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Article Contents
Clin Exp Pediatr > Volume 64(5); 2021 |
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Meta-analyses | No. of SNP studies | P<0.05 |
FPRP values at prior probability |
BFDP 0.001 | BFDP 0.000001 | |||
---|---|---|---|---|---|---|---|---|
OR 1.2 |
OR 1.5 |
|||||||
0.001 | 0.000001 | 0.001 | 0.000001 | |||||
Observational studies | 133 | 133 (100) | 23 (17) | 11 (8) | 34 (26) | 18 (14) | 50 (38) | 29 (22) |
GWAS (P<5×10-8)a) | 89 | 89 (100) | 64 (100) | 64 (100) | 64 (100) | 64 (100) | 89 (100) | 89 (100) |
GWAS (5×10-8<P<0.05) | 27 | 27 (100) | 13 (48) | 2 (7) | 13 (48) | 2 (7) | 15 (56) | 1 (4) |
Study | Gene | Variant (RS number) | Ethnicity, study No. (types of study) | Comparison | OR (95% CI) | P value | Function of genes |
---|---|---|---|---|---|---|---|
Bentham, et al. 2015 [35] | ABHD6-PXK | rs9311676 | European 2 (MG) | C<T | 1.17 (1.13–1.22) | 3.06×10-14 | ABHD6 gene codes for the abhydrolase domain-containing protein 6. ABHD6 catalyzes the hydrolysis of 2-arachidonylglycerol and takes part in the endocannabinoid signaling regulation. [36] PXK gene encodes a phox (PX) domain-containing protein which may be involved in synaptic transmission and the ligand-induced internalization and degradation of epidermal growth factors. PXK also operates on the B-cell antigen receptor (BCR) and influences the rate of BCR internalization. [37,38] |
Lessard, et al. 2016 [39] | AHNAK2 | rs1048257 | Chinese 2 (MG) | T<C | 0.82 (0.76–0.89) | 8.66×10-7 | AHNAK2 gene encodes a large nucleoprotein that may play a role in calcium signaling by associating with calcium channel proteins. [38] |
Zhang, et al. 2016 [40] | ALOX5AP | rs12876893 | Asain 5 (MG) | G<A | 1.12 (1.06–1.180) | 6.20×10-5 | ALOX5AP gene encodes a protein which is required for leukotriene synthesis. ALOX5AP is expressed in airway leukocytes in response to stimuli implicated in various inflammatory responses including asthma, arthritis and psoriasis. [38,40] |
Molineros, et al. 2017 [41] | ANKS1A | rs2762340 | Overall 9 (MG) | G<A | 0.87 (0.84–0.90) | 4.93×10-15 | ANKS1A, also known as ODIN, a Src kinase that negatively regulates growth factor receptor signaling pathways. ANKS1Ainteracts with and is phosphorylated by Lck (lymphocyte-specific protein tyrosine kinase), a critical component of T-cell activation. [41] |
Bentham, et al. 2015 [35] | ARID5B | rs4948496 | European 2 (MG) | C<T | 1.14 (1.10–1.19) | 1.04×10-10 | The encoded protein forms a histone H3K9Me2 demethylase complex with PHD finger protein 2 and regulates the transcription of target genes involved in adipogenesis and liver development. This gene also plays a role in cell growth and differentiation of B-lymphocyte progenitors. [38] |
Molineros, et al. 2017 [41] | ATG16L2 | rs11235604 | Asian 8 (MG) | T<C | 0.78 (0.71–0.85) | 8.87×10-12 | An autophagy-related gene associated with systemic lupus erythematosus (SLE), multiple sclerosis, and Crohn disease. ATG16L2 is involved in apoptosis and physically interacts with SLE locus ATG5. |
Morris, et al. 2016 [42] | ATXN1 | rs17603856 | Overall 3 (MG) | T<G | 0.88 (0.85–0.91) | 3.27×10-12 | ATXN1 binds RNA and several transcription factors, and is involved in transcriptional regulation. [43] The diseased allele of ATXN1 with the expansion of CAG repeats is associated with spinocerebellar ataxia type 1. [38] |
