Association between ATG16L1 rs2241880(T300A) and rs4663421 and ANCA‑associated vasculitis in the Guangxi population of China: Propensity score matching analysis

Tang,Wenlv; Zhang,Yurong; Lu,Shurong; Xue,Chao

doi:10.3892/br.2024.1880

Association between ATG16L1 rs2241880(T300A) and rs4663421 and ANCA‑associated vasculitis in the Guangxi population of China: Propensity score matching analysis

Authors:
- Wenlv Tang
- Yurong Zhang
- Shurong Lu
- Chao Xue
View Affiliations

Affiliations: Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China, Department of Electrocardiographic Diagnosis, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530000, P.R. China, Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
Published online on: October 15, 2024 https://doi.org/10.3892/br.2024.1880
Article Number: 3
Copyright: © Tang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Antineutrophil cytoplasmic antibody‑associated vasculitis (AAV) is a rare autoimmune disease with an unclear pathogenesis. The present study investigated the associations between autophagy‑related protein 16‑like 1 (ATG16L1) rs2241880(T300A) and rs4663421 and AAV. A total of 177 patients with AAV and 216 healthy controls were included. Propensity score matching was used to match the two groups of subjects in terms of sex, age and ethnicity. Analyses of the relationships between these genetic polymorphisms and AAV susceptibility, including comparisons of allele and genotype frequency distribution, linkage disequilibrium analysis and analysis of single nucleotide polymorphism (SNP) interactions between two loci were performed. The association between the loci and laboratory test results and renal pathology were also analysed. A total of 154 pairs of patients with AAV and healthy controls was successfully matched. Neither polymorphism was associated with AAV susceptibility. However, SNP interaction in the model constructed with the two loci was statistically significant (P=0.018), and the combination of the AA genotype of rs2241880(T300A) and GG genotype of rs4663421 was associated the highest disease risk. The differences in the Birmingham Vasculitis Activity Score (BVAS), C‑reactive protein (CRP) levels and 24‑h urine protein level between patients with the rs2241880(T300A) AA + AG genotypes and the GG genotype were statistically significant (P<0.05). Furthermore, significant differences in the severity of glomerulosclerosis and global sclerosis were detected between individuals with the AA + AG genotype and those with the GG genotype at the rs2241880(T300A) locus (P<0.05). Similarly, there were statistically significant differences in degree of segmental sclerosis between individuals with CC + CG genotypes and those with GG genotypes at the rs2243421 locus (P<0.05). In summary, the single gene polymorphisms of these loci were not associated with genetic susceptibility to AAV. However, SNP interactions may serve a role in the risk of AAV. The rs2241880(T300A) polymorphism may be associated with BVAS, CRP levels and 24‑h urine protein level in AAV. These SNPs may be associated with glomerulosclerosis and segmental sclerosis.

