Evaluation of WNT Signaling Pathway Gene Variants WNT7B rs6519955, SFRP4 rs17171229 and RSPO2 rs611744 in Patients with Dupuytren’s Contracture

Dupuytren’s contracture (DC) represents a chronic fibroproliferative pathology of the palmar aponeurosis, which leads to flexion contractures of finger joints and hand disability. In recent decades, the WNT signaling pathway has been revealed to play a significant role in the manifestation and pathogenesis of DC. Our study aimed to evaluate the associations between Dupuytren’s contracture and WNT-related single-nucleotide polymorphisms: Wnt Family Member 7B (WNT7B) rs6519955 (G/T), Secreted Frizzled Related Protein 4 (SFRP4) rs17171229 (C/T) and R-spondin 2 (RSPO2) rs611744 (A/G). We enrolled 216 patients (113 DC cases and 103 healthy controls), and DNA samples were extracted from the peripheral blood. Genotyping of WNT7B rs6519955, SFRP4 rs17171229 and RSPO2 rs611744 was performed using the Real-Time PCR System 7900HT from Applied Biosystems. WNT7B rs6519955 genotype TT carriers were found to possess a higher prevalence of DC (OR = 3.516; CI = 1.624–7.610; p = 0.001), whereas RSPO2 rs611744 genotype GG appears to reduce the likelihood of the manifestation of DC nearly twofold (OR = 0.484, CI = 0.258–0.908, p = 0.024). In conclusion, SNPs WNT7B rs6519955 and RSPO2 rs611744 are associated with the development of Dupuytren’s contracture: WNT7B rs6519955 TT genotype increases the chances by 3.5-fold, and RSPO2 rs611744 genotype GG appears to attenuate the likelihood of the manifestation of DC nearly twofold. Findings of genotype distributions among DC patients and control groups suggest that SFRP4 rs17171229 is not significantly associated with development of the disease.

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

PLoS ONE ◽

10.1371/journal.pone.0059555 ◽

2013 ◽

Vol 8 (3) ◽

pp. e59555 ◽

Cited By ~ 36

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

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Association between affective temperaments and brain-derived neurotrophic factor, Glycogen synthase kinase 3β and Wnt signaling pathway gene polymorphisms in healthy subjects

Journal of Affective Disorders ◽

10.1016/j.jad.2010.10.053 ◽

2011 ◽

Vol 131 (1-3) ◽

pp. 353-357 ◽

Cited By ~ 7

Author(s):

Takashi Tsutsumi ◽

Takeshi Terao ◽

Kengo Hatanaka ◽

Shinjiro Goto ◽

Nobuhiko Hoaki ◽

...

Keyword(s):

Wnt Signaling ◽

Signaling Pathway ◽

Neurotrophic Factor ◽

Gene Polymorphisms ◽

Healthy Subjects ◽

Glycogen Synthase ◽

Wnt Signaling Pathway ◽

Glycogen Synthase Kinase 3Β ◽

Pathway Gene ◽

Signaling Pathway Gene

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

10.21007/etd.cghs.2021.0548 ◽

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.

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WNT Signaling Pathway Gene Polymorphisms and Risk of Hepatic Fibrosis and Inflammation in HCV-Infected Patients

PLoS ONE ◽

10.1371/journal.pone.0084407 ◽

2013 ◽

Vol 8 (12) ◽

pp. e84407 ◽

Cited By ~ 12

Author(s):

Yanhong Liu ◽

Hashem B. El-Serag ◽

Li Jiao ◽

JuSeog Lee ◽

David Moore ◽

...

Keyword(s):

Wnt Signaling ◽

Signaling Pathway ◽

Hepatic Fibrosis ◽

Gene Polymorphisms ◽

Wnt Signaling Pathway ◽

Pathway Gene ◽

Signaling Pathway Gene

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Association between Wnt signaling pathway gene polymorphisms and bone response to hormone therapy in postmenopausal Korean women

Menopause The Journal of The North American Menopause Society ◽

10.1097/gme.0b013e318208f9b2 ◽

2011 ◽

Vol 18 (7) ◽

pp. 808-813 ◽

Cited By ~ 12

Author(s):

Hoon Kim ◽

Seung Ah Choe ◽

Seung Yup Ku ◽

Seok Hyun Kim ◽

Jung Gu Kim

Keyword(s):

Wnt Signaling ◽

Hormone Therapy ◽

Signaling Pathway ◽

Gene Polymorphisms ◽

Wnt Signaling Pathway ◽

Korean Women ◽

Pathway Gene ◽

Bone Response ◽

Signaling Pathway Gene

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Use of genetic variants in wnt signaling pathway to predict gender and tumor location dependent survival in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI and bevacizumab (BEV).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3568 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3568-3568

Author(s):

Yan Ning ◽

Wu Zhang ◽

Dongyun Yang ◽

Fotios Loupakis ◽

Takeru Wakatsuki ◽

...