Morris, et al. 2016 [42] | BACH2 | rs597325 | Overall 3 (MG) | G<A | 0.89 (0.86–0.92) | 4.03×10-12 | A transcription regulator protein. BACH2 is expressed in primary B cells. BACH2 protein play important role as transcriptional activators or repressors. [44] The superenhancer associated genes critical for T-cell biology are repressed by BACH2. [45] |
Bentham, et al. 2015 [35] | BANK1 | rs10028805 | European 2 (MG) | G<A | 1.20 (1.15–1.25) | 4.31×10-17 | BANK1 encodes a protein adaptor that is predominantly expressed in B cells. It promotes LYN-mediated tyrosine phosphorylation of inositol 1,4,5-triphosphate receptors. [46] |
Lee, et al. 2012 [47] | BLK | rs13277113 | European 2 (MG) | A<G | 1.391 (1.256–1.540) | 2.28×10-10 | BLK gene encodes a nonreceptor tyrosine kinase of the Src family of proto-oncogenes that are typically involved in cell proliferation and differentiation. The protein has a role in B-cell receptor signaling and B-cell development. [38] |
Bentham, et al. 2015 [35] | BLK | rs2736340 | European 2 (MG) | T<C | 1.29 (1.22–1.37) | 6.28×10-20 | |
Molineros, et al. 2017 [41] | CCL22 | rs223881 | Overall 9 (MG) | C<T | 0.87 (0.84–0.90) | 5.87×10-16 | CCL22 is a Cys-Cys (CC) cytokine gene. The encoded cytokine displays chemotactic activity for monocytes, dendritic cells (DCs), natural killer cells, and chronically activated T lymphocytes. It binds to chemokine receptor CCR4. [38] |
Lee, et al. 2015 [48] | CD40 | rs4810485 | European 2 (MO) | TT vs. TG+GG | 0.339 (0.205–0.508) | 1.7×10-8 | The encoded protein of CD40 gene is a receptor on antigenpresenting cells of the immune system and is essential for mediating a broad variety of immune responses including T-cell-dependent immunoglobulin class switching, memory B-cell development, and germinal center formation. [38] |
Lessard, et al. 2011 [49] | CD44 | rs387619 | European (MG) | C<T | 0.82 (0.76–0.88) | 1.46×10-8 | The protein encoded by the CD44 gene is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration. This protein participates in a wide variety of cellular functions including lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis. [38] |
Sheng, et al. 2015 [50] | CD44 | rs2732547 | Chinese 3 (MG) | G<A | 0.82 (0.77–0.87) | 1.55×10-11 | |
Bentham, et al. 2015 [35] | CD44 | rs2732549 | European 2 (MG) | T<C | 1.24 (1.19–1.29) | 1.20×10-23 | |
Lessard, et al. 2011 [49] | CD44 | rs2732552 | European (MG) | C<T | 0.82 (0.76–0.88) | 1.82×10-9 | |
Zhang, et al. 2016 [40] | CD80 | rs2222631 | Asain 5 (MG) | A<G | 0.86 (0.81–0.91) | 4.50×10-8 | The protein encoded by the CD80 gene is a membrane receptor that is activated by the binding of CD28 or CTLA-4. The activated protein induces T-cell proliferation and cytokine production. [38] |
Sheng, et al. 2015 [50] | CD80 | rs6804441 | Chinese 3 (MG) | G<A | 0.86 (0.82–0.91) | 5.90×10-4 | |
Bentham, et al. 2017 [35] | CFB | rs1270942 | European 2 (MG) | G<A | 2.28 (2.15–2.42) | 2.25×10-165 | CFB gene encodes complement factor B, a component of the alternative pathway of complement activation. [38] |
Bentham, et al. 2017 [35] | CIITA-SOCS1 | rs9652601 | European 2 (MG) | A<G | 1.21 (1.15–1.26) | 7.42×10-17 | CIITA gene encodes a protein with an acidic transcriptional activation domain, 4 LRRs (leucine-rich repeats) and a guanosine triphosphate binding domain. The protein acts as a positive regulator of class II major histocompatibility complex gene transcription. [38] SOCS1 gene encodes a member of the signal transducer and activator of transcription (STAT)-induced STAT inhibitor (SSI) family, also known as suppressor of cytokine signaling. It takes part in a negative feedback loop to attenuate cytokine signaling. [38] |
