Sains Malaysiana 49(11)(2020): 2755-2761

http://dx.doi.org/10.17576/jsm-2020-4911-14

Association of STAT4 rs7574865 with Sysceptibility to Juvenile Onset Systemic Lupus Erythematous in Pakistani Population

(Perkaitan STAT4 rs7574865 dengan Kebolehlihatan terhadap Penyakit Lupus Erythematous Sistemik Juvenil pada Penduduk Pakistan)

BASHIR RASHEEDA¹*, ALI HIRA¹, MALIK SAIRA², MUNIR NEELMA¹, HAQ RUKHAMA¹, NAZ SHAGUFTA¹ & ALTAF IMRAN³

¹Department of Biotechnology, Lahore College for Women University, Lahore, Pakistan

²Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan

³Institute of Microbiology, University of Veterinary and Animal Sciences, Lahore, Pakistan

Diserahkan: 30 Oktober 2019/Diterima: 10 Jun 2020

ABSTRACT

Association of STAT4 (signal transducer and activator of transcription4) haplotype tagged by single nucleotide polymorphism (SNP) rs7574865 with systemic lupus erythematosus (SLE) was reported in different populations. This study was aimed to investigate a genetic association between STAT4 single nucleotide polymorphism (rs7574865) with susceptibility and clinical features of systemic lupus erythematosus in Pakistani population. A total of 75 clinically diagnosed individuals affected with SLE were enrolled from Children’s Hospital and Institute of Child Health Lahore.  Sixty-eight healthy individuals of same ethnicity were also enrolled for this study. Clinical assessment of patients was done with the help of clinical features suggestive for SLE and some diagnostic tests specific for the disease were performed. SNP rs7574865 was genotyped by allele specific tetra ARMS PCR assay to check and compare the genotypic allele frequencies between SLE patients and healthy controls. Different statistical analysis ChiSquare, Fisher’s exact tests and binary Logistic Regression is performed to determine association of risk alleles with SLE in Pakistani population. p value less than >0.05 consider significant. This study showed the frequency of GG (28%), TT (12%), and GT alleles (60%) in SLE patients while controls showed allele frequencies of GG (5%), TT (29%) and GT (64%), respectively. The results showed that GG genotype and G allele in STAT4 rs7574865 was the risk allele for SLE while T allele proved to be the protective one for disease susceptibility when compared with healthy controls genotypic frequencies. This study suggests the strong association of SNP rs7574865 in STAT4 with the risk of SLE in Pakistani population. However, G allele showed no association with organ damage and immune disorder of SLE.

Keywords: Single nucleotide polymorphism; STAT4; systemic lupus erythematosus

ABSTRAK

Perkaitan antara STAT4 (transduser isyarat dan pengaktif transkripsi4) haplotip bertanda oleh polimorfisme nukleotida tunggal (SNP) rs7574865 dengan lupus eritematosus sistemik (SLE) dilaporkan dalam populasi berbeza. Kajian ini bertujuan untuk mengkaji hubungan genetik antara polimorfisme nukleotida tunggal STAT4 (rs7574865) dengan kerentanan dan ciri klinikal lupus eritematosus sistemik dalam populasi Pakistan. Seramai 75 individu yang didiagnosis secara klinikal terkesan oleh SLE telah didaftarkan dari Hospital Kanak-kanak dan Institut Kesihatan Kanak-kanak Lahore. Enam puluh lapan individu sihat daripada etnik yang sama juga telah didaftarkan untuk kajian ini. Penilaian klinikal pesakit dilakukan dengan bantuan ciri klinikal untuk SLE dan beberapa ujian diagnostik khusus untuk penyakit tersebut dijalankan. SNP rs7574865 digenotip dengan alel khusus tetra asai ARMS PCR untuk menyemak dan membandingkan frekuensi alel genotip antara pesakit SLE dan kawalan sihat. Analisis statistik ChiSquare berbeza, ujian tepat Fisher dan Regresi Logistik binari dijalankan untuk menentukan hubungan risiko alel dengan SLE dalam populasi Pakistan. Nilai p kurang daripada >0.05 dianggap signifikan. Kajian ini menunjukkan frekuensi alel GG (28%), TT (12%) dan GT (60%) pada pesakit SLE sementara kawalan menunjukkan frekuensi alel GG (5%), TT (29%) dan GT (64%). Hasil kajian menunjukkan bahawa genotip GG dan alel G pada STAT4 rs7574865 adalah alel risiko untuk SLE sementara alel T terbukti menjadi pelindung bagi kerentanan penyakit apabila dibandingkan dengan frekuensi genotipik kawalan sihat. Kajian ini mencadangkan perkaitan yang kuat oleh SNP rs7574865 dalam STAT4 dengan risiko SLE dalam populasi Pakistan. Walau bagaimanapun, alel G tidak menunjukkan kaitan dengan kerosakan organ dan gangguan imun SLE.

Kata kunci: Lupus eritematosus sistemik; polimorfisme nukleotida tunggal; STAT4

RUJUKAN

Abelson, A.K., Delgado-Vega, A.M., Kozyrev, S.V., Sánchez, E., Velázquez-Cruz, R., Eriksson, N., Wojcik, J., Linga Reddy, M.V., Lima, G., D'Alfonso, S., Migliaresi S., Baca, V., Orozco, L., Witte, T. & Ortego-Centeno, N. 2009. STAT4 associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk. Ann. Rheum. Dis. 68(11) 1746-1753.

AlArfaj, A.S. & Khalil, N. 2009. Clinical and immunological manifestations in 624 SLE patients in Saudi Arabia. Lupus 18(5): 465-473.

