A common missense variant rs874881 of PADI4 gene and rheumatoid arthritis: Genetic association study and in-silico analysis
•PADI4 rs874881 was found to confer RA susceptibility in Pakistani population.•Significant genotype-gender and genotype-smoking interactions were found.•Significant association with radiographic damage was observed.•The in-silico analysis was done for predicting structural and functional impacts.•Th...
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| Veröffentlicht in: | Gene 2023-02, Vol.854, p.147123-147123, Article 147123 |
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| creator | Bashir, Mutshaba Mateen, Wajeeha Khurshid, Sadia Mehmood Malik, Javaid Agha, Zehra Khan, Fariha Ajmal, Muhammad Ali, Syeda Hafiza Benish |
| description | •PADI4 rs874881 was found to confer RA susceptibility in Pakistani population.•Significant genotype-gender and genotype-smoking interactions were found.•Significant association with radiographic damage was observed.•The in-silico analysis was done for predicting structural and functional impacts.•These novel results have implications in understanding RA pathology and progression.
The peptidylarginine-deiminase 4 (PADI4) is involved in the post-translational catalytic conversion of arginine into citrulline. The autoantibodies including anti-citrullinated protein antibodies (ACPAs) produced in response to hypercitrullinated proteins are a hallmark of rheumatoid arthritis (RA) autoimmunity. Therefore, the role of a missense variant rs874881 (Gly112Ala) of PADI4 in RA susceptibility was analyzed, along with in-silico analysis of structural and functional impacts of this substitution.
We did a case-control association study and in-silico analysis. For the case-control study, confirmed RA cases and healthy controls were recruited. Genotyping for rs874881 (n = 750) was performed through polymerase chain reaction-restriction fragment length polymorphism. Multivariate logistic regression analysis was employed to determine association. The in-silico analysis was carried out through HOPE, VarMap, MutationAssessor, MutPred2, SIFT, PolyPhen, CADD, REVEL and MetaLR.
In the case-control study, the rs874881 exhibited a strong association with increased RA susceptibility (G vs C odds ratio = 3.85, 95 % confidence interval = 2.81–5.27). Interaction analysis revealed significant interaction of genotype with smoking and gender (p |
| doi_str_mv | 10.1016/j.gene.2022.147123 |
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The peptidylarginine-deiminase 4 (PADI4) is involved in the post-translational catalytic conversion of arginine into citrulline. The autoantibodies including anti-citrullinated protein antibodies (ACPAs) produced in response to hypercitrullinated proteins are a hallmark of rheumatoid arthritis (RA) autoimmunity. Therefore, the role of a missense variant rs874881 (Gly112Ala) of PADI4 in RA susceptibility was analyzed, along with in-silico analysis of structural and functional impacts of this substitution.
We did a case-control association study and in-silico analysis. For the case-control study, confirmed RA cases and healthy controls were recruited. Genotyping for rs874881 (n = 750) was performed through polymerase chain reaction-restriction fragment length polymorphism. Multivariate logistic regression analysis was employed to determine association. The in-silico analysis was carried out through HOPE, VarMap, MutationAssessor, MutPred2, SIFT, PolyPhen, CADD, REVEL and MetaLR.
In the case-control study, the rs874881 exhibited a strong association with increased RA susceptibility (G vs C odds ratio = 3.85, 95 % confidence interval = 2.81–5.27). Interaction analysis revealed significant interaction of genotype with smoking and gender (p < 0.05). Significant results (p < 0.05) were also obtained in stratified analysis by presence/absence of comorbidities and radiographic damage. According to in-silico pathogenicity prediction analysis, this Gly112Ala substitution does not exert a major effect on protein structure and function including its enzymatic activity.
We report a significant association of PADI4 rs874881 with overall RA susceptibility. To our knowledge, this is the first study to do the interaction and stratified analyses on the PADI4 rs874881 in RA. Similar detailed studies should also be performed in other populations.</description><identifier>ISSN: 0378-1119</identifier><identifier>EISSN: 1879-0038</identifier><identifier>DOI: 10.1016/j.gene.2022.147123</identifier><identifier>PMID: 36535460</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Arthritis, Rheumatoid - genetics ; Autoimmune diseases ; Case-control association study ; Case-Control Studies ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Hydrolases - genetics ; In-silico analysis ; PADI4 ; Polymorphism, Single Nucleotide ; Protein-Arginine Deiminase Type 4 - genetics ; Protein-Arginine Deiminases - genetics ; Rheumatoid arthritis ; rs874881</subject><ispartof>Gene, 2023-02, Vol.854, p.147123-147123, Article 147123</ispartof><rights>2022 Elsevier B.V.</rights><rights>Copyright © 2022 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-9383c105ba0b43f1bdec2518f5ea35aad925fc4a8bfbc3ec5ae6896e245a70ac3</citedby><cites>FETCH-LOGICAL-c356t-9383c105ba0b43f1bdec2518f5ea35aad925fc4a8bfbc3ec5ae6896e245a70ac3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.gene.2022.147123$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,778,782,3539,27911,27912,45982</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36535460$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bashir, Mutshaba</creatorcontrib><creatorcontrib>Mateen, Wajeeha</creatorcontrib><creatorcontrib>Khurshid, Sadia</creatorcontrib><creatorcontrib>Mehmood Malik, Javaid</creatorcontrib><creatorcontrib>Agha, Zehra</creatorcontrib><creatorcontrib>Khan, Fariha</creatorcontrib><creatorcontrib>Ajmal, Muhammad</creatorcontrib><creatorcontrib>Ali, Syeda Hafiza Benish</creatorcontrib><title>A common missense variant rs874881 of PADI4 gene and rheumatoid arthritis: Genetic association study and in-silico analysis</title><title>Gene</title><addtitle>Gene</addtitle><description>•PADI4 rs874881 was found to confer RA susceptibility in Pakistani population.•Significant genotype-gender and genotype-smoking interactions were found.•Significant association with radiographic damage was observed.•The in-silico analysis was done for predicting structural and functional impacts.•These novel results have implications in understanding RA pathology and progression.
