Abstract
Previous studies are inconclusive on the relationships between BLK gene polymorphisms and clinical features of systemic lupus erythematosus (SLE). The present study aimed to estimate association between BLK loci and SLE clinical features in Chinese population. Associations between BLK single-nucleotide polymorphisms (SNPs) and susceptibility to SLE in this study were estimated using data of 1205 health controls previously reported in the same population. And a total of 814 SLE patients recruited from two different sources according with ACR criteria were analyzed for genotype–phenotype associations. A meta-analysis was conducted of the associations between BLK loci and renal disorder in SLE. The expression quantitative trait locus (eQTL) data were also extracted from the public databases for the selected SNPs. Significant associations were observed between these SNPs and susceptibility to SLE. In addition, the data showed that rs2618479 and rs7812879 were associated with renal disorder [OR = 1.51 (95% CI: 1.15, 1.99) and 1.61 (95% CI: 1.21, 2.14), Pcorr = 0.033 and 0.011, respectively] and proteinuria [OR = 1.47 (95% CI: 1.12, 1.95) and 1.52 (95% CI: 1.14, 2.03), Pcorr = 0.048 and 0.040, respectively]. The consistent associations were observed in two independent centers as well as new cases group. The result of meta-analysis for rs2618479 was also significant [OR = 1.35 (95% CI: 1.12, 1.62)]. In addition, bioinformatics analysis demonstrated that the two SNPs were significantly associated with the expression of BLK in whole blood and several immune cells. Our data support that variant loci of BLK are associated with presence of renal disorder in patients with SLE.
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References
Song GG, Lee YH. Association between BLK polymorphisms and susceptibility to SLE: a meta-analysis. Z Rheumatol. 2017;76:176–82. https://doi.org/10.1007/s00393-016-0072-8.2
Di D, Yuan H, Zhang L, Wu X, Pan H, Ye D, et al. X chromosome and female bias in systemic lupus erythematosus: focus on population-based evidence. Autoimmun Rev. 2019;18:109–11. https://doi.org/10.1016/j.autrev.2018.08.005
Edwards CJ, Cooper C. Early environmental exposure and the development of lupus. Lupus. 2006;15:814–9. https://doi.org/10.1177/0961203306069347
Chen Y, Wu Q, Shao Y, Zhang J, Guan M, Wan J, et al. Identify the association between polymorphisms of BLK and systemic lupus erythematosus through unlabelled probe-based high-resolution melting analysis. Int J Immunogenet. 2012;39:321–7. https://doi.org/10.1111/j.1744-313X.2012.01094.x
Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med. 2008;358:900–9. https://doi.org/10.1056/NEJMoa0707865
Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008;40:204–10. https://doi.org/10.1038/ng.81
Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009;41:1234–7. https://doi.org/10.1038/ng.472
Alonso-Perez E, Suarez-Gestal M, Calaza M, Ordi-Ros J, Balada E, Bijl M, et al. Further evidence of subphenotype association with systemic lupus erythematosus susceptibility loci: a European cases only study. PLoS ONE. 2012;7:e45356. https://doi.org/10.1371/journal.pone.0045356
Richman IB, Taylor KE, Chung SA, Trupin L, Petri M, Yelin E, et al. European genetic ancestry is associated with a decreased risk of lupus nephritis. Arthritis Rheum. 2012;64:3374–82. https://doi.org/10.1002/art.34567
Sanchez E, Nadig A, Richardson BC, Freedman BI, Kaufman KM, Kelly JA, et al. Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus. Ann Rheum Dis. 2011;70:1752–7. https://doi.org/10.1136/ard.2011.154104.
Pamuk ON, Gurkan H, Pamuk GE, Tozkır H, Duymaz J, Yazar M. BLK pathway-associated rs13277113 GA genotype is more frequent in SLE patients and associated with low gene expression and increased flares. Clin Rheumatol. 2017;36:103–9. https://doi.org/10.1007/s10067-016-3475-7
Taylor KE, Chung SA, Graham RR, Ortmann WA, Lee AT, Langefeld CD, et al. Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes. PLoS Genet. 2011;7:e1001311. https://doi.org/10.1371/journal.pgen.1001311
Zhang Z, Zhu KJ, Xu Q, Zhang XJ, Sun LD, Zheng HF, et al. The association of the BLK gene with SLE was replicated in Chinese Han. Arch Dermatol Res. 2010;302:619–24. https://doi.org/10.1007/s00403-010-1029-4
Samuelson EM, Laird RM, Papillion AM, Tatum AH, Princiotta MF, Hayes SM. Reduced B lymphoid kinase (Blk) expression enhances proinflammatory cytokine production and induces nephrosis in C57BL/6-lpr/lpr mice. PLoS ONE. 2014;9:e92054. https://doi.org/10.1371/journal.pone.0092054
Wu YY, Georg I, Díaz-Barreiro A, Varela N, Lauwerys B, Kumar R, et al. Concordance of increased B1 cell subset and lupus phenotypes in mice and humans is dependent on BLK expression levels. J Immunol. 2015;194:5692–702. https://doi.org/10.4049/jimmunol.1402736
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725. https://doi.org/10.1002/art.1780400928
Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29:288–91.
Zhen Q, Yang Z, Wang W, Li B, Bai M, Wu J, et al. Genetic study on small insertions and deletions in psoriasis reveals a role in complex human diseases. J Investig. Dermatol. 2019;139:2302–2312.e14. https://doi.org/10.1016/j.jid.2019.03.1157
Carithers LJ, Moore HM. The Genotype-Tissue Expression (GTEx) Project. Biopreserv Biobank. 2015;13:307–8. https://doi.org/10.1089/bio.2015.29031.hmm
Ishigaki K, Kochi Y, Suzuki A, Tsuchida Y, Tsuchiya H, Sumitomo S, et al. Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis. Nat Genet. 2017;49:1120–5. https://doi.org/10.1038/ng.3885
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75. https://doi.org/10.1086/519795
Guthridge JM, Lu R, Sun H, Sun C, Wiley GB, Dominguez N, et al. Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. Am J Hum Genet. 2014;94:586–98. https://doi.org/10.1016/j.ajhg.2014.03.008
Odhams CA, Cunninghame Graham DS, Vyse TJ. Profiling RNA-Seq at multiple resolutions markedly increases the number of causal eQTLs in autoimmune disease. PLoS Genet. 2017;13:e1007071. https://doi.org/10.1371/journal.pgen.1007071
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This study was supported by grants from the National Natural Science Foundation of China (grants 81602914 and 81502871).
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RL provided direction and guidance throughout the preparation of this paper. DD, QY, XW, LZ, XW, RL, and QH investigated the patients’ data. DD, QY, XW, and JN analyzed the data and prepared the tables and the figures. DD, QY, and XW drafted the paper. RL and DD reviewed and made significant revisions to the paper. All authors reviewed and approved the final paper.
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Di, D., Ye, Q., Wu, X. et al. Polymorphisms of BLK are associated with renal disorder in patients with systemic lupus erythematosus. J Hum Genet 65, 675–681 (2020). https://doi.org/10.1038/s10038-020-0756-4
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DOI: https://doi.org/10.1038/s10038-020-0756-4