Ankylosing spondylitis risk factors: a systematic literature review

Abstract

Radiographic axial spondyloarthritis (also known as ankylosing spondylitis [AS]) is a chronic immune-mediated arthritis characterized by inflammation of the axial skeleton, peripheral joints, and entheses. It is estimated that 1 in every 200 people are affected by AS, making it an important healthcare and socioeconomic issue. In this review, we aim to explore the current understanding of AS risk factors and provide a comprehensive update. Multiple search strings were used to identify articles of interest published in PubMed between January 1, 2013, and February 1, 2021. On the basis of the literature review and analysis, we present up-to-date information on the risk factors of developing AS and our viewpoints on disease onset and progression. Multiple genetic and nongenetic risk factors have been suggested in the onset of AS. HLA-B27 is known to have a strong association with the disease, but other genes have been implicated in disease development. Aside from genetics, other factors are thought to be involved; up to 70% of patients with AS have subclinical intestinal inflammation, suggesting that the origin of the disease may be in the gut. The exact mechanism by which AS onset begins is most likely complex and multifactorial. Key Points • It remains unclear how interactions between genes, microbes, mechanical stress, gender, and other environmental and lifestyle factors predispose patients to the development of ankylosing spondylitis (AS). • The exact mechanisms of AS are complex and multifactorial which will require much future research • Recognizing the risk factors, as well as understanding gene-environment interactions, may offer valuable insights into the etiology of AS and have important implications for diagnosis and treatment strategies.

Keywords: Ankylosing spondylitis; Genetics; HLA-B27; Pathogenesis; Radiographic axial spondyloarthritis; Risk factors.

Fig. 1

PRISMA flow diagram

Fig. 2

Derivation of main and rare HLA-B27 subtypes from founder HLA-B*27 allele B*27:05. AF, African; EA, Eastern Asian; EU, European; FI, Filipino; JA, Japanese; NA, North American; SA, South American; SCA, Scandinavian; SEA, Southeast Asian; TUR, Turkic. Subtypes where ethnicity origin was not designated derived from individuals where ethnicity was not recorded. Source: https://www.ebi.ac.uk/ipd/imgt/hla/allele.html; accessed September 27, 2020