View Figures

View References

1	Cornec D, Cornec-Le Gall E, Fervenza FC and Specks U: ANCA-associated vasculitis-clinical utility of using ANCA specificity to classify patients. Nat Rev Rheumatol. 12:570–579. 2016.PubMed/NCBI View Article : Google Scholar
2	Geetha D and Jefferson JA: ANCA-Associated Vasculitis: Core Curriculum 2020. Am J Kidney Dis. 75:124–137. 2020.PubMed/NCBI View Article : Google Scholar
3	Kitching AR, Anders HJ, Basu N, Brouwer E, Gordon J, Jayne DR, Kullman J, Lyons PA, Merkel PA, Savage COS, et al: ANCA-associated vasculitis. Nat Rev Dis Primers. 6(71)2020.PubMed/NCBI View Article : Google Scholar
4	Lyons PA, Peters JE, Alberici F, Liley J, Coulson RMR, Astle W, Baldini C, Bonatti F, Cid MC, Elding H, et al: Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nat Commun. 10(5120)2019.PubMed/NCBI View Article : Google Scholar
5	Prendecki M, Cairns T and Pusey CD: Familial vasculitides: Granulomatosis with polyangiitis and microscopic polyangiitis in two brothers with differing anti-neutrophil cytoplasm antibody specificity. Clin Kidney J. 9:429–431. 2016.PubMed/NCBI View Article : Google Scholar
6	Tanna A, Salama AD, Brookes P and Pusey CD: Familial granulomatosis with polyangiitis: Three cases of this rare disorder in one Indoasian family carrying an identical HLA DPB1 allele. BMJ Case Rep. 2012(bcr0120125502)2012.PubMed/NCBI View Article : Google Scholar
7	Matoba K and Noda NN: A structural catalog of core Atg proteins opens a new era of autophagy research. J Biochem. 169:517–525. 2021.PubMed/NCBI View Article : Google Scholar
8	Yin Z, Pascual C and Klionsky DJ: Autophagy: Machinery and regulation. Microb Cell. 3:588–596. 2016.PubMed/NCBI View Article : Google Scholar
9	Arias E and Cuervo AM: Pros and cons of chaperone-mediated autophagy in cancer biology. Trends Endocrinol Metab. 31:53–66. 2020.PubMed/NCBI View Article : Google Scholar
10	Celia AI, Colafrancesco S, Barbati C, Alessandri C and Conti F: Autophagy in Rheumatic Diseases: Role in the pathogenesis and therapeutic approaches. Cells. 11(1359)2022.PubMed/NCBI View Article : Google Scholar
11	Pei Y, Chen S, Zhou F, Xie T and Cao H: Construction and evaluation of Alzheimer's disease diagnostic prediction model based on genes involved in mitophagy. Front Aging Neurosci. 15(1146660)2023.PubMed/NCBI View Article : Google Scholar
12	Yang M, Luo S, Chen W, Zhao L and Wang X: Chaperone-Mediated Autophagy: A potential target for metabolic diseases. Curr Med Chem. 30:1887–1899. 2023.PubMed/NCBI View Article : Google Scholar
13	Masucci MT, Minopoli M, Del Vecchio S and Carriero MV: The emerging role of neutrophil extracellular traps (NETs) in tumor progression and metastasis. Front Immunol. 11(1749)2020.PubMed/NCBI View Article : Google Scholar
14	Arneth B and Arneth R: Neutrophil Extracellular Traps (NETs) and Vasculitis. Int J Med Sci. 18:1532–1540. 2021.PubMed/NCBI View Article : Google Scholar
15	Sha LL, Wang H, Wang C, Peng HY, Chen M and Zhao MH: Autophagy is induced by anti-neutrophil cytoplasmic Abs and promotes neutrophil extracellular trap formation. Innate Immun. 22:658–665. 2016.PubMed/NCBI View Article : Google Scholar
16	Romanov J, Walczak M, Ibiricu I, Schuchner S, Ogris E, Kraft C and Martens S: Mechanism and functions of membrane binding by the Atg5-Atg12/Atg16 complex during autophagosome formation. EMBO J. 31:4304–4317. 2012.PubMed/NCBI View Article : Google Scholar
17	Gammoh N: The multifaceted functions of ATG16L1 in autophagy and related processes. J Cell Sci. 133(jcs249227)2020.PubMed/NCBI View Article : Google Scholar
18	Salem M, Ammitzboell M, Nys K, Seidelin JB and Nielsen OH: ATG16L1: A multifunctional susceptibility factor in Crohn's disease. Autophagy. 11:585–594. 2015.PubMed/NCBI View Article : Google Scholar
19	Mo YJ, Zhang W, Wen QW, Wang TH, Qin W, Zhang Z, Huang H, Cen H and Wu XD: Corrigendum to ‘Genetic association analysis of ATG16L1 rs2241880, rs6758317 and ATG16L2 rs11235604 polymorphisms with rheumatoid arthritis in a Chinese population’ [Int. Immunopharmacol 93 (2021) 107378]. Int. Immunopharmacol 104: 108511, 2022.
