The Molecular Mechanisms of Estrogen Receptor α on Two Single Nucleotide Polymorphisms to Regulate WNT Signaling in Osteoblasts

2021 ◽  
Author(s):  
◽  
Sarocha Suthon ◽  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Bone Mass ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Osteoblast Differentiation ◽  
Association Studies ◽  
Wnt Signaling Pathway ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Osteoporosis is the most common bone metabolic disorder, affecting over 200 million people globally. It is characterized by bone mass depletion and microarchitectural deterioration, leading to bone fragility and susceptibility to bone fracture. Genetic factors, estrogen deficiency, and dysregulation of the WNT signaling pathway contribute to the development of this disease. Genome-wide association studies have predicted that the single nucleotide polymorphisms (SNPs) rs2887571 and rs9921222 associate with low bone mass, but the mechanism of these SNPs has remained unknown. Analysis of osteoblasts from 112 different joint replacement patients reveals that the genotype of rs2887571 correlates with WNT5B expression, and the genotype of rs9921222 correlates with AXIN1 expression. Mechanistically, SNP rs2887571 has less binding of ERα and NFATc1 to allele A than allele G, resulting in more expression of WNT5B in homozygous AA than homozygous GG. Furthermore, WNT5B exhibits distinct effects from other WNTs on osteoblastogenesis. WNT5B increases mesenchymal stem cell proliferation, promotes adipogenesis, and suppresses osteoblast differentiation via ROR1/2, then activates DVL2/3, Rac1/Cdc42, JNK, and SIN3A signaling, as well as inhibits ROCK2 and β-catenin activity. For SNP rs9921222, homozygous TT has a higher expression of AXIN1 than homozygous CC. Molecular analysis shows that GATA4 favors binding at rs9921222 allele T to promote AXIN1 expression; in contrast, ERα prefers to bind at allele C to suppress the expression, resulting in more expression of AXIN1 in homozygous TT than homozygous CC. Functionally, the level of AXIN1 negatively correlates with the level of active β-catenin, which enhances osteoblast differentiation. Taken together, the biological mechanisms of SNPs rs2887571 and rs9921222, which are associated with osteoporosis via the WNT signaling pathway, are revealed, as well as the inhibitory effect of WNT5B on osteoblastogenesis. These data will be the fundamental knowledge for the development of osteoporosis prediction and therapeutic strategies.

scholarly journals Association of Single Nucleotide Polymorphisms in Wnt Signaling Pathway Genes with Breast Cancer in Saudi Patients

PLoS ONE ◽  
2013 ◽  
Vol 8 (3) ◽  
pp. e59555 ◽  
Author(s):  
Mohammad Saud Alanazi ◽  
Narasimha Reddy Parine ◽  
Jilani Purusottapatnam Shaik ◽  
Huda A. Alabdulkarim ◽  
Sana Abdulla Ajaj ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Nucleotide Polymorphisms ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Saudi Patients

scholarly journals Associations of Two Obesity-Related Single-Nucleotide Polymorphisms with Adiponectin in Chinese Children

2017 ◽  
Vol 2017 ◽  
pp. 1-5 ◽  
Author(s):  
Lijun Wu ◽  
Liwang Gao ◽  
Xiaoyuan Zhao ◽  
Meixian Zhang ◽  
Jianxin Wu ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Multiple Testing ◽  
Association Studies ◽  
Statistical Significance ◽  
Additive Model ◽  
Recessive Model ◽  
Chinese Children ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Purpose. Genome-wide association studies have found two obesity-related single-nucleotide polymorphisms (SNPs), rs17782313 near the melanocortin-4 receptor (MC4R) gene and rs6265 near the brain-derived neurotrophic factor (BDNF) gene, but the associations of both SNPs with other obesity-related traits are not fully described, especially in children. The aim of the present study is to investigate the associations between the SNPs and adiponectin that has a regulatory role in glucose and lipid metabolism. Methods. We examined the associations of the SNPs with adiponectin in Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. A total of 3503 children participated in the study. Results. The SNP rs6265 was significantly associated with adiponectin under an additive model (P=0.02 and 0.024, resp.) after adjustment for age, gender, and BMI or obesity statuses. The SNP rs17782313 was significantly associated with low adiponectin under a recessive model. No statistical significance was found between the two SNPs and low adiponectin after correction for multiple testing. Conclusion. We demonstrate for the first time that the SNP rs17782313 near MC4R and the SNP rs6265 near BDNF are associated with adiponectin in Chinese children. These novel findings provide important evidence that adiponectin possibly mediates MC4R and BDNF involved in obesity.

