Single Nucleotide Polymorphism rs6445975 in the PXK Gene Is Correlated with Susceptibility and Clinical Characteristics of Systemic Lupus Erythematosus
-
Mansour Karimifar
,
Nafiseh Sereshti
,
Rasoul Salehi
,
Maryam Mousavi
,
Hadi Karimzadeh
,
Amirhossein Salehi
,
Bahram Pakzad
Abstract
Background: Recently, genome-wide association studies (GWAS) have discovered several single nucleotide polymorphisms (SNPs) and loci associated with the risk of systemic lupus erythematosus (SLE). rs6445975 (T>G; intronic variant) polymorphism in the PXK gene is one of these loci. However, there was an inconsistency between the results of replicative studies on European and Asia ancestry. This study aimed to assess the possible association between rs6445975 polymorphism with SLE risk in the Iranian population.
Methods: Genotype and allele distribution of rs6445975 polymorphism were investigated in 110 patients with SLE and 115 healthy controls in Isfahan University of Medical Sciences, Isfahan, Iran in 2019 via real-time PCR high resolution melting method (HRM).
Results: GG and TG genotypes, but not TT genotype, were associated with increased risk of SLE (GG vs TT; OR= 7.538; 95%CI [3.47, 17.066] and TG vs TT; OR=2.21; 95%CI [1.06, 4.72]). Inheritance analysis revealed that TG + GG was correlated with the increased risk of SLE disease in the dominant model (OR=3.928; 95%CI [2.056, 7.74]). Moreover, subjects with the G allele were more frequently affected with SLE than individuals with the T allele (OR= 3.55; 95%CI [2.37, 5.36]). The G allele in patients was correlated with serum concentration of CRP, ESR, anti-dsDNA antibody, C3, and C4 and presentation of some clinical manifestations such as kidney involvements and skin lesions (P<0.05).
Conclusion: Our findings suggest a substantial association between rs6445975 polymorphism in the PXK gene with susceptibility and clinical characteristics of SLE in the Iranian population.
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15. Harley JB, Alarcón-Riquelme ME, Criswell LA, et al (2008). Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet, 40(2):204-10.
16. Stahl EA, Raychaudhuri S, Remmers EF, et al (2010). Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet, 42(6):508.
17. Kim EM, Bang SY, Kim I, Shin HD, et al (2012). Different genetic effect of PXK on systemic lupus erythematosus in the Korean population. Rheumatol Int, 32(1):277-80.
18. Yu B, Wu Q, Chen Y, et al (2011). Polymorphisms of PXK are associated with autoantibody production, but not disease risk, of systemic lupus erythematosus in Chinese mainland population. Lupus, 20(1):23-7.
19. Suarez-Gestal M, Calaza M, Endreffy E, et al (2009). Replication of recently identified systemic lupus erythematosus genetic associations: a case–control study. Arthritis Res Ther, 11(3):1-9.
20. Lindén M, Sepúlveda JIR, James T, et al (2017). Sex influences eQTL effects of SLE and Sjögren’s syndrome-associated genetic polymorphisms. Biol Sex Differ, 8(1):1-12.
21. Aringer M, Costenbader K, Daikh D, et al (2019). 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol, 71(9):1400-12.
22. Pakzad B, Shirpour R, Mousavi M, et al (2020). C1QTNF4 gene p. His198Gln mutation is correlated with early‐onset systemic lupus erythematosus in Iranian patients. Int J Rheum Dis, 23(11):1594-8.
23. Karimifar M, Pakzad B, Karimzadeh H, et al (2019). Interferon-induced protein 44-like gene promoter is differentially methylated in peripheral blood mononuclear cells of systemic lupus erythematosus patients. Journal of research in medical sciences: J Res Med Sci, 24.
24. Simonian M, Mosallaei M, Khosravi S, Salehi R (2019). rs12904 polymorphism in the 3'-untranslated region of ephrin A1 ligand and the risk of sporadic colorectal cancer in the Iranian population. J Cancer Res Ther, 15(1):15.