20	Li X, Chen M, Zhang X, Wang M, Yang X, Xia Q, Han R, Liu R, Xu S, Xu J, et al: Single nucleotide polymorphisms of autophagy-related 16-like 1 gene are associated with ankylosing spondylitis in females: A case-control study. Int J Rheum Dis. 21:322–329. 2018.PubMed/NCBI View Article : Google Scholar
21	Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, et al: 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 65:1–11. 2013.PubMed/NCBI View Article : Google Scholar
22	Mukhtyar C, Lee R, Brown D, Carruthers D, Dasgupta B, Dubey S, Flossmann O, Hall C, Hollywood J, Jayne D, et al: Modification and validation of the Birmingham Vasculitis Activity Score (version 3). Ann Rheum Dis. 68:1827–1832. 2009.PubMed/NCBI View Article : Google Scholar
23	Stevens LA, Schmid CH, Zhang YL, Coresh J, Manzi J, Landis R, Bakoush O, Contreras G, Genuth S, Klintmalm GB, et al: Development and validation of GFR-estimating equations using diabetes, transplant and weight. Nephrol Dial Transplant. 25:449–457. 2010.PubMed/NCBI View Article : Google Scholar
24	Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, Neumann I, Noël LH, Pusey CD, Waldherr R, et al: Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol. 21:1628–1636. 2010.PubMed/NCBI View Article : Google Scholar
25	Barrett JC, Fry B, Maller J and Daly MJ: Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics. 21:263–265. 2005.PubMed/NCBI View Article : Google Scholar
26	Huang F, DU C, Sun M, Ning B, Luo Y and An S: Propensity score matching in SPSS. Nan Fang Yi Ke Da Xue Xue Bao. 35:1597–1601. 2015.PubMed/NCBI(In Chinese).
27	Austin PC, Yu AYX, Vyas MV and Kapral MK: Applying propensity score methods in clinical research in neurology. Neurology. 97:856–863. 2021.PubMed/NCBI View Article : Google Scholar
28	Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, Baslund B, Brenchley P, Bruchfeld A, Chaudhry AN, et al: Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 367:214–223. 2012.PubMed/NCBI View Article : Google Scholar
29	Tang H, Tan B, Shen BB, Zhang SL and Qian JM: Diagnostic value of different serological markers and correlation analysis with disease phenotype in inflammatory bowel disease. Zhonghua Yi Xue Za Zhi. 102:3743–3748. 2022.PubMed/NCBI View Article : Google Scholar : (In Chinese).
30	Laass MW, Ziesmann J, de Laffolie J, Röber N and Conrad K: Anti-Proteinase 3 Antibodies as a Biomarker for Ulcerative Colitis and Primary Sclerosing Cholangitis in Children. J Pediatr Gastroenterol Nutr. 74:463–470. 2022.PubMed/NCBI View Article : Google Scholar
31	Plafkin C, Zhong W and Singh T: ANCA vasculitis presenting with acute interstitial nephritis without glomerular involvement. Clin Nephrol Case Stud. 7:46–50. 2019.PubMed/NCBI View Article : Google Scholar
32	Freeman HJ: Atypical perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn's disease. Can J Gastroenterol. 11:689–693. 1997.PubMed/NCBI View Article : Google Scholar
33	Mommersteeg MC, Simovic I, Yu B, van Nieuwenburg SAV, Bruno IMJ, Doukas M, Kuipers EJ, Spaander MCW, Peppelenbosch MP, Castaño-Rodríguez N and Fuhler GM: Autophagy mediates ER stress and inflammation in Helicobacter pylori-related gastric cancer. Gut Microbes. 14(2015238)2022.PubMed/NCBI View Article : Google Scholar
34	Plantinga TS, Crisan TO, Oosting M, van de Veerdonk FL, de Jong DJ, Philpott DJ, van der Meer JW, Girardin SE, Joosten LA and Netea MG: Crohn's disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2. Gut. 60:1229–1235. 2011.PubMed/NCBI View Article : Google Scholar
35	Hao J, Lv TG, Wang C, Xu LP and Zhao JR: Macrophage migration inhibitory factor contributes to anti-neutrophil cytoplasmic antibody-induced neutrophil activation. Hum Immunol. 77:1209–1214. 2016.PubMed/NCBI View Article : Google Scholar
36	Takeda S, Watanabe-Kusunoki K, Nakazawa D, Kusunoki Y, Nishio S and Atsumi T: The Pathogenicity of BPI-ANCA in a Patient with Systemic Vasculitis. Front Immunol. 10(1334)2019.PubMed/NCBI View Article : Google Scholar