Bentham, et al. 2017 [35] | CSK | rs2289583 | European 2 (MG) | A<C | 1.19 (1.14–1.24) | 6.22×10-15 | The protein encoded by the CSK gene is involved in multiple pathways, including the regulation of Src family kinases. It plays an important role in T-cell activation through its association with the protein encoded by the protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) gene. An intronic polymorphism (rs34933034) in this gene has been found to affect B-cell activation and is associated with SLE. [38] |
Shojaa, et al. 2017 [51] | CTLA-4 | rs733618 | Overall 8 (MO) | TT vs. CC | 2.32 (1.62–3.32) | <0.001 | CTLA-4 gene is a member of the immunoglobulin superfamily and encodes a protein which transmits an inhibitory signal to T cells. [38] |
Zhang, et al. 2017 [52] | CXCR5 | rs10892301 | Asian 3 (MG) | A<G | 0.85 (0.80–0.90) | 2.51×10-8 | CXCR5 gene encodes a multipass membrane protein that belongs to the CXC chemokine receptor family. This cytokine receptor is involved in B-cell migration into B-cell follicles of spleen and Peyer patches. [38] |
Bentham, et al. 2017 [35] | CXorf21 | rs887369 | European 2 (MG) | A<C | 1.15 (1.10–1.21) | 5.26×10-10 | A protein coding gene of unknown function. [53] |
Lessard, et al. 2017 [39] | DOCK1 | rs10901656 | Asian 2 (MG) | T<C | 1.21 (1.12–1.32) | 9.56×10-6 | DOCK1 gene encodes a member of the dedicator of cytokinesis protein family. Dedicator of cytokinesis proteins regulates the small GTPase Rac, thereby influencing several biological processes, including phagocytosis and cell migration. [38] |
Wang, et al. 2017 [54] | ETS1 | rs6590330 | Caucasian 3 (MG) | A<G | 1.22 (1.10–1.34) | 9.8×10-5 | ETS1 gene encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. [55] |
Bentham, et al. 2017 [35] | ETS1-FLI1 | rs7941765 | European 2 (MG) | T<C | 1.14 (1.10–1.19) | 1.35×10-10 | FLI1 gene encodes a transcription factor containing an ETS DNA-binding domain. [38] |
Lee, et al. 2017 [47] | FAM167A | rs12680762 | European 2 (MG) | A<G | 1.335 (1.208–1.475) | 1.45×10-8 | FAM167A gene is a ubiquitously expressed gene of unknown function. |
Bentahm, et al. 2017 [35] | FCGR2A | rs1801274 | European 2 (MG) | C<T | 1.16 (1.11–1.21) | 1.04×10-12 | FCGR2A gene encodes a cell-surface receptor found on phagocytic cells such as macrophages and neutrophils, and is involved in the process of phagocytosis and clearing of immune complexes. [38] |
Zhu, et al. 2017 [56] | FCGR2B | rs1050501 | Overall 12 (MO) | CC vs. CT+TT | 1.754 (1.422–2.165) | 1.61×10-7 | FCGR2B is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor and it mediates both endocytotic and apoptotic signaling on B cells and myelomonocytic cells. |
Zhu, et al. 2017 [56] | FCGR3A | rs396991 | Overall 26 (MO) | TT vs. TG+GG | 1.263 (1.123–1.421) | 9.62×10-5 | FCGR3A gene is involved in the removal of antigen-antibody complexes from the circulation, as well as other antibodydependent responses. The encoded receptor is expressed on natural killer (NK) cells. [38] |
Lessard, et al. 2017 [39] | FCHSD2-P2RY2 | rs11235667 | Asian 2 (MG) | G<A | 0.63 (0.55–0.72) | 6.67×10-11 | FCHSD2 gene has been described as regulator of F-actin assembly through interactions with WAS (also known as WASP) and WASL (also known as N-WASP). WAS plays an important role in the migration of T cells through reorganization of the actin cytoskeleton subsequent to interactions with dendritic or B cells. P2RY2 is a receