Interleukin Variants Are Associated with the Development and Progression of IgA Nephropathy: A Candidate-Gene Association Study and Meta-Analysis
Abstract
:1. Introduction
2. Results
2.1. Association Analysis
2.1.1. Clinical Profile of Participants
2.1.2. Development of Progressive IgA Nephropathy
2.1.3. Linkage Disequilibrium Analysis
2.1.4. Analysis of Haplotypes
2.2. Meta-Analysis
Study Characteristics
3. Discussion
4. Materials and Methods
4.1. Association Study
4.1.1. Participants
4.1.2. Genotyping
4.1.3. Data Analysis
4.2. Meta-Analysis
4.2.1. Identification and Eligibility of Relevant Studies
4.2.2. Data Extraction
4.2.3. Data Synthesis and Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Lai, K.N.; Tang, S.C.W.; Schena, F.P.; Novak, J.; Tomino, Y.; Fogo, A.B.; Glassock, R.J. IgA nephropathy. Nat. Rev. Dis. Primer 2016, 2, 16001. [Google Scholar] [CrossRef]
- Lai, K.N. Pathogenesis of IgA nephropathy. Nat. Rev. Nephrol. 2012, 8, 275–283. [Google Scholar] [CrossRef]
- Mucha, K.; Pac, M.; Pączek, L. Omics are Getting Us Closer to Understanding IgA Nephropathy. Arch. Immunol. Ther. Exp. 2023, 71, 12. [Google Scholar] [CrossRef] [PubMed]
- A Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Roberts, I.S.D.; Cook, H.T.; Troyanov, S.; Alpers, C.E.; Amore, A.; Barratt, J.; Berthoux, F.; Bonsib, S.; Bruijn, J.A.; et al. The Oxford classification of IgA nephropathy: Pathology definitions, correlations, and reproducibility. Kidney Int. 2009, 76, 546–556. [Google Scholar] [CrossRef] [PubMed]
- Gentile, M.; Sanchez-Russo, L.; Riella, L.V.; Verlato, A.; Manrique, J.; Granata, S.; Fiaccadori, E.; Pesce, F.; Zaza, G.; Cravedi, P. Immune abnormalities in IgA nephropathy. Clin. Kidney J. 2023, 16, 1059–1070. [Google Scholar] [CrossRef]
- Montinaro, V.; Hevey, K.; Aventaggiato, L.; Fadden, K.; Esparza, A.; Chen, A.; Finbloom, D.S.; Rifai, A. Extrarenal cytokines modulate the glomerular response to IgA immune complexes. Kidney Int. 1992, 42, 341–353. [Google Scholar] [CrossRef] [PubMed]
- Schena, F.P.; Gesualdo, L.; Montinaro, V.; Schena, F.P.; Gesualdo, L.; Montinaro, V. Immunopathological Aspects of Immunoglobulin A Nephropathy and Other Mesangial Proliferative Glomerulonephritides. J. Am. Soc. Nephrol. 1992, 2, S167–S172. [Google Scholar] [CrossRef]
- Yoshioka, K.; Takemura, T.; Murakami, K.; Okada, M.; Yagi, K.; Miyazato, H.; Matsushima, K.; Maki, S. In situ expression of cytokines in IgA nephritis. Kidney Int. 1993, 44, 825–833. [Google Scholar] [CrossRef]
- Chen, A.; Chen, W.-P.; Sheu, L.-F.; Lin, C.-Y. Pathogenesis of IgA nephropathy: In vitro activation of human mesangial cells by IgA immune complex leads to cytokine secretion. J. Pathol. 1994, 173, 119–126. [Google Scholar] [CrossRef]
- Lovett, D.H.; Larsen, A. Cell cycle-dependent interleukin 1 gene expression by cultured glomerular mesangial cells. J. Clin. Investig. 1988, 82, 115–122. [Google Scholar] [CrossRef]
- Myllymäki, J.M.; Honkanen, T.T.; Syrjänen, J.T.; Helin, H.J.; Rantala, I.S.; Pasternack, A.I.; Mustonen, J.T. Severity of tubulointerstitial inflammation and prognosis in immunoglobulin A nephropathy. Kidney Int. 2007, 71, 343–348. [Google Scholar] [CrossRef]
- Chan, L.Y.Y.; Leung, J.C.K.; Tsang, A.W.L.; Tang, S.C.W.; Lai, K.N. Activation of tubular epithelial cells by mesangial-derived TNF-a: Glomerulotubular communication in IgA nephropathy. Kidney Int. 2005, 67, 602–612. [Google Scholar] [CrossRef] [PubMed]