Keyword(s):

Clinical Outcome ◽

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Tumor Location ◽

Rank Test ◽

Candidate Snps ◽

First Line ◽

Pathway Gene ◽

Tcf7l2 Rs7903146

3568 Background: CRC is generally characterized by aberrant Wnt signaling. Wnt signaling pathway genes AXIN2 and TCF7L2 complex control the proliferation and differentiation of intestinal epithelial cells. Previous study showed polymorphisms in TCF7L2 and AXIN2 were associated with increase risk of colon cancer. We tested the hypothesis whether single nucleotide polymorphisms (SNPs) in TCF7L2 (rs7903146) and AXIN2 (rs2240308, rs3923087) will predict clinical outcome in a cohort of mCRC pts treated with first line FOLFIRI/BEV. Methods: Genomic DNA were extracted from blood of 455 mCRC pts which prospectively enrolled in a pharmacogenetic translational study. Females(n=172) and males(n=252); Median follow up is 24 months, median PFS and OS were 10.5 and 29.9 months, respectively. Candidate SNPs were analyzed by PCR-based direct sequencing. Results: In the overall population analysis, TCF7L2 and AXIN2 polymorphisms were not associated with OS and PFS, but our data showed that 2 polymorphisms may predict clinical outcome when adjusted by pts gender and tumor location: 1) In right-sided tumors, male pts with any T allele of TCF7L2rs7903146 were associated with significantly worse PFS in comparison to those carrying C/C genotype (HR: 2.15; 95% CI: 1.09-4.22; P = 0.027, log-rank test). However, female pts with any T allele reversly showed better PFS compared with those carrying C/C variants (HR: 0.39; 95% CI: 0.17-0.94; P = 0.035, logrank test). 2) In women, pts with AXIN2 rs2240308 any A allele had better PFS and OS in right-sided tumors compared to those with any A allele but located in left side(pinteraction=0.047)(PFS) and (pinteraction=0.025)(OS), respectively. Conclusions: Our data show for the first time Wnt signaling pathway gene polymorphisms TCF7L2 rs7903146 and AXIN2 rs2240308 may predict PFS and OS in mCRC pts treated with first-line FOLFIRI/BEV. More importantly, this predictive value is dependent on gender and tumor location, suggesting a different role of Wnt signaling in female vs male and in right vs left side tumor. Our preliminary data warrants clinical trial validation.

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Overexpressed microRNA-140 inhibits pulmonary fibrosis in interstitial lung disease via the Wnt signaling pathway by downregulating osteoglycin

AJP Cell Physiology ◽

10.1152/ajpcell.00479.2019 ◽

2020 ◽

Vol 319 (5) ◽

pp. C895-C905

Author(s):

Songtao Shi ◽

Hongli Li

Keyword(s):

Interstitial Lung Disease ◽

Pulmonary Fibrosis ◽

Lung Disease ◽

Wnt Signaling ◽

Signaling Pathway ◽

Ectopic Expression ◽

Wnt Signaling Pathway ◽

Lung Fibroblasts ◽

Related Factors ◽

Pathway Gene

Interstitial lung disease (ILD) comprises of a group of diffuse parenchymal lung disorders that are strongly associated with substantial morbidity and mortality. Previous studies have highlighted the therapeutic significance of microRNAs (miRNAs) in the treatment of ILD. Thus this study aims to investigate the mechanism by which miR-140 affects ILD through the regulation of osteoglycin (OGN) -Wnt signaling pathway. Gene expression microarray analysis was performed to screen ILD-related differentially expressed genes and miRNAs that regulated OGN. The targeting relationship between miR-140 and OGN was verified. Ectopic expression and knockdown experiments were performed in lung fibroblasts to explore the potential mechanism of action of miR-140 in ILD. The expression of miR-140, OGN, as well as Wnt- and pulmonary fibrosis-related factors, was determined by RT-qPCR and Western blot analysis. In addition, cell viability and apoptosis were examined. OGN was found to be negatively regulated by miR-140. The ectopic expression of miR-140 and OGN silencing resulted in increased lung fibroblast apoptosis and Wnt3a expression, along with reduced proliferation and pulmonary fibrosis. Our results also revealed that miR-140 decreased OGN, thereby activating the Wnt signaling pathway, which was observed to further affect the expression of genes associated with the progression of pulmonary fibrosis in mouse fibroblasts. In conclusion, the key findings from our study suggest that overexpressed miR-140 suppresses ILD development via the Wnt signaling pathway by downregulating OGN, which could potentially be used as a therapeutic target for ILD.

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