Impact of IL-17F 7488T/C Functional Polymorphism on Progressive Rheumatoid Arthritis: Novel Insight from the Molecular Dynamic Simulations

Haseeb Nisar; Usman Pasha; Muhammad Usman Mirza; Rizwan Abid; Kiran Hanif; Haja N Kadarmideen; Saima Sadaf

doi:10.1080/08820139.2020.1775642

Impact of IL-17F 7488T/C Functional Polymorphism on Progressive Rheumatoid Arthritis: Novel Insight from the Molecular Dynamic Simulations

Haseeb Nisar, Usman Pasha, Muhammad Usman Mirza, Rizwan Abid, Kiran Hanif, Haja N Kadarmideen, Saima Sadaf

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

11 Citations (Scopus)

Abstract

Resorption of bones and cartilage coupled with structural changes in the inflamed joints are the major hallmark of rheumatoid arthritis (RA). Genetic polymorphisms in pro-inflammatory interleukins (ILs) appear to play an important role in the susceptibility towards progressive RA. We therefore aimed to investigate the association of single nucleotide polymorphisms (SNP), present in the hotspot coding/promoter regions of IL-6, -17 and -18, with RA susceptibility or severity in a larger study cohort from Pakistan together with finding clues as to how a functional SNP impacts the predisposition towards RA. TaqMan SNP genotyping approach was first used to assess IL-6 (rs1800795), IL-17 F (rs763780), IL-17A (rs2275913), and IL-18 (rs1946518) polymorphisms in 310 subjects (150 RA and 160 control). Molecular dynamic simulations (MDS) of wild- and mutant-type IL-17A with corresponding receptor were thereafter performed using AMBER-16; Chimera 1.13 was used for analyses. Our results showed the association of two SNPs, namely IL-6 - 174 G/C [allelic (OR = 0.960, 95% CI = 0.929-0.992, p = .009)] and IL-17 F 7488 T/C [allelic (OR = 0.907, 95%CI = 0.861-0.954, p = .000)] with increased RA risk in Pakistani subjects. When mapped, IL-17 F 7488 T/C was found involved in His161→Arg161 change near the C-terminus of IL-17 F. Comparative MDS revealed enhanced stability of the mutant hence advocating a potential role of IL-17F functional SNP in RA susceptibility and/or severity. This study provides a novel structural insight for SNP-derived functional mutation and its overall impact on binding with heterotrimeric receptor complex of IL-17 receptor thereby opening new avenues for understanding the biochemical basis of the disease.

Original language	English
Journal	Immunological Investigations
Pages (from-to)	1-11
Number of pages	11
ISSN	0882-0139
DOIs	https://doi.org/10.1080/08820139.2020.1775642
Publication status	Published - 16 Jun 2020
Externally published	Yes

Keywords

Rheumatoid arthritis
SNP genotyping
autoimmune
molecular dynamic simulations
pro-inflammatory interleukins

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10.1080/08820139.2020.1775642

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@article{6e004b7022214815bbe04cbb4415b9a6,

title = "Impact of IL-17F 7488T/C Functional Polymorphism on Progressive Rheumatoid Arthritis: Novel Insight from the Molecular Dynamic Simulations",

abstract = "Resorption of bones and cartilage coupled with structural changes in the inflamed joints are the major hallmark of rheumatoid arthritis (RA). Genetic polymorphisms in pro-inflammatory interleukins (ILs) appear to play an important role in the susceptibility towards progressive RA. We therefore aimed to investigate the association of single nucleotide polymorphisms (SNP), present in the hotspot coding/promoter regions of IL-6, -17 and -18, with RA susceptibility or severity in a larger study cohort from Pakistan together with finding clues as to how a functional SNP impacts the predisposition towards RA. TaqMan SNP genotyping approach was first used to assess IL-6 (rs1800795), IL-17 F (rs763780), IL-17A (rs2275913), and IL-18 (rs1946518) polymorphisms in 310 subjects (150 RA and 160 control). Molecular dynamic simulations (MDS) of wild- and mutant-type IL-17A with corresponding receptor were thereafter performed using AMBER-16; Chimera 1.13 was used for analyses. Our results showed the association of two SNPs, namely IL-6 - 174 G/C [allelic (OR = 0.960, 95% CI = 0.929-0.992, p = .009)] and IL-17 F 7488 T/C [allelic (OR = 0.907, 95%CI = 0.861-0.954, p = .000)] with increased RA risk in Pakistani subjects. When mapped, IL-17 F 7488 T/C was found involved in His161→Arg161 change near the C-terminus of IL-17 F. Comparative MDS revealed enhanced stability of the mutant hence advocating a potential role of IL-17F functional SNP in RA susceptibility and/or severity. This study provides a novel structural insight for SNP-derived functional mutation and its overall impact on binding with heterotrimeric receptor complex of IL-17 receptor thereby opening new avenues for understanding the biochemical basis of the disease.",

keywords = "Rheumatoid arthritis, SNP genotyping, autoimmune, molecular dynamic simulations, pro-inflammatory interleukins",

author = "Haseeb Nisar and Usman Pasha and Mirza, {Muhammad Usman} and Rizwan Abid and Kiran Hanif and Kadarmideen, {Haja N} and Saima Sadaf",

year = "2020",

month = jun,

day = "16",

doi = "10.1080/08820139.2020.1775642",

language = "English",

pages = "1--11",

journal = "Immunological Investigations",

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Impact of IL-17F 7488T/C Functional Polymorphism on Progressive Rheumatoid Arthritis: Novel Insight from the Molecular Dynamic Simulations. / Nisar, Haseeb; Pasha, Usman; Mirza, Muhammad Usman et al.
In: Immunological Investigations, 16.06.2020, p. 1-11.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Impact of IL-17F 7488T/C Functional Polymorphism on Progressive Rheumatoid Arthritis

T2 - Novel Insight from the Molecular Dynamic Simulations

AU - Nisar, Haseeb

AU - Pasha, Usman

AU - Mirza, Muhammad Usman

AU - Abid, Rizwan

AU - Hanif, Kiran

AU - Kadarmideen, Haja N

AU - Sadaf, Saima

PY - 2020/6/16

Y1 - 2020/6/16

N2 - Resorption of bones and cartilage coupled with structural changes in the inflamed joints are the major hallmark of rheumatoid arthritis (RA). Genetic polymorphisms in pro-inflammatory interleukins (ILs) appear to play an important role in the susceptibility towards progressive RA. We therefore aimed to investigate the association of single nucleotide polymorphisms (SNP), present in the hotspot coding/promoter regions of IL-6, -17 and -18, with RA susceptibility or severity in a larger study cohort from Pakistan together with finding clues as to how a functional SNP impacts the predisposition towards RA. TaqMan SNP genotyping approach was first used to assess IL-6 (rs1800795), IL-17 F (rs763780), IL-17A (rs2275913), and IL-18 (rs1946518) polymorphisms in 310 subjects (150 RA and 160 control). Molecular dynamic simulations (MDS) of wild- and mutant-type IL-17A with corresponding receptor were thereafter performed using AMBER-16; Chimera 1.13 was used for analyses. Our results showed the association of two SNPs, namely IL-6 - 174 G/C [allelic (OR = 0.960, 95% CI = 0.929-0.992, p = .009)] and IL-17 F 7488 T/C [allelic (OR = 0.907, 95%CI = 0.861-0.954, p = .000)] with increased RA risk in Pakistani subjects. When mapped, IL-17 F 7488 T/C was found involved in His161→Arg161 change near the C-terminus of IL-17 F. Comparative MDS revealed enhanced stability of the mutant hence advocating a potential role of IL-17F functional SNP in RA susceptibility and/or severity. This study provides a novel structural insight for SNP-derived functional mutation and its overall impact on binding with heterotrimeric receptor complex of IL-17 receptor thereby opening new avenues for understanding the biochemical basis of the disease.

AB - Resorption of bones and cartilage coupled with structural changes in the inflamed joints are the major hallmark of rheumatoid arthritis (RA). Genetic polymorphisms in pro-inflammatory interleukins (ILs) appear to play an important role in the susceptibility towards progressive RA. We therefore aimed to investigate the association of single nucleotide polymorphisms (SNP), present in the hotspot coding/promoter regions of IL-6, -17 and -18, with RA susceptibility or severity in a larger study cohort from Pakistan together with finding clues as to how a functional SNP impacts the predisposition towards RA. TaqMan SNP genotyping approach was first used to assess IL-6 (rs1800795), IL-17 F (rs763780), IL-17A (rs2275913), and IL-18 (rs1946518) polymorphisms in 310 subjects (150 RA and 160 control). Molecular dynamic simulations (MDS) of wild- and mutant-type IL-17A with corresponding receptor were thereafter performed using AMBER-16; Chimera 1.13 was used for analyses. Our results showed the association of two SNPs, namely IL-6 - 174 G/C [allelic (OR = 0.960, 95% CI = 0.929-0.992, p = .009)] and IL-17 F 7488 T/C [allelic (OR = 0.907, 95%CI = 0.861-0.954, p = .000)] with increased RA risk in Pakistani subjects. When mapped, IL-17 F 7488 T/C was found involved in His161→Arg161 change near the C-terminus of IL-17 F. Comparative MDS revealed enhanced stability of the mutant hence advocating a potential role of IL-17F functional SNP in RA susceptibility and/or severity. This study provides a novel structural insight for SNP-derived functional mutation and its overall impact on binding with heterotrimeric receptor complex of IL-17 receptor thereby opening new avenues for understanding the biochemical basis of the disease.

KW - Rheumatoid arthritis

KW - SNP genotyping

KW - autoimmune

KW - molecular dynamic simulations

KW - pro-inflammatory interleukins

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DO - 10.1080/08820139.2020.1775642

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JO - Immunological Investigations

JF - Immunological Investigations

ER -

Impact of IL-17F 7488T/C Functional Polymorphism on Progressive Rheumatoid Arthritis: Novel Insight from the Molecular Dynamic Simulations

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