The peptidylarginine-deiminase 4 (PADI4) is involved in the post-translational catalytic conversion of arginine into citrulline. The autoantibodies including anti-citrullinated protein antibodies (ACPAs) produced in response to hypercitrullinated proteins are a hallmark of rheumatoid arthritis (RA) autoimmunity. Therefore, the role of a missense variant rs874881 (Gly112Ala) of PADI4 in RA susceptibility was analyzed, along with in-silico analysis of structural and functional impacts of this substitution.
We did a case-control association study and in-silico analysis. For the case-control study, confirmed RA cases and healthy controls were recruited. Genotyping for rs874881 (n = 750) was performed through polymerase chain reaction-restriction fragment length polymorphism. Multivariate logistic regression analysis was employed to determine association. The in-silico analysis was carried out through HOPE, VarMap, MutationAssessor, MutPred2, SIFT, PolyPhen, CADD, REVEL and MetaLR.
In the case-control study, the rs874881 exhibited a strong association with increased RA susceptibility (G vs C odds ratio = 3.85, 95 % confidence interval = 2.81–5.27). Interaction analysis revealed significant interaction of genotype with smoking and gender (p < 0.05). Significant results (p < 0.05) were also obtained in stratified analysis by presence/absence of comorbidities and radiographic damage. According to in-silico pathogenicity prediction analysis, this Gly112Ala substitution does not exert a major effect on protein structure and function including its enzymatic activity.
We report a significant association of PADI4 rs874881 with overall RA susceptibility. To our knowledge, this is the first study to do the interaction and stratified analyses on the PADI4 rs874881 in RA. Similar detailed studies should also be performed in other populations.</description><subject>Arthritis, Rheumatoid - genetics</subject><subject>Autoimmune diseases</subject><subject>Case-control association study</subject><subject>Case-Control Studies</subject><subject>Genetic Association Studies</subject><subject>Genetic Predisposition to Disease</subject><subject>Humans</subject><subject>Hydrolases - genetics</subject><subject>In-silico analysis</subject><subject>PADI4</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein-Arginine Deiminase Type 4 - genetics</subject><subject>Protein-Arginine Deiminases - genetics</subject><subject>Rheumatoid arthritis</subject><subject>rs874881</subject><issn>0378-1119</issn><issn>1879-0038</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9v1DAQxS0EotvCF-CAfOSSxX_ixEFcVgXaSpXgAGdr4kyoV0lcPE6lVb88XrZwZC6j0bz3RvNj7I0UWylk836__YkLbpVQaivrVir9jG2kbbtKCG2fs43Qra2klN0ZOyfai1LGqJfsTDdGm7oRG_a44z7Oc1z4HIhwIeQPkAIsmSeybW2t5HHk33afbmp-PMdhGXi6w3WGHMPAIeW7FHKgD_yqrHPwHIiiD5BDSaW8Doc_nrBUFKbgY5lgOlCgV-zFCBPh66d-wX58-fz98rq6_Xp1c7m7rbw2Ta46bbWXwvQg-lqPsh_QKyPtaBC0ARg6ZUZfg-3H3mv0BrCxXYOqNtAK8PqCvTvl3qf4a0XKrvzqcZpgwbiSU61ppFK6bYtUnaQ-RaKEo7tPYYZ0cFK4I3S3d0cK7gjdnaAX09un_LWfcfhn-Uu5CD6eBFi-fAiYHPmAi8chJPTZDTH8L_83NaeTtw</recordid><startdate>20230220</startdate><enddate>20230220</enddate><creator>Bashir, Mutshaba</creator><creator>Mateen, Wajeeha</creator><creator>Khurshid, Sadia</creator><creator>Mehmood Malik, Javaid</creator><creator>Agha, Zehra</creator><creator>Khan, Fariha</creator><creator>Ajmal, Muhammad</creator><creator>Ali, Syeda Hafiza Benish</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20230220</creationdate><title>A common missense variant rs874881 of PADI4 gene and rheumatoid arthritis: Genetic association study and in-silico analysis</title><author>Bashir, Mutshaba ; Mateen, Wajeeha ; Khurshid, Sadia ; Mehmood Malik, Javaid ; Agha, Zehra ; Khan, Fariha ; Ajmal, Muhammad ; Ali, Syeda Hafiza Benish</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-9383c105ba0b43f1bdec2518f5ea35aad925fc4a8bfbc3ec5ae6896e245a70ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Arthritis, Rheumatoid - genetics</topic><topic>Autoimmune diseases</topic><topic>Case-control association study</topic><topic>Case-Control Studies</topic><topic>Genetic Association Studies</topic><topic>Genetic Predisposition to Disease</topic><topic>Humans</topic><topic>Hydrolases - genetics</topic><topic>In-silico analysis</topic><topic>PADI4</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Protein-Arginine