Fig. 3

Overlap between AS, Crohn’s disease, ulcerative colitis, and psoriasis susceptibility genes. ACTA2, alpha actin 2, smooth muscle aortic; ADCY3, adenylate cyclase 3; ANKRD55, ankyrin repeat domain-containing protein 55; ANTXR2, anthrax toxin receptor 2; ASAP2, ArfGAP with SH3 domain, ankyrin repeat and PH domain 2; ATG16L1, autophagy16-like 1; BACH2, BTB and CNC homology 2; BANK1, B cell scaffold protein with ankyrin repeats-1; BSN, bassoon mouse, homolog of (zinc finger 231); C17orf67, chromosome 17 open reading frame 67; CARD9, caspase recruitment domain family member 9; CCL21, C-C motif chemokine ligand 21; CD6, CD6 molecule; CD28, CD28 molecule; CD40, CD40 molecule; CD226, CD226 molecule; CDKAL1, CDK5 regulatory subunit associated protein 1 like 1; CLEC16A, C-type lectin domain containing 16A; CMC1, C-X9-C motif containing 1; CPEB4, cytoplasmic polyadenylation element binding protein 4; CREM, cAMP responsive element modulator; CXCR2, C-X-C motif chemokine receptor 2; DAP, death-associated protein; DENND1B, DENN domain containing 1B; DLEU1, deleted in lymphocyte leukemia 1; DNMT3A, DNA methyltransferase 3 alpha; DNMT3B, DNA methyltransferase 3 beta; EIF2S2P3, eukaryotic translation initiation factor 2 subunit 2 beta pseudogene 3; ERAP1, endoplasmic reticulum aminopeptidase 1; ERAP2, endoplasmic reticulum aminopeptidase 2; ERN1, endoplasmic reticulum to nucleus signaling 1; ETS1, ETS proto-oncogene 1, transcription factor; FAM118A, family with sequence similarity 118 member A; FAP, fibroblast activation protein alpha; FBXL19, F-box and leucine rich repeat protein 19; FCGR2A, Fc fragment of IgG receptor IIa; FGFR1OP, FGFR1 oncogene partner; FIBP, FGF1 intracellular binding protein; FNDC3A, fibronectin type III domain containing 3A; FOS-V, Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog; FOSL2, FOS-related antigen 2; FUT2, fucosyltransferase 2; GAL3ST2, galactose-3-O-sulfotransferase 2; GBAP1, glucosylceramidase beta pseudogene 1; GCKR, glucokinase regulator; GLYAT, glycine-N-acyltransferase; GNA12, G protein subunit alpha 12; GPR35, G protein-coupled receptor 35; HDAC7, histone deacetylase 7; HIPK1, homeodomain interacting protein kinase 1; HLA-A, human eukocyte antigen A; HLA-B, human leukocyte antigen B; HLA-C, human leukocyte antigen C; HLA-DP, human leukocyte antigen DP; HLA-DRA, human leukocyte antigen DR alpha; HLA-DRB1, human leukocyte antigen DR beta 1; HMGN2P18, high mobility group nucleosomal binding domain 2 pseudogene 18; HNF4A, hepatocyte nuclear factor 4-alpha; HSPA6, heat shock 70kd protein 6; ICOSLG, inducible T cell costimulator ligand; IFIH1, interferon-induced helicase C domain-containing protein 1; IFNG-AS1, interferon gamma; IFNGR2, interferon gamma receptor 2; IFNLR1, interferon lambda receptor 1; IL1R1, interleukin 1 receptor type 1; IL1R2, interleukin 1 receptor type 2; IL2RA, interleukin 2 receptor alpha; IL6R, interleukin 6 receptor; IL7R, Interleukin 7 receptor; IL10, interleukin 10; IL12B, interleukin 12B (IL12 p40 subunit); IL18R1, interleukin 18 receptor 1 (alpha chain); IL21, interleukin 21; IL23A, interleukin 23 alpha (IL12 p19 subunit); IL23R, interleukin 23 receptor; IL27, interleukin 27; INAVA, innate immunity activator; IRF1, interferon regulatory factor 1; IRF5, interferon regulatory factor 5; IRGM, immunity-related GTPase family, M; ITGAL, integrin alpha-L; ITLN1, intelectin 1; JAK2, Janus kinase 2; JAZF1, JAZF zinc finger 1; KEAP1, kelch like ECH associated protein 1; KIF21B, kinesin family member 21B; KSR1, kinase suppressor of ras 1; LCE3B, late cornified envelope 3B; LNPEP, leucyl-cystinyl aminopeptidase; LRRK2, leucine rich repeat kinase 2; LSM14A, LSM14A mRNA processing body assembly factor; LTBR, lymphotoxin B receptor; MST1, macrophage stimulating 1; MYRF, myelin regulatory