- Lai, K.N.; Leung, J.C.K.; Chan, L.Y.Y.; Saleem, M.A.; Mathieson, P.W.; Lai, F.M.; Tang, S.C.W. Activation of podocytes by mesangial-derived TNF-α: Glomerulo-podocytic communication in IgA nephropathy. Am. J. Physiol. Ren. Physiol. 2008, 294, F945–F955. [Google Scholar] [CrossRef] [PubMed]
- Radford, M.G.; Donadio, J.V.; Bergstralh, E.J.; Grandet, J.P. Predicting Renal Outcome in IgA Nephropathy. J. Am. Soc. Nephrol. 1997, 8, 199–207. [Google Scholar] [CrossRef] [PubMed]
- Hahn, W.; Cho, B.; Kim, S.; Kim, S.; Kang, S. Interleukin-1 cluster gene polymorphisms in childhood IgA nephropathy. Pediatr. Nephrol. 2009, 24, 1329–1336. [Google Scholar] [CrossRef]
- Liu, H.; Liang, D.; Wang, L.; Zhou, N.; Yao, C.; Hong, T.; Tang, D.; Chen, X. Effects of specific interleukin-1beta-converting enzyme inhibitor on ischemic acute renal failure in murine models. Acta Pharmacol. Sin. 2005, 26, 1345–1351. [Google Scholar] [CrossRef]
- Akash, M.S.H.; Rehman, K.; Sun, H.; Chen, S. Sustained delivery of IL-1Ra from PF127-gel reduces hyperglycemia in diabetic GK-rats. PLoS ONE 2013, 8, e55925. [Google Scholar] [CrossRef]
- Berry, M.; Clatworthy, M.R. Immunotherapy for acute kidney injury. Immunotherapy 2012, 4, 323–334. [Google Scholar] [CrossRef]
- Wu, T.H.; Wu, S.C.; Huang, T.P.; Yu, C.L.; Tsai, C.Y. Increased excretion of tumor necrosis factor alpha and interleukin 1 beta in urine from patients with IgA nephropathy and Schönlein-Henoch purpura. Nephron 1996, 74, 79–88. [Google Scholar] [CrossRef]
- Rauta, V.; Teppo, A.-M.; Törnroth, T.; Honkanen, E.; Grönhagen-Riska, C. Lower urinary-interleukin-1 receptor-antagonist excretion in IgA nephropathy than in Henoch-Schönlein nephritis. Nephrol. Dial. Transplant. 2003, 18, 1785–1791. [Google Scholar] [CrossRef]
- Hung, A.M.; Ellis, C.D.; Shintani, A.; Booker, C.; Ikizler, T.A. IL-1β receptor antagonist reduces inflammation in hemodialysis patients. J. Am. Soc. Nephrol. 2011, 22, 437–442. [Google Scholar] [CrossRef] [PubMed]
- Zintzaras, E. The power of generalized odds ratio in assessing association in genetic studies. J. Appl. Stat. 2012, 39, 2569–2581. [Google Scholar] [CrossRef]
- Zintzaras, E. The generalized odds ratio as a measure of genetic risk effect in the analysis and meta-analysis of association studies. Stat. Appl. Genet. Mol. Biol. 2010, 9, 21. [Google Scholar] [CrossRef]
- Liu, Z.-H.; Cheng, Z.-H.; Yu, Y.-S.; Tang, Z.; Li, L.-S. Interleukin-1 receptor antagonist allele: Is it a genetic link between Henoch-Schönlein nephritis and IgA nephropathy? Kidney Int. 1997, 51, 1938–1942. [Google Scholar] [CrossRef] [PubMed]
- Shu, K.H.; Lee, S.H.; Cheng, C.H.; Wu, M.J.; Lian, J.D. Impact of interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphism on IgA nephropathy. Kidney Int. 2000, 58, 783–789. [Google Scholar] [CrossRef] [PubMed]
- Syrjänen, J.; Hurme, M.; Lehtimäki, T.; Mustonen, J.; Pasternack, A. Polymorphism of the cytokine genes and IgA nephropathy. Kidney Int. 2002, 61, 1079–1085. [Google Scholar] [CrossRef] [PubMed]
- Watanabe, M.; Iwano, M.; Akai, Y.; Kurioka, H.; Nishitani, Y.; Harada, K.; Hamano, K.; Shiiki, H. Association of Interleukin-1 Receptor Antagonist Gene Polymorphism with IgA Nephropathy. Nephron 2002, 91, 744–746. [Google Scholar] [CrossRef] [PubMed]
- Bantis, C.; Heering, P.J.; Aker, S.; Klein-Vehne, N.; Grabensee, B.; Ivens, K. Association of interleukin-10 gene G-1082A polymorphism with the progression of primary glomerulonephritis. Kidney Int. 2004, 66, 288–294. [Google Scholar] [CrossRef]