25. Ehtesham N, Zare Rafie M, Esmaeilzadeh E, et al (2021). Three functional variants in the NLRP3 gene are associated with susceptibility and clinical characteristics of systemic lupus erythematosus. Lupus, 30(8):1273-82.
26. Norambuena PA, Copeland JA, Křenková P, Štambergová A, Macek Jr M (2009). Diagnostic method validation: High resolution melting (HRM) of small amplicons genotyping for the most common variants in the MTHFR gene. Clin Biochem, 42(12):1308-16.
27. Hosking L, Lumsden S, Lewis K, et al (2004). Detection of genotyping errors by Hardy–Weinberg equilibrium testing. Eur J Hum Genet, 12(5):395-9.
28. Kwon Y-C, Chun S, Kim K, Mak A (2019). Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond. Cells, 8(10):1180.
29. Julià A, López-Longo FJ, Pérez Venegas JJ, et al (2018). Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus. Arthritis Res Ther, 20(1):1-10.
30. Fike AJ, Elcheva I, Rahman ZSM (2019). The Post-GWAS Era: How to Validate the Contribution of Gene Variants in Lupus. Curr Rheumatol Rep, 21(1):3.
31. Zou X, Qiu G, Chen C, et al (2005). Expression pattern and subcellular localization of five splice isoforms of human PXK. Int J Mol Med, 16(4):701-7.
32. Kim E-M, Bang S-Y, Kim I, et al (2012). Different genetic effect of PXK on systemic lupus erythematosus in the Korean population. Rheumatol Int, 32(1):277-80.
33. Yang W, Ng P, Zhao M, et al (2009). Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese. Genes Immun, 10(3):219-26.
2. Chen L, Morris DL, Vyse TJ (2017). Genetic advances in systemic lupus erythematosus: an update. Curr Opin Rheumatol, 29(5):423-33.
3. Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD (2011). Manifestations of systemic lupus erythematosus. Maedica (Bucur), 6(4):330-6.
4. Signorini V, Elefante E, Zucchi D, Trentin F, Bortoluzzi A, Tani C (2020). One year in review 2020: systemic lupus erythematosus. Clin Exp Rheumatol, 38(0):592-601.
5. Ramírez Sepúlveda JI, Bolin K, Mofors J, et al (2019). Sex differences in clinical presentation of systemic lupus erythematosus. Biol Sex Differ, 10(1):60.
6. Guerra SG, Vyse TJ, Cunninghame Graham DS (2012). The genetics of lupus: a functional perspective. Arthritis Res Ther, 14(3):211.
7. Cooper GS, Miller FW, Pandey JP (1999). The role of genetic factors in autoimmune disease: implications for environmental research. Environ Health Perspect, 107 Suppl 5:693-700.
8. Cui Y, Sheng Y, Zhang X (2013). Genetic susceptibility to SLE: recent progress from GWAS.
J. Autoimmun, 41:25-33.
9. Lee YH, Bae S-C, Choi SJ, Ji JD, Song GG (2012). Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis. Mol Biol Rep, 39(12):10627-35.
10. Martínez-Bueno M, Alarcón-Riquelme ME (2019). Exploring impact of rare variation in systemic lupus erythematosus by a genome wide imputation approach. Front Immunol, 10:258.
11. Julià A, López-Longo FJ, Pérez Venegas JJ, et al (2018). Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus. Arthritis Res Ther, 20(1):100.
12. Gualtierotti R, Biggioggero M, Penatti A, Meroni P (2010). Updating on the pathogenesis of systemic lupus erythematosus. Autoimmun Rev, 10(1):3-7.
13. Ye J, Gillespie KM, Rodriguez S (2018). Unravelling the roles of susceptibility loci for autoimmune diseases in the post-GWAS era. Genes, 9(8):377.
14. Hassani M, Dehani M, Rafie MZ, et al, (2021) . Investigation of rs531564 polymorphism in the primary microRNA-124 gene in patients with systemic lupus erythematosus and rheumatoid arthritis: association with disease susceptibility and clinical characteristics. Iran J Allergy Asthma Immunol, 20(3):303-313.
15. Harley JB, Alarcón-Riquelme ME, Criswell LA, et al (2008). Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet, 40(2):204-10.