Deiminase Type 4 - genetics</topic><topic>Protein-Arginine Deiminases - genetics</topic><topic>Rheumatoid arthritis</topic><topic>rs874881</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bashir, Mutshaba</creatorcontrib><creatorcontrib>Mateen, Wajeeha</creatorcontrib><creatorcontrib>Khurshid, Sadia</creatorcontrib><creatorcontrib>Mehmood Malik, Javaid</creatorcontrib><creatorcontrib>Agha, Zehra</creatorcontrib><creatorcontrib>Khan, Fariha</creatorcontrib><creatorcontrib>Ajmal, Muhammad</creatorcontrib><creatorcontrib>Ali, Syeda Hafiza Benish</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Gene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bashir, Mutshaba</au><au>Mateen, Wajeeha</au><au>Khurshid, Sadia</au><au>Mehmood Malik, Javaid</au><au>Agha, Zehra</au><au>Khan, Fariha</au><au>Ajmal, Muhammad</au><au>Ali, Syeda Hafiza Benish</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A common missense variant rs874881 of PADI4 gene and rheumatoid arthritis: Genetic association study and in-silico analysis</atitle><jtitle>Gene</jtitle><addtitle>Gene</addtitle><date>2023-02-20</date><risdate>2023</risdate><volume>854</volume><spage>147123</spage><epage>147123</epage><pages>147123-147123</pages><artnum>147123</artnum><issn>0378-1119</issn><eissn>1879-0038</eissn><abstract>•PADI4 rs874881 was found to confer RA susceptibility in Pakistani population.•Significant genotype-gender and genotype-smoking interactions were found.•Significant association with radiographic damage was observed.•The in-silico analysis was done for predicting structural and functional impacts.•These novel results have implications in understanding RA pathology and progression.
The peptidylarginine-deiminase 4 (PADI4) is involved in the post-translational catalytic conversion of arginine into citrulline. The autoantibodies including anti-citrullinated protein antibodies (ACPAs) produced in response to hypercitrullinated proteins are a hallmark of rheumatoid arthritis (RA) autoimmunity. Therefore, the role of a missense variant rs874881 (Gly112Ala) of PADI4 in RA susceptibility was analyzed, along with in-silico analysis of structural and functional impacts of this substitution.
We did a case-control association study and in-silico analysis. For the case-control study, confirmed RA cases and healthy controls were recruited. Genotyping for rs874881 (n = 750) was performed through polymerase chain reaction-restriction fragment length polymorphism. Multivariate logistic regression analysis was employed to determine association. The in-silico analysis was carried out through HOPE, VarMap, MutationAssessor, MutPred2, SIFT, PolyPhen, CADD, REVEL and MetaLR.
In the case-control study, the rs874881 exhibited a strong association with increased RA susceptibility (G vs C odds ratio = 3.85, 95 % confidence interval = 2.81–5.27). Interaction analysis revealed significant interaction of genotype with smoking and gender (p < 0.05). Significant results (p < 0.05) were also obtained in stratified analysis by presence/absence of comorbidities and radiographic damage. According to in-silico pathogenicity prediction analysis, this Gly112Ala substitution does not exert a major effect on protein structure and function including its enzymatic activity.
We report a significant association of PADI4 rs874881 with overall RA susceptibility. To our knowledge, this is the first study to do the interaction and stratified analyses on the PADI4 rs874881 in RA. Similar detailed studies should also be performed in other populations.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>36535460</pmid><doi>10.1016/j.gene.2022.147123</doi><tpages>1</tpages></addata></record> |
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| subjects | Arthritis, Rheumatoid - genetics Autoimmune diseases Case-control association study Case-Control Studies Genetic Association Studies Genetic Predisposition to Disease Humans Hydrolases - genetics In-silico analysis PADI4 Polymorphism, Single Nucleotide Protein-Arginine Deiminase Type 4 - genetics Protein-Arginine Deiminases - genetics Rheumatoid arthritis rs874881 |
| title | A common missense variant rs874881 of PADI4 gene and rheumatoid arthritis: Genetic association study and in-silico analysis |
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