- Chin, H.J.; Na, K.Y.; Kim, S.J.; Oh, K.-H.; Kim, Y.S.; Lim, C.S.; Kim, S.; Chae, D.-W. Interleukin-10 promoter polymorphism is associated with the predisposition to the development of IgA nephropathy and focal segmental glomerulosclerosis in Korea. J. Korean Med. Sci. 2005, 20, 989–993. [Google Scholar] [CrossRef]
- Liu, X.-Q.; Paterson, A.D.; He, N.; St George-Hyslop, P.; Rauta, V.; Gronhagen-Riska, C.; Laakso, M.; Thibaudin, L.; Berthoux, F.; Cattran, D.; et al. IL5RA and TNFRSF6B gene variants are associated with sporadic IgA nephropathy. J. Am. Soc. Nephrol. 2008, 19, 1025–1033. [Google Scholar] [CrossRef]
- Jung, H.Y.; Cho, J.H.; Lim, J.H.; Yu, C.H.; Choi, J.Y.; Yoon, S.H.; Park, S.H.; Kim, Y.L.; Kim, C.D. Impact of gene polymorphisms of interleukin-18, transforming growth factor-β, and vascular endothelial growth factor on development of IgA nephropathy and thin glomerular basement membrane disease. Kidney Res. Clin. Pract. 2012, 31, 234–241. [Google Scholar] [CrossRef]
- Yamamoto, R.; Nagasawa, Y.; Shoji, T.; Katakami, N.; Ohtoshi, K.; Hayaishi-okano, R.; Yamasaki, Y.; Yamauchi, A.; Tsubakihara, Y.; Imai, E.; et al. A candidate gene approach to genetic contributors to the development of IgA nephropathy. Nephrol. Dial. Transplant. 2012, 27, 1020–1030. [Google Scholar] [CrossRef]
- Wang, W.; Sun, Y.; Fu, Y.; Yu, X.; Li, M. Interaction of C1GALT1-IL5RA on the susceptibility to IgA nephropathy in Southern Han Chinese. J. Hum. Genet. 2013, 58, 40–46. [Google Scholar] [CrossRef] [PubMed]
- Yang, B.; Feng, W.; Li, Y.; Shi, Y.; Cai, B.; Liao, Y.; Zhang, J.; Huang, Z.; Wang, L. Interleukin 18-607 A/C Gene Polymorphism is Associated with Susceptibility to IgA Nephropathy in a Chinese Han Population. Appl. Immunohistochem. Mol. Morphol. 2016, 25, 725–730. [Google Scholar] [CrossRef] [PubMed]
- Gao, J.; Wei, L.; Fu, R.; Wei, J.; Niu, D.; Wang, L.; Ge, H.; Yu, Q.; Wang, M.; Liu, X.; et al. Association of interleukin-10 polymorphisms (rs1800872, rs1800871, and rs1800896) with predisposition to IgA nephropathy in a Chinese han population: A case-control study. Kidney Blood Press. Res. 2017, 42, 89–98. [Google Scholar] [CrossRef] [PubMed]
- Zhang, D.; Xie, M.; Yang, X.; Zhang, Y.; Su, Y.; Wang, Y.; Huang, H.; Han, H.; Li, W.; Fu, K.; et al. Determination of IL-1B (rs16944) and IL-6 (rs1800796) genetic polymorphisms in IgA nephropathy in a northwest Chinese Han population. Oncotarget 2017, 8, 71750–71758. [Google Scholar] [CrossRef]
- Ding, X.; Mei, Y.; Mao, Z.; Long, L.; Han, Q.; You, Y.; Zhu, H. Association of Immune and Inflammatory Gene Polymorphism with the Risk of IgA Nephropathy: A Systematic Review and Meta-Analysis of 45 Studies. Front. Immunol. 2021, 12, 683913. [Google Scholar] [CrossRef]
- Goto, M.; Wakai, K.; Kawamura, T.; Ando, M.; Endoh, M.; Tomino, Y. A scoring system to predict renal outcome in IgA nephropathy: A nationwide 10-year prospective cohort study. Nephrol. Dial. Transplant. 2009, 24, 3068–3074. [Google Scholar] [CrossRef]
- Shen, P.; He, L.; Li, Y.; Wang, Y.; Chan, M. Natural history and prognostic factors of IgA nephropathy presented with isolated microscopic hematuria in Chinese patients. Nephron Clin. Pract. 2007, 106, c157–c161. [Google Scholar] [CrossRef]
- Imai, H.; Miura, N. A treatment dilemma in adult immunoglobulin A nephropathy: What is the appropriate target, preservation of kidney function or induction of clinical remission? Clin. Exp. Nephrol. 2012, 16, 195–201. [Google Scholar] [CrossRef]