16. Stahl EA, Raychaudhuri S, Remmers EF, et al (2010). Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet, 42(6):508.
17. Kim EM, Bang SY, Kim I, Shin HD, et al (2012). Different genetic effect of PXK on systemic lupus erythematosus in the Korean population. Rheumatol Int, 32(1):277-80.
18. Yu B, Wu Q, Chen Y, et al (2011). Polymorphisms of PXK are associated with autoantibody production, but not disease risk, of systemic lupus erythematosus in Chinese mainland population. Lupus, 20(1):23-7.
19. Suarez-Gestal M, Calaza M, Endreffy E, et al (2009). Replication of recently identified systemic lupus erythematosus genetic associations: a case–control study. Arthritis Res Ther, 11(3):1-9.
20. Lindén M, Sepúlveda JIR, James T, et al (2017). Sex influences eQTL effects of SLE and Sjögren’s syndrome-associated genetic polymorphisms. Biol Sex Differ, 8(1):1-12.
21. Aringer M, Costenbader K, Daikh D, et al (2019). 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol, 71(9):1400-12.
22. Pakzad B, Shirpour R, Mousavi M, et al (2020). C1QTNF4 gene p. His198Gln mutation is correlated with early‐onset systemic lupus erythematosus in Iranian patients. Int J Rheum Dis, 23(11):1594-8.
23. Karimifar M, Pakzad B, Karimzadeh H, et al (2019). Interferon-induced protein 44-like gene promoter is differentially methylated in peripheral blood mononuclear cells of systemic lupus erythematosus patients. Journal of research in medical sciences: J Res Med Sci, 24.
24. Simonian M, Mosallaei M, Khosravi S, Salehi R (2019). rs12904 polymorphism in the 3'-untranslated region of ephrin A1 ligand and the risk of sporadic colorectal cancer in the Iranian population. J Cancer Res Ther, 15(1):15.
25. Ehtesham N, Zare Rafie M, Esmaeilzadeh E, et al (2021). Three functional variants in the NLRP3 gene are associated with susceptibility and clinical characteristics of systemic lupus erythematosus. Lupus, 30(8):1273-82.
26. Norambuena PA, Copeland JA, Křenková P, Štambergová A, Macek Jr M (2009). Diagnostic method validation: High resolution melting (HRM) of small amplicons genotyping for the most common variants in the MTHFR gene. Clin Biochem, 42(12):1308-16.
27. Hosking L, Lumsden S, Lewis K, et al (2004). Detection of genotyping errors by Hardy–Weinberg equilibrium testing. Eur J Hum Genet, 12(5):395-9.
28. Kwon Y-C, Chun S, Kim K, Mak A (2019). Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond. Cells, 8(10):1180.
29. Julià A, López-Longo FJ, Pérez Venegas JJ, et al (2018). Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus. Arthritis Res Ther, 20(1):1-10.
30. Fike AJ, Elcheva I, Rahman ZSM (2019). The Post-GWAS Era: How to Validate the Contribution of Gene Variants in Lupus. Curr Rheumatol Rep, 21(1):3.
31. Zou X, Qiu G, Chen C, et al (2005). Expression pattern and subcellular localization of five splice isoforms of human PXK. Int J Mol Med, 16(4):701-7.
32. Kim E-M, Bang S-Y, Kim I, et al (2012). Different genetic effect of PXK on systemic lupus erythematosus in the Korean population. Rheumatol Int, 32(1):277-80.
33. Yang W, Ng P, Zhao M, et al (2009). Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese. Genes Immun, 10(3):219-26.
| Files | ||
| Issue | Vol 51 No 8 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v51i8.10273 | |
| Keywords | ||
| Systemic lupus erythematosus Gene Single nucleotide polymorphism Autoimmune disease | ||
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How to Cite
1.
Karimifar M, Sereshti N, Salehi R, Mousavi M, Karimzadeh H, Salehi A, Pakzad B. Single Nucleotide Polymorphism rs6445975 in the PXK Gene Is Correlated with Susceptibility and Clinical Characteristics of Systemic Lupus Erythematosus. Iran J Public Health. 2022;51(8):1866-1874.
