc.668A>G variant was significantly more frequent in the cases compared with the controls [43.4% vs. 10.2%; OR = 6.44; 95%CI (3.98-10.40); P < 0.001]. In variant LEPRc.668A>G, genotype AG was the prevalent genotype in the cases compared with the controls, and it was significantly associated with preeclampsia risk [37.7% vs. 15.5%; AOR = 3.48; 95%CI (1.15-10.54); P = 0.027]. Likewise, the GG genotype was the second most common genotype in the cases compared with the controls, and was associated with preeclampsia risk [24.6% vs. 2.5%; AOR = 14.19; 95%CI (1.77-113.76); P = 0.012]. None of the LEPRc.1968G>C variant genotypes were associated with preeclampsia. The CC genotype was not detected in neither the cases nor the controls. The haplotype A-G 70.1% was the prevalent haplotype in this population, and it significantly protected against preeclampsia [OR = 0.14; 95%CI (0.09-0.23); P < 0.001]. However, the haplotype G-G 26.8% was significantly associated with preeclampsia risk [OR = 6.70; 95%CI (4.16-11.05); P < 0.001]. Both variants c.668A>G and c.1968G>C were in strong linkage disequilibrium (D′ = 1, r 2 = 0.012). Conclusions: Our data indicate that the rs1137101 (c.668A>G) variant and G-G haplotype may independently associate with the development of preeclampsia.

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“…Also, it has been reported that hypoxia was associated with an increase expression of a group of leptin genes in trophoblastic cells (4). HA associated hypoxia increases the Ob (Lep) gene expression and the LEPR gene expression in preeclamptic mothers (24). Involvement of leptin in pathogenesis of PE has been previously investigated.…”

Section: Discussionmentioning

confidence: 99%

Impact of High Altitude on Maternal Serum Leptin Level and Its Correlation with Oxidative Stress and Endothelial Inflammatory Markers in Preeclamptic Women

Morsy

et al. 2018

Chin. J. Physiol.

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Involvement of leptin in the pathogensis of preeclampsia (PE) is still a controversy subject. Several researches reported the changes in serum leptin in high altitude (HA) residents. The aim of the present work was to investigate the impact of oxidative stress (OS) induced by HA residence on maternal serum leptin in PE and if there was a significant correlation between the serum leptin with either OS or endothelial inflammatory markers. One hundred fifty eight pregnant women were included in this study, divided into: low altitude normal pregnancies (NL), HA normal pregnancies (NH), low altitude preeclamptic (PL), and HA preeclamptic (PH) who presented to the obstetrics and gynecology outpatient clinic in both Muhayl (500 m over sea level) and Abha General Hospitals (all of them resident at Alsoda district with the average altitude 2700 m over sea level). Serum leptin, superoxide dismutase (SOD) activity, malondialdehyde (MDA), plasma nitrite/nitrate (NOx), serum tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), blood urea nitrogen (BUN) and creatinine were determined. Both NH and PL groups showed significant increases in leptin (P< 0.01), SOD (P < 0.01), MDA (P< 0.001), NOx (P < 0.001), TNF-α (P < 0.001) and IL-6 (P < 0.001) compared with the NL group without any significant changes between both groups. The PH group showed significant accentuation of the previously measured parameters (P< 0.001 for all) compared with all other groups (NL, NH and PL groups). We can conclude that the combination of PE and HA residence resulted in significantly elevated maternal serum leptin suggesting involvement of leptin in the pathogenesis of PE accentuated by HA residence.

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High leptin level and leptin receptor Lys656Asn variant are risk factors for preeclampsia

Cited by 9 publications

References 26 publications

Computational and artificial neural network based study of functional SNPs of human LEPR protein associated with reproductive function

Computational and artificial neural network based study of functional SNPs of human LEPR protein associated with reproductive function

Leptin receptor gene polymorphisms c.668A>G and c.1968G>C in Sudanese women with preeclampsia: a case-control study

Impact of High Altitude on Maternal Serum Leptin Level and Its Correlation with Oxidative Stress and Endothelial Inflammatory Markers in Preeclamptic Women

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