Al-Maini, M.H., El-Ageb, E.M., Al-Wahaibi, S.S., Al-Farsi, Y. & Richens, E.R. 2003. Demographic, autoimmune, and clinical profiles of patients with systemic lupus erythematosus in Oman. Rheumatol. Int. 23(4): 186-191.

Bolin, K., Sandling, J.K., Zickert, A. & Jonsen, A. 2013. Association of STAT4 polymorphism with severe renal insufficiency in lupus nephritis. PLoS ONE 8(12): e84450.

Candace, H., Feldman, L.T. & Hiraki, J.K. 2013. Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among us adults with medicaid coverage, 2000-2004. Arthritis Rhem. 65(3): 753-763.

Cruz, D.P. 2006. Systemic lupus erythematosus. British Medical Journal 332(7546): 890-894.

Gabriel, S.B., Schaffner, S.F. & Nguyen, H. 2002. The structure of haplotype blocks in the human genome. Science 296(78): 2225-2229.

Grimberg, J., Nawoschik, S., Belluscio, L., McKee, R. & Turck, A. 1989. A simple and efficient non-organic procedure for the isolation of genomic DNA from blood. Nucleic Acids Res. 17(20): 8390-8390.

Habibi, S., Saleem, M.A. & Ramanan, A.V. 2011. Juvenile systemic lupus erythematosus: Review of clinical features and management. Indian Pediatr. 48(11): 879-887.

Han, J.W., Zheng, H.F., Cui, Y., Sun, L.D., Ye, D.Q. & Hu, Z. 2009. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 41(8): 1234-1237.

Harley, I.T., Kaufman, K.M. & Langefeld, C.D. 2009. Genetic susceptibility to SLE. Molecular Biology Reports 10: 285-290.

Hoffecker, B.M., Raffield, L.M., Kamen, D.L. & Nowling, T.K. 2013. Systemic lupus erythematosus and vitamin D deficiency are associated with shorter telomere length among African Americans: A case-control study. PLoS ONE 8(5): e63725.

Hom, G., Graham, R.R. & Modrek, B. 2008. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358(8): 900-909.

Kawasaki, A., Ito, I., Hikami, K., Ohashi, J. & Hayashi, T. 2008. Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: A case-control association study of the STAT1-STAT4 region. Arthritis Res. Ther. 10(5): R113.

Kimberly, E.T., Elaine, F., Remmers, T. & Annette, L. 2008. Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet. 4: 5e.

Kuenkele, S., Beyer, T.D., Voll, R.E., Kalden, J.R. & Herrmann, M. 2003. Impaired clearance of apoptotic cells in systemic lupus erythematosus: Challenge of T and B cell tolerance. Cur. Rheumatol. Rep. 5: 175-177.

Mahajan, A., Herrmann, M. & Muñoz, L.E. 2016. Clearance deficiency and cell death pathways: A model for the pathogenesis of SLE. Front Immunol. 7: 35.

Malaviya, A.N., Chandrasekaran, A.N., Kumar, A. & Shamar, P.N. 1997. Systemic lupus erythematosus in India. Lupus 6: 690-700.

Marti, J., Varade, A., Marquez, M.C. & Cenit, L. 2008. Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum. 58(9): 2598-2602.

Mirkazemi, S., Akbarian, M., Jamshidi, A.R. & Mansouri, R. 2013. Association of STAT4 rs7574865 with susceptibility to systemic lupus erythematosus in Iranian population. Inflammation 36(6): 1548-1552.

Morales, R.J., Gonzalez, C.I. & Ramrez, G. 2008. STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in Colombians. Genes Immun. 4: 1466-4879.

Munoz, L.E., Gaipl, U., Franz, S. & Sheriff, A. 2005. SLE a disease of clearance deficiency? Rheumatology 44: 1101-1107.

Piotr, P., Margarita, L., Mariusz, W. & Marzena, O.P. 2012. Contribution of STAT4 gene single-nucleotide polymorphism to systemic lupus erythematosus in the Polish population. Mol. Biol. Rep. 39: 8861-8866.

Sigurdsson, S., Nordmark, G., Garnier, S., Grundberg, E., Kwan, T. & Nilsson, O. 2008. A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5. Hum. Mol. Genet. 17: 2868-2876.

Su, D.L., Lu, Z.M., Shen, M.N., Li, X. & Sun, L.Y. 2012. Roles of pro -and anti-inflammatory cytokines in the pathogenesis of SLE. J. Biomed. Biotechnol.  2012: 347141.

Taylor, K.E., Remmers, E.F., Lee, A.T., Ortmann, W.A. & Plenge, R.M. 2008. Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet. 4: 5e.

Tsao, B.P. & Grossman, J.M. 2001. Genetics and systemic lupus erythematosus. Cur. Rheumatol. Rep. 3: 183-190.

Yin, S., Zhao, Y., Xu, L., Guo, J.P., Jiang, Q., Liu, X.Y., Zhang, F.C., Zheng, Y., Li, X.X., Song, H., Huang, C.B., Huang, Y.H., Wang, T., Pan, S.S., Li,  C., Liu, X., Zhu, L., Zhang, C.F. & Li, Z.G. 2010. Variation in STAT4 is associated with systemic lupus erythematosus in Chinese Northern Han population. Chinese Medical Journal. 123(22): 3173-3177.

Zervou, M.I., Vazgiourakis, V.M., Yilmaz, N., Kontaki, E. & Trouw, L. 2011. TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus erythematosus in Turkey. Hum. Immunol. 72(12): 1210-1213.

Zhao, M., Hirankarn, N., Lau, C.S. & Mok, C.C. 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: 219-226.

*Pengarang untuk surat-menyurat; email: rashidasbs@yahoo.com