37	Matsumoto K, Suzuki K, Yoshimoto K, Seki N, Tsujimoto H, Chiba K and Takeuchi T: Longitudinal immune cell monitoring identified CD14(++) CD16(+) intermediate monocyte as a marker of relapse in patients with ANCA-associated vasculitis. Arthritis Res Ther. 22(145)2020.PubMed/NCBI View Article : Google Scholar
38	Pugazhendhi S, Baskaran K, Santhanam S and Ramakrishna BS: Association of ATG16L1 gene haplotype with inflammatory bowel disease in Indians. PLoS One. 12(e0178291)2017.PubMed/NCBI View Article : Google Scholar
39	Kee BP, Ng JG, Ng CC, Hilmi I, Goh KL and Chua KH: Genetic polymorphisms of ATG16L1 and IRGM genes in Malaysian patients with Crohn's disease. J Dig Dis. 21:29–37. 2020.PubMed/NCBI View Article : Google Scholar
40	Teimoori-Toolabi L, Samadpoor S, Mehrtash A, Ghadir M and Vahedi H: Among autophagy genes, ATG16L1 but not IRGM is associated with Crohn's disease in Iranians. Gene. 675:176–184. 2018.PubMed/NCBI View Article : Google Scholar
41	Zhang J, Chen J, Gu J, Guo H and Chen W: Association of IL23R and ATG16L1 with susceptibility of Crohn's disease in Chinese population. Scand J Gastroenterol. 49:1201–1206. 2014.PubMed/NCBI View Article : Google Scholar
42	Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J, et al: A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn's disease in ATG16L1. Nat Genet. 39:207–211. 2007.PubMed/NCBI View Article : Google Scholar
43	Salem M, Nielsen OH, Nys K, Yazdanyar S and Seidelin JB: Impact of T300A Variant of ATG16L1 on antibacterial response, risk of culture positive infections, and clinical course of crohn's disease. Clin Transl Gastroenterol. 6(e122)2015.PubMed/NCBI View Article : Google Scholar
44	Zhang HF, Qiu LX, Chen Y, Zhu WL, Mao C, Zhu LG, Zheng MH, Wang Y, Lei L and Shi J: ATG16L1 T300A polymorphism and Crohn's disease susceptibility: Evidence from 13,022 cases and 17,532 controls. Hum Genet. 125:627–631. 2009.PubMed/NCBI View Article : Google Scholar
45	Merkel PA, Xie G, Monach PA, Ji X, Ciavatta DJ, Byun J, Pinder BD, Zhao A, Zhang J, Tadesse Y, et al: Identification of functional and expression polymorphisms associated with risk for antineutrophil cytoplasmic autoantibody-associated vasculitis. Arthritis Rheumatol. 69:1054–1066. 2017.PubMed/NCBI View Article : Google Scholar
46	Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, Savage C and Adu D: Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 87:671–678. 1994.PubMed/NCBI
47	Hind CR, Winearls CG, Lockwood CM, Rees AJ and Pepys MB: Objective monitoring of activity in Wegener's granulomatosis by measurement of serum C-reactive protein concentration. Clin Nephrol. 21:341–345. 1984.PubMed/NCBI
48	Lassen KG, Kuballa P, Conway KL, Patel KK, Becker CE, Peloquin JM, Villablanca EJ, Norman JM, Liu TC, Heath RJ, et al: Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc Natl Acad Sci USA. 111:7741–7746. 2014.PubMed/NCBI View Article : Google Scholar
49	Le Naour J, Sztupinszki Z, Carbonnier V, Casiraghi O, Marty V, Galluzzi L, Szallasi Z, Kroemer G and Vacchelli E: A loss-of-function polymorphism in ATG16L1 compromises therapeutic outcomes in head and neck carcinoma patients. Oncoimmunology. 11(2059878)2022.PubMed/NCBI View Article : Google Scholar
50	Guo Y, Gao F, Wang X, Pan Z, Wang Q, Xu S, Pan S, Li L, Zhao D and Qian J: Spontaneous formation of neutrophil extracellular traps is associated with autophagy. Sci Rep. 11(24005)2021.PubMed/NCBI View Article : Google Scholar
51	Yu Y and Sun B: Autophagy-mediated regulation of neutrophils and clinical applications. Burns Trauma. 8(tkz001)2020.PubMed/NCBI View Article : Google Scholar
52	Hamaoui D and Subtil A: ATG16L1 functions in cell homeostasis beyond autophagy. FEBS J. 289:1779–1800. 2022.PubMed/NCBI View Article : Google Scholar
53	Kawakami T, Gomez IG, Ren S, Hudkins K, Roach A, Alpers CE, Shankland SJ, D'Agati VD and Duffield JS: Deficient autophagy results in mitochondrial dysfunction and FSGS. J Am Soc Nephrol. 26:1040–1052. 2015.PubMed/NCBI View Article : Google Scholar