Detecting associated single-nucleotide polymorphisms on the X chromosome in case control genome-wide association studies

2014 ◽  
Vol 26 (2) ◽  
pp. 567-582 ◽  
Author(s):  
Zhongxue Chen ◽  
Hon Keung Tony Ng ◽  
Jing Li ◽  
Qingzhong Liu ◽  
Hanwen Huang
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
X Chromosome ◽  
Association Studies ◽  
Statistical Tests ◽  
Real Data ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide

In the past decade, hundreds of genome-wide association studies have been conducted to detect the significant single-nucleotide polymorphisms that are associated with certain diseases. However, most of the data from the X chromosome were not analyzed and only a few significant associated single-nucleotide polymorphisms from the X chromosome have been identified from genome-wide association studies. This is mainly due to the lack of powerful statistical tests. In this paper, we propose a novel statistical approach that combines the information of single-nucleotide polymorphisms on the X chromosome from both males and females in an efficient way. The proposed approach avoids the need of making strong assumptions about the underlying genetic models. Our proposed statistical test is a robust method that only makes the assumption that the risk allele is the same for both females and males if the single-nucleotide polymorphism is associated with the disease for both genders. Through simulation study and a real data application, we show that the proposed procedure is robust and have excellent performance compared to existing methods. We expect that many more associated single-nucleotide polymorphisms on the X chromosome will be identified if the proposed approach is applied to current available genome-wide association studies data.

Association betweenCYP1A2gene single nucleotide polymorphisms and clinical responses to clozapine in patients with treatment-resistant schizophrenia

2013 ◽  
Vol 25 (1) ◽  
pp. 2-11 ◽  
Author(s):  
Anto P. Rajkumar ◽  
B. Poonkuzhali ◽  
Anju Kuruvilla ◽  
Alok Srivastava ◽  
Molly Jacob ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Adverse Effects ◽  
Clinical Response ◽  
Treatment Response ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Treatment Resistant ◽  
Single Nucleotide ◽  
Clinical Responses

ObjectivesDespite clozapine's superior clinical efficacy in treatment-resistant schizophrenia (TRS), its adverse effects, need for periodic leukocyte monitoring, cost and variable clinical outcomes mandate a clinical need to predict its treatment response. Although cytochrome P450 1A2 (CYP1A2) is the principal determinant of metabolism of clozapine, the role ofCYP1A2gene in the clinical response to clozapine is uncertain. Hence, we investigated its association with treatment responses and adverse events of clozapine in TRS.MethodsWe evaluated four single nucleotide polymorphisms (SNP) in theCYP1A2gene, clinical responses and serum clozapine levels in 101 consecutive patients with TRS on stable doses of clozapine. We defined clozapine responsea prioriand investigated allelic and genotypic associations. We assessed the socio-demographic and clinical profiles, premorbid adjustment, traumatic life events, cognition and disability of the participants, using standard assessment schedules for appropriate multivariate analyses.ResultsOur results revealed thatCYP1A2gene SNP (*1C, *1D, *1Eand*1F) were not associated with clozapine treatment response, adverse effects, serum clozapine levels or with disability (pvalues > 0.10).ConclusionAsCYP1A2gene SNP do not help to predict the clinical response to clozapine, routine screening for them prior to start clozapine is currently unwarranted. We suggest future longitudinal genome-wide association studies investigating clinical and pharmacogenetic variables together.

Where in the Genome Are Significant Single Nucleotide Polymorphisms from Genome-Wide Association Studies Located?

2011 ◽  
Vol 15 (7-8) ◽  
pp. 507-512 ◽  
Author(s):  
Torsten Günther ◽  
Armin O. Schmitt ◽  
Ralf H. Bortfeldt ◽  
Anke Hinney ◽  
Johannes Hebebrand ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide

scholarly journals From Single Nucleotide Polymorphisms to Constant Immunosuppression: Mesenchymal Stem Cell Therapy for Autoimmune Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Raghavan Chinnadurai ◽  
Edmund K. Waller ◽  
Jacques Galipeau ◽  
Ajay K. Nooka
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Autoimmune Diseases ◽  
Association Studies ◽  
Autoimmune Disorders ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Mesenchymal Stem Cell Therapy ◽  
Immune Mediated ◽  
Wide Range

The regenerative abilities and the immunosuppressive properties of mesenchymal stromal cells (MSCs) make them potentially the ideal cellular product of choice for treatment of autoimmune and other immune mediated disorders. Although the usefulness of MSCs for therapeutic applications is in early phases, their potential clinical use remains of great interest. Current clinical evidence of use of MSCs from both autologous and allogeneic sources to treat autoimmune disorders confers conflicting clinical benefit outcomes. These varied results may possibly be due to MSC use across wide range of autoimmune disorders with clinical heterogeneity or due to variability of the cellular product. In the light of recent genome wide association studies (GWAS), linking predisposition of autoimmune diseases to single nucleotide polymorphisms (SNPs) in the susceptible genetic loci, the clinical relevance of MSCs possessing SNPs in the critical effector molecules of immunosuppression is largely undiscussed. It is of further interest in the allogeneic setting, where SNPs in the target pathway of MSC's intervention may also modulate clinical outcome. In the present review, we have discussed the known critical SNPs predisposing to disease susceptibility in various autoimmune diseases and their significance in the immunomodulatory properties of MSCs.

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