- Szeto, C.-C.; Fernand, M.-M.; Lai, K.-F.; To, T.; Wong, Y.-H.; Chow, K.-M.; Cheung-Lung, P.; Choi, S.-F.; Lui, P.; Li, K.-T. The Natural History of Immunoglobulin A Nephropathy among Patients with Hematuria and Minimal Proteinuria. Am. J. Med. 2001, 110, 434–437. [Google Scholar] [CrossRef]
- Neelakantappa, K.; Gallo, G.R.; Baldwin, D.S. Proteinuria in IgA nephropathy. Kidney Int. 1988, 33, 716–721. [Google Scholar] [CrossRef]
- Waldherr, R.; Rambausek, M.; Duncker, W.D.; Ritz, E. Nephrology Dialysis Transplantation Original Article Frequency of Mesangial IgA Deposits in a Non-Selected Autopsy Series. Nephrol. Dial. Transplant. 1989, 4, 943–946. [Google Scholar] [CrossRef]
- Suzuki, K.; Honda, K.; Tanabe, K.; Toma, H.; Nihei, H.; Yamaguchi, Y. Incidence of latent mesangial IgA deposition in renal allograft donors in Japan. Kidney Int. 2003, 63, 2286–2294. [Google Scholar] [CrossRef]
- Hosking, L.; Lumsden, S.; Lewis, K.; Yeo, A.; McCarthy, L.; Bansal, A.; Riley, J.; Purvis, I.; Xu, C.-F. Detection of genotyping errors by Hardy-Weinberg equilibrium testing. Eur. J. Hum. Genet. 2004, 12, 395–399. [Google Scholar] [CrossRef] [PubMed]
- Tziastoudi, M.; Chronopoulou, I.; Pissas, G.; Cholevas, C.; Eleftheriadis, T.; Stefanidis, I. Tumor Necrosis Factor-α G-308A Polymorphism and Sporadic IgA Nephropathy: A Meta-Analysis Using a Genetic Model-Free Approach. Genes 2023, 14, 1488. [Google Scholar] [CrossRef]
- Tziastoudi, M.; Stefanidis, I.; Hadjigeorgiou, G.M.; Stravodimos, K.; Zintzaras, E. A systematic review and meta-analysis of genetic association studies for the role of inflammation and the immune system in diabetic nephropathy. Clin. Kidney J. 2017, 10, 293–300. [Google Scholar] [CrossRef] [PubMed]
- Tziastoudi, M.; Stefanidis, I.; Zintzaras, E. The genetic map of diabetic nephropathy: Evidence from a systematic review and meta-analysis of genetic association studies. Clin. Kidney J. 2020, 13, 768–781. [Google Scholar] [CrossRef]
- Tziastoudi, M.; Dardiotis, E.; Pissas, G.; Filippidis, G.; Golfinopoulos, S.; Siokas, V.; Tachmitzi, S.V.; Eleftheriadis, T.; Hadjigeorgiou, G.M.; Tsironi, E.; et al. Serpin Family E Member 1 Tag Single-Nucleotide Polymorphisms in Patients with Diabetic Nephropathy: An Association Study and Meta-Analysis Using a Genetic Model-Free Approach. Genes 2021, 12, 1887. [Google Scholar] [CrossRef] [PubMed]
- Tziastoudi, M.; Theoharides, T.C.; Nikolaou, E.; Efthymiadi, M.; Eleftheriadis, T.; Stefanidis, I. Key Genetic Components of Fibrosis in Diabetic Nephropathy: An Updated Systematic Review and Meta-Analysis. Int. J. Mol. Sci. 2022, 23, 5331. [Google Scholar] [CrossRef]
- Stefanidis, I.; Tziastoudi, M.; Tsironi, E.E.; Dardiotis, E.; Tachmitzi, S.V.; Fotiadou, A.; Pissas, G.; Kytoudis, K.; Sounidaki, M.; Ampatzis, G.; et al. The contribution of genetic variants of SLC2A1 gene in T2DM and T2DM-nephropathy: Association study and meta-analysis. Ren. Fail. 2018, 40, 561–576. [Google Scholar] [CrossRef] [PubMed]
- Tziastoudi, M.; Pissas, G.; Raptis, G.; Cholevas, C.; Eleftheriadis, T.; Dounousi, E.; Stefanidis, I.; Theoharides, T.C. A Systematic Review and Meta-Analysis of Pharmacogenetic Studies in Patients with Chronic Kidney Disease. Int. J. Mol. Sci. 2021, 22, 4480. [Google Scholar] [CrossRef] [PubMed]
- Cordell, H.J.; Clayton, D.G. Genetic association studies. Lancet 2005, 366, 1121–1131. [Google Scholar] [CrossRef] [PubMed]
- Burton, P.R.; Hansell, A.L.; Fortier, I.; Manolio, T.A.; Khoury, M.J.; Little, J.; Elliott, P. Size matters: Just how big is BIG?: Quantifying realistic sample size requirements for human genome epidemiology. Int. J. Epidemiol. 2009, 38, 263–273. [Google Scholar] [CrossRef]
- McCarthy, M.I.; Abecasis, G.R.; Cardon, L.R.; Goldstein, D.B.; Little, J.; Ioannidis, J.P.A.; Hirschhorn, J.N. Genome-wide association studies for complex traits: Consensus, uncertainty and challenges. Nat. Rev. Genet. 2008, 9, 356–369. [Google Scholar] [CrossRef]
- Von Hippel, P.T. The heterogeneity statistic I(2) can be biased in small meta-analyses. BMC Med. Res. Methodol. 2015, 15, 35. [Google Scholar] [CrossRef]
- Storey, J.D.; Tibshirani, R. Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 2003, 100, 9440–9445. [Google Scholar] [CrossRef]
- Thomas, D.C. Are we ready for genome-wide association studies? Cancer Epidemiol. Biomark. Prev. 2006, 15, 595–598. [Google Scholar] [CrossRef]
- D’Amico, G. Natural history of idiopathic IgA nephropathy: Role of clinical and histological prognostic factors. Am. J. Kidney Dis. 2000, 36, 227–237. [Google Scholar] [CrossRef]
- Tarlow, J.K.; Blakemore, A.I.F.; Lennard, A.; Solari, R.; Hughes, H.N.; Steinkasserer, A.; Duff, G.W. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum. Genet. 1993, 91, 403–404. [Google Scholar] [CrossRef]
- McDowell, T.L.; Symons, J.A.; Ploski, R.; Førre, O.; Duff, G.W. A genetic association between juvenile rheumatoid arthritis and a novel interleukin-1 alpha polymorphism. Arthritis Rheum. 1995, 38, 221–228. [Google Scholar] [CrossRef] [PubMed]
- Di Giovine, F.S.; Takhsh, E.; Blakemore, A.I.; Duff, G.W. Single base polymorphism at -511 in the human interleukin-1 beta gene (IL1 beta). Hum. Mol. Genet. 1992, 1, 450. [Google Scholar] [CrossRef] [PubMed]
- Li, Z.; Zhang, Z.; He, Z.; Tang, W.; Li, T.; Zeng, Z.; He, L.; Shi, Y. A partition-ligation-combination-subdivision em algorithm for haplotype inference with multiallelic markers: Update of the SHEsis (http://analysis.bio-x.cn). Cell Res. 2009, 19, 519–523. [Google Scholar] [CrossRef] [PubMed]
- Shi, Y.Y.; He, L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005, 15, 97–98. [Google Scholar] [CrossRef] [PubMed]
- Meirmans, P.G. Using the AMOVA framework to estimate a standardized genetic differentiation measure. Evol. Int. J. Org. Evol. 2006, 60, 2399–2402. [Google Scholar] [CrossRef]
- Peakall, R.; Smouse, P.E. GenAlEx 6.5: Genetic analysis in Excel. Population genetic software for teaching and research--an update. Bioinforma. Oxf. Engl. 2012, 28, 2537–2539. [Google Scholar] [CrossRef]
- Dersimonian, R.; Laird, N. Meta-Analysis in Clinical Trials. Control. Clin. Trials 1986, 188, 177–188. [Google Scholar] [CrossRef]
- Cochran, W. The combination of estimates from different experiments. Biometrics 1954, 10, 101–129. [Google Scholar] [CrossRef]
- Higgins, J.P.T.; Thompson, S.G.; Deeks, J.J.; Altman, D.G. Measuring inconsistency in meta-analyses. BMJ 2003, 327, 557–560. [Google Scholar] [CrossRef]
- Egger, M.; Davey Smith, G.; Schneider, M.; Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997, 315, 629–634. [Google Scholar] [CrossRef]
Parameters | Case-Control Study Population Groups (n = 367) | ||||
---|---|---|---|---|---|
Healthy Controls | IgA Nephropathy * | Diseased Controls | Cases | p | |
n | 246 | 121 | 54 | 67 | n.a. |
Sex (m/f) | 182/64 | 88/33 | 34/20 | 54/13 | 0.030 |
Age (years) | 44.6 ± 15.0 | 45.6 ± 15.2 | 42.3 ± 15.5 | 49.8 ± 14.3 | 0.012 |
IgA duration (years) | n.a. | 5.9 ± 4.7 | 6.0 ± 4.9 | 5.7 ± 4.3 | 0.946 |
End-stage renal disease [n (%)] | - | 15 (12.4) | 0 | 15 (22.4) | <0.001 |
Mean blood pressure (mmHg) | - | 72.7 ± 12.1 | 69.1 ± 10.1 | 75.3 ± 12.3 | 0.004 |
Macroscopic hematuria [n (%)] | - | 19 (15.7) | 11 (20.4) | 8 (11.9) | 0.205 |
Microscopic hematuria | - | 85 (70.2) | 34 (62.9) | 51 (76.1) | 0.099 |
Proteinuria (mg/d) | - | 2170 ± 34,988 | 613 ± 471 | 3438 ± 4306 | <0.001 |
Creatinine (mg/dL) | - | 2.46 ± 3.01 | 1.07 ± 0.22 | 3.50 ± 3.65 | <0.001 |
Hematocrit (%) | - | 38.6 ± 7.1 | 41.6 ± 4.7 | 36.4 ± 7.7 | <0.001 |
Gene Variant | Genotype | Progressive IgA Nephropathy | Diseased Controls | Healthy Controls | p Value | ORG (95% CI) |
---|---|---|---|---|---|---|
n (%) | ||||||
IL1A C-899T rs1800587 | C C | 30 (44.8) | 30 (55.6) | 120 (48.8) | 0.458 | 0.97 (0.68–1.38) |
C T | 30 (44.8) | 22 (40.7) | 98 (39.8) | |||
T T | 7 (10.4) | 2 (3.7) | 28 (11.4) | |||
IL1B C-511T rs16944 | C C | 22 (32.8) | 30 (55.6) | 94 (38.2) | 0.118 | 0.96 (0.67–1.35) |
C T | 37 (55.2) | 19 (35.2) | 126 (51.2) | |||
T T | 8 (11.9) | 5 (9.3) | 26 (10.6) | |||
IL1RN allele L vs. 2 | L L | 41 (61.2) | 33 (61.7) | 139 (56.5) | 0.740 | 0.82 (0.57–1.19) |
L 2 | 23 (34.3) | 17 (31.5) | 84 (34.1) | |||
2 2 | 3 (4.5) | 4 (7.4) | 23 (9.3) |
Gene Variant | Genotype | IgA Nephropathy | Healthy Controls | p Value | ORG (95% CI) |
---|---|---|---|---|---|
IL1A C-899T rs1800587 | C C | 60 | 120 (48.8) | 0.482 | 0.91 (0.62–1.34) |
C T | 52 | 98 (39.8) | |||
T T | 9 | 28 (11.4) | |||
IL1B C-511T rs16944 | C C | 52 | 94 (38.2) | 0.649 | 0.87 (0.59–1.28) |
C T | 56 | 126 (51.2) | |||
T T | 13 | 26 (10.6) | |||
IL1RN allele L vs. 2 | L L | 74 | 139 (56.5) | 0.451 | 0.81 (0.54–1.21) |
L 2 | 40 | 84 (34.1) | |||
2 2 | 7 | 23 (9.3) |
Gene Variant | Genotype | Progressive IgA Nephropathy | Diseased Controls | p Value | ORG (95% CI) |
---|---|---|---|---|---|
n (%) | |||||
IL1A C-899T rs1800587 | C C | 30 (44.8) | 30 (55.6) | 0.267 | 1.62 (0.83–3.15) |
C T | 30 (44.8) | 22 (40.7) | |||
T T | 7 (10.4) | 2 (3.7) | |||
IL1B C-511T rs16944 | C C | 22 (32.8) | 30 (55.6) | 0.041 | 2.11 (1.09–4.07) |
C T | 37 (55.2) | 19 (35.2) | |||
T T | 8 (11.9) | 5 (9.3) | |||
IL1RN allele L vs. 2 | L L | 41 (61.2) | 33 (61.7) | 0.772 | 0.95 (0.48–1.90) |
L 2 | 23 (34.3) | 17 (31.5) | |||
2 2 | 3 (4.5) | 4 (7.4) |
Progressive IgAN (Diseased Controls) | ||
---|---|---|
IL1B | IL1RN | |
IL1A | D’ = 0.438 (0.233) | D’ = 0.826 (0.131) |
r2 = 0.061 (0.047) | r2 = 0.118 (0.012) | |
p = 0.004 (0.025) | p < 0.001 (p = 0.186) | |
IL1B | D’ = 0.497 (0.404) | |
r2 = 0.111 (0.134) | ||
p < 0.001 (<0.001) |
Haplotypes | Haplotype Frequency | χ2 test | |||
---|---|---|---|---|---|
(rs1800587, rs16944, 86 bp VNTR) | Progressive IgA Nephropathy | Diseased Controls | p-Value | OR (95% CI) | Overall p-Value |
C C 1 | 0.282 | 0.454 | 0.005 | 0.456 (0.261~0.797) | |
C C 2 | 0.049 | 0.097 | 0.155 | 0.485 (0.176~1.337) | |
C T 1 | 0.141 | 0.133 | 0.814 | 1.094 (0.519~2.306) | 0.003 |
C T 2 | 0.167 | 0.047 | 0.003 | 4.208 (1.545~11.50) | |
T C 1 | 0.229 | 0.153 | 0.112 | 1.718 (0.877~3.363) |
First Author, Year | Country | Racial Descent | IgA Nephropathy | Cases (n) | Controls (n) | HWE (p-Value) | Progression of IgA Nephropathy | Cases (n) | Controls (n) | ||
---|---|---|---|---|---|---|---|---|---|---|---|
