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Association between vascular endothelial growth factor receptor 2 rs11941492 C/T polymorphism and Chinese Han patients in rheumatoid arthritis.

ABSTRACT: The aim of the present study was to examine the association between vascular endothelial growth factor receptor 2 (VEGFR2) rs11941492 C/T polymorphism and rheumatoid arthritis (RA) risk in an eastern Chinese Han population. We examined VEGFR2 rs11941492 C/T polymorphism in 615 RA patients and 839 controls in an East Chinese Han population. The power analysis was used for evaluating the reliability of the results. Genotyping was performed using a custom-by-design 48-Plex single nucleotide polymorphism scan Kit. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression.Our results indicated that VEGFR2 rs11941492 C/T polymorphism (TT vs CC, P?=?.012, OR?=?0.61, 95% CI?=?0.41-0.89; TT vs CT + CC, P?=?.017, OR?=?0.63, 95% CI?=?0.43-0.92) was associated with a significantly decreased risk of RA. The power analysis showed that this study had a power of 98.5% to detect the effect of rs11941492 C/T polymorphism on RA susceptibility, assuming an OR of 0.61. After stratification analysis, a decreased risk of RA was associated with VEGFR2 rs11941492 TT genotype (TT vs CC) among female patients (TT vs CC, P?=?.007, OR?=?0.53, 95% CI?=?0.33-0.84), older patients (Yr ?55) (TT vs CC, P?=?.039, OR?=?0.58, 95% CI?=?0.35-0.97), C-reactive protein-positive patients, anti-cyclic citrullinated peptide antibody-negative patients, rheumatoid factor-positive patients (TT vs CT + CC, P?=?.015, OR?=?0.60, 95% CI?=?0.39-0.90), functional class III + IV patients, patients with a DAS28 of ?3.20, and those with an erythrocyte sedimentation rate of <25. However, our results were obtained from only a moderate-sized sample. Studies with larger sample sizes in other ethnic populations are needed to confirm these results. The VEGFR2 rs11941492 genotype is associated with decreased susceptibility to RA.

SUBMITTER: Yang Z

PROVIDER: S-EPMC6946575 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Association between vascular endothelial growth factor receptor 2 rs11941492 C/T polymorphism and Chinese Han patients in rheumatoid arthritis.

Yang Zhicheng Z Wang Mingjie M Yan Ting T Hu Zhiyong Z Zhang Hui H Liu Ruiping R

Medicine 20191201 52

The aim of the present study was to examine the association between vascular endothelial growth factor receptor 2 (VEGFR2) rs11941492 C/T polymorphism and rheumatoid arthritis (RA) risk in an eastern Chinese Han population. We examined VEGFR2 rs11941492 C/T polymorphism in 615 RA patients and 839 controls in an East Chinese Han population. The power analysis was used for evaluating the reliability of the results. Genotyping was performed using a custom-by-design 48-Plex single nucleotide polymor ...[more]

PMID: 31876763

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Project description:Rheumatoid arthritis (RA), is marked by joint inflammation leading to pannus formation which results in cartilage destruction promoting bone erosion. The pathological hallmark of RA includes synovial hyperplasia and synovial angiogenesis. Active tissue neovascularization is observed in RA. Vascular endothelial Growth factor A (VEGFA), an endothelial cell-specific proangiogenic molecule is triggered by hypoxic cells and its levels are upregulated in RA. The aim of this study was to investigate functional and pathogenic VEGFA variants and to identify the impact of point mutation in VEGFA's interaction with VEGFR2 and how these polymorphisms affect the susceptibility and severity of RA. We investigated impact of these point mutations on the stability of VEGFA using various computational tools. These mutations were further identified by conservational profile as they are highly involved as structural and functional mutations. Furthermore, these selected variants were modelled and docked against targeted domain regions IGD2 and IGD3 of VEGFR2. Further molecular dynamic simulations were performed using Gromacs. Out of 168 nsSNPS, 19 were highlighted as highly pathogenic using insilico prediction tools. InterPro and ConSurf revealed domains and conserved variants respectively. After stability analysis, we concluded that almost all the mutations were responsible for decreasing the protein stability. HOPE predicted that all the selected damaging nsSNPs were present in the domain which is essential for the functioning of VEGFA protein. Constructed Ramachandran plot and ERRAT validated the quality of all the models. Based on the interactions predicted by STRING database, we performed Protein-Protein docking between VEGFA and VEGFR2. We found few conserved interactions and new polar contacts among wild-type and mutants with VEGFR2. From the simulations, we concluded that mutant R108Q was the most stabilizing mutant among all others whereas R82Q, C86Y, and R108W complexed with VEGFR2 were comparatively less stabilizing as compared to the wild type. This study provides insight into pathogenic nsSNPs that can affect VEGFA protein structure and function. These high-risk variants must be taken into consideration for genetic screening of patients suffering from RA.

Dataset Information

Association between vascular endothelial growth factor receptor 2 rs11941492 C/T polymorphism and Chinese Han patients in rheumatoid arthritis.

Publications

Association between vascular endothelial growth factor receptor 2 rs11941492 C/T polymorphism and Chinese Han patients in rheumatoid arthritis.

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