factor; NDFIP1, neural precursor cell expressed, developmentally downregulated 4 family-interacting protein 1; NFATC1, nuclear factor of activated t cells, cytoplasmic, calcineurin-dependent 1; NFIP1; Nedd4 Family Interacting Protein 1;NFKB1, nuclear factor kappa-b, subunit 1; NFKBIA, nuclear factor of kappa light chain gene enhancer in b cells inhibitor, alpha; NKX2-3, NK2 homeobox 3; NOD2, nucleotide-binding oligomerization domain protein 2; NOS2, nitric oxide synthase 2A; NOTCH1, NOTCH, Drosophila, homolog of, 1; NPEPPS, aminopeptidase, puromycin-sensitive; NR5A2, nuclear receptor subfamily 5 group A member 2; NXPE1, neurexophilin and PC-esterase domain family member 1; OR5B21, olfactory receptor family 5 subfamily B member 21; OSMR, oncostatin M receptor; PARK7, Parkinsonism associated deglycase; PKIG, cAMP-dependent protein kinase inhibitor gamma; PLAU, plasminogen activator, urokinase; PPP2R3C, protein phosphatase 2 regulatory subunit B double prime gamma; PPP5C, protein phosphatase 5 catalytic subunit; PRDM1, PR domain-containing protein 1; PRKCB, protein kinase C beta; PRKCQ, protein kinase C theta; PTGER4, prostaglandin E receptor 4, EP4 subtype; PTPN2, protein tyrosine phosphatase, non-receptor type 2; PTPN22, protein tyrosine phosphatase, non-receptor type 22; PUS10, pseudouridylate synthase 10; RAVER1, RAVER1, mouse, homolog of; RIC8B, RIC8, C. elegans, homolog of, B; RNF114, ring finger protein 114; RNF186, ring finger protein 186; RORC, RAR-related orphan receptor C; RPS6KB1, ribosomal protein S6 kinase, 70-Kd, 1; RUNX3, runt-related transcription factor 3; SBNO2, strawberry notch, Drosophila, homolog of, 2; SDF4, stromal cell derived factor 4; SETD1A, SET domain-containing protein 1A; SH2B3, SH2B adaptor protein 3; SKAP2, SRC kinase-associated phosphoprotein 2; SLC9A8, solute carrier family 9 (zinc transporter), member 8; SLC26A3, solute carrier family 26 (zinc transporter), member 26; SLC39A11, solute carrier family 39 (zinc transporter), member 11; SMAD3, mothers against decapentaplegic, Drosophila, homolog of, 3; SP140, nuclear body protein SP140; STAT3, signal transducer and activator of transcription 3; STK11, serine/threonine protein kinase 11; SULT1A2, sulfotransferase family 1A, cytosolic-phenol preferring member 2; TBKBP1, tank binding kinase binding protein 1; TBX21, T-box 21; TEX41, testis expressed 41; THADA, thyroid adenoma associated gene; TLR4, Toll receptor 4; TNFAIP3, tumor necrosis factor alpha-induced protein 3; TNFRSF1A, tumor necrosis factor receptor superfamily, member 1A; TNFRSF6B, tumor necrosis factor receptor superfamily, member 6B; TNFRSF14, tumor necrosis factor receptor superfamily, member 14; TNFSF8, tumor necrosis factor ligand superfamily, member 8; TNFSF15, tumor necrosis factor ligand superfamily, member 15; TNIP1, TNFAIP3-interacting protein 1; TNP2, transition protein 2; TSPAN14, tetraspanin 14; TYK2, tyrosine kinase 2; UBAC2, UBA domain-containing protein 2; UBASH3, ubiquitin-associated and SH3 domain-containing protein A; UBE2L3, ubiquitin conjugating enzyme 2EL 3; UQCR10, ubiquinol-cytochrome c reductase complex, 7.2 kd subunit; ZPBP2, zona pellucida-binding protein 2; ZC3H12C, zinc finger CCCH domain-containing protein 12C; ZMIZ1, Zinc finger MIZ-domain containing 1; ZNF365, zinc finger protein 365; ZNF831, melanoma, cutaneous malignant-susceptibility to 1. Not shown are genetic markers from noncoding regions: AC008697.1, Homo sapiens chromosome 5 clone CIT978SKB_70D3; AC020743.4, Homo sapiens chromosome 7 clone RP11-813 K3; AL031590.1, Homo sapiens chromosome 22, clone 232D4; AP001057.1, uncharacterized LOC107983952; CTD-2260A1, DNA marker; NPM1P17, nucleophosmin 1 pseudogene 17; RP1-66C13.4; RP11-24F11.2; RP11-129 J12.1; RP11-300 J18.1; RP11-1C1.5; RP11-84D1.2; and RP11-672A2.7