Selection Criteria and Demographic Data of Cases | Selection Criteria and Demographic Data of Healthy Controls | Selection Criteria and Demographic Data of Cases (Progressors) | Selection Criteria and Demographic Data of Controls (Non-Progressors) | ||||||||
Liu 1997 [24] | China | Asians | Biopsy-proven IgA nephropathy (67 males, 30 females, ranging in age from 10 to 58 years). | Normal subjects (51 males and 47 females, ranging in age from 18 to 55 years), without renal diseases | 97 | 98 | - | - | - | - | - |
Shu, 2000 [25] | China | Asians | Biopsy-proven IgA nephropathy (57 males, 54 females; mean age 30.3 years). Cases with Henoch–Schoenlein purpura not mentioned. | Healthy controls not matched to cases for age and gender; further demographic data not mentioned. | 111 | 100 | 0.5 | Increase in serum creatinine or more than 50% increase in daily proteinuria or appearance of hypertension. | Patients with stable renal disease or those in remission. | 45 | 66 |
Syrjanen, 2002 [26] | Finland | Caucasians | Biopsy-proven IgA nephropathy (102 males, 65 females), no evidence of primary causes. Nine cases with Henoch–Schoenlein purpura. | Healthy blood donors (100 males, 100 females) from local center; not matched to cases for age and gender. | 167 | 400 | 0.04 | Presence of chronic renal failure (serum creatinine ≥ 125 μmol/L in males and ≥105 μmol/L in females) initially or rise of serum creatinine over 20% at follow-up. | Absence of chronic renal failure (serum creatinine ≥ 125 μmol/L in males and ≥105 μmol/L in females) initially or at follow-up. | 26 | 140 |
Watanabe et al., 2002 [27] | Japan | Asians | Biopsy-proven IgA nephropathy | Individuals without a history of renal disease | 106 | 74 | - | - | - | - | - |
Bantis, 2004 [28] | Germany | Caucasians | Biopsy-proven IgA nephropathy (93 males and 30 females with mean age at diagnosis of 37.1 ± 14 years) | 44 males and 56 females without history of kidney diseases or arterial hypertension matched for age | 123 | 100 | - | Fast progressors | Low progressors | 48 | 75 |
Chin 2005 [29] | Korea | Asians | Biopsy-proven IgA nephropathy | Normotensive individuals with no evidence of renal disease | 108 | 100 | - | - | - | - | - |
Liu 2008 [30] | Canada | Caucasians | Biopsy-proven IgAN, exclusion of secondary IgAN | Healthy controls matched to cases for age and gender | 255 | 187 | >0.05 | ||||
Liu 2008 [30] | France | Caucasians | Biopsy-proven IgAN, exclusion of secondary IgAN | Healthy controls matched to cases for age and gender | 271 | 205 | >0.05 | ||||
Liu 2008 [30] | Finland | Caucasians | Biopsy-proven IgAN, exclusion of secondary IgAN | Healthy controls matched to cases for age and gender | 206 | 111 | >0.05 | ||||
Hahn 2009 [15] | Korea | Asians | Pediatric patients with biopsy-proven IgAN | Healthy controls | 182 | 500 | >0.05 | - | - | - | - |
Jung 2012 [31] | Korea | Asians | Biopsy-proven IgAN | Healthy controls | 69 | 146 | >0.05 | ||||
Yamamoto, 2012 [32] | Japan | Asians | Biopsy-proven IgA nephropathy patients aged between 25 and 50 years | Healthy hospital employees aged between 25 and 50 years. | 230 | 262 | 0.80 | - | - | - | - |
Wang, 2013 [33] | China | Asians | Biopsy-proven primary IgAN with no evidence of systemic diseases such as diabetes, chronic liver disease, or systemic lupus erythematosus. | Gender- and age-matched healthy controls with no history of renal disease or hypertension. | 527 | 543 | 0.45 | - | - | - | - |
Yang 2016 [34] | China | Asians | Biopsy-proven IgAN | Healthy controls | 166 | 198 | >0.05 | - | - | - | - |
Gao 2017 [35] | China | Asians | Biopsy-proven IgAN, exclusion of secondary IgAN | Healthy controls matched for age, gender, and ethnicity | 351 | 310 | >0.05 | - | - | - | - |
Zhang 2017 [36] | China | Asians | Biopsy-proven IgAN, exclusion of secondary IgAN | Healthy controls | 417 | 463 | >0.05 | - | - | - | - |
GENE | VARIANT | RS | Studies (n) | Cases/Controls (n) | RE ORG | 95% LL | 95% UL | I2(%)/ Gamma | PQ/ SE(Gamma) | PE |
---|---|---|---|---|---|---|---|---|---|---|
IL1A | C-899T | rs1800587 | 2 | 594/789 | 0.94 | 0.71 | 1.24 | 0.00 | 0.75 | - |
IL1B | C-511T | rs16944 | 2 | 530/661 | 0.92 | 0.60 | 1.42 | 64.36 | 0.09 | - |
IL1B | rs1143627 | 1 | 178/495 | 1.44 | 1.08 | 1.93 | 0.18 | 0.07 | - | |
IL1RN | allele L vs. 2 | 1 | 67/246 | 0.79 | 0.47 | 1.31 | −0.12 | 0.13 | - | |
IL1RN | rs928940 | 1 | 179/466 | 0.72 | 0.54 | 0.97 | −0.16 | 0.07 | - | |
IL1RN | rs439154 | 1 | 180/490 | 0.68 | 0.50 | 0.92 | −0.19 | 0.07 | - | |
IL1RN | rs315951 | 1 | 181/483 | 0.73 | 0.55 | 0.98 | −0.15 | 0.07 | - | |
IL4R | rs1805015 | 3 | 732/499 | 0.75 | 0.44 | 1.29 | 76.83 | 0.01 | 0.35 | |
IL5RA | rs340833 | 3 | 729/503 | 1.12 | 0.61 | 2.06 | 19.20 | <0.001 | 0.58 | |
IL6 | rs1800796 | 2 | 693/677 | 0.86 | 0.56 | 1.32 | 77.69 | 0.03 | - | |
IL10 | C-819Τ | rs1800871 | 2 | 581/572 | 0.79 | 0.64 | 0.97 | 0.82 | 0.37 | - |
IL10 | -1082A>G | rs1800896 | 3 | 1108/1115 | 1.06 | 0.82 | 1.37 | 0.00 | 0.98 | 0.20 |
IL18 | C-607A | rs1946518 | 3 | 465/606 | 0.81 | 0.46 | 1.45 | 85.89 | <0.001 | 0.54 |
IL18 | -137G/C | rs187238 | 2 | 298/408 | 1.05 | 0.74 | 1.47 | 0.00 | 0.74 | - |
GENE | VARIANT | RS | Studies (n) | Cases/Controls (n) | RE OR | 95% LL | 95% UL | PQ/ SE(Gamma) | PE |
---|---|---|---|---|---|---|---|---|---|
IL1B | -511C/T | rs16944 | 1 | 167/400 | 1.35 | 1.05 | 1.75 | - | - |
IL1B | rs1143627 | 1 | 417/463 | 1.21 | 1.00 | 1.46 | - | - | |
IL1RN | Allele L vs. 2 | 4 | 481/672 | 1.56 | 1.00 | 2.44 | 0.127 | 0.19 | |
IL1RN | Allele L vs. 2 | 1 | 67/246 | 0.79 | 0.47 | 1.31 | 0.12 | 0.13 | |
IL10 | C-819Τ | rs1800871 | 1 | 108/100 | 1.42 | 0.95 | 2.14 | - | - |
IL10 | -1082A>G | rs1800896 | 2 | 123/100 | 0.61 | 0.23 | 1.60 | 0.043 | - |
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Chronopoulou, I.; Tziastoudi, M.; Pissas, G.; Dardiotis, E.; Dardioti, M.; Golfinopoulos, S.; Filippidis, G.; Mertens, P.R.; Tsironi, E.E.; Liakopoulos, V.; et al. Interleukin Variants Are Associated with the Development and Progression of IgA Nephropathy: A Candidate-Gene Association Study and Meta-Analysis. Int. J. Mol. Sci. 2023, 24, 16347. https://doi.org/10.3390/ijms242216347
Chronopoulou I, Tziastoudi M, Pissas G, Dardiotis E, Dardioti M, Golfinopoulos S, Filippidis G, Mertens PR, Tsironi EE, Liakopoulos V, et al. Interleukin Variants Are Associated with the Development and Progression of IgA Nephropathy: A Candidate-Gene Association Study and Meta-Analysis. International Journal of Molecular Sciences. 2023; 24(22):16347. https://doi.org/10.3390/ijms242216347
Chicago/Turabian StyleChronopoulou, Ioanna, Maria Tziastoudi, Georgios Pissas, Efthimios Dardiotis, Maria Dardioti, Spyridon Golfinopoulos, Georgios Filippidis, Peter R. Mertens, Evangelia E. Tsironi, Vassilios Liakopoulos, and et al. 2023. "Interleukin Variants Are Associated with the Development and Progression of IgA Nephropathy: A Candidate-Gene Association Study and Meta-Analysis" International Journal of Molecular Sciences 24, no. 22: 16347. https://doi.org/10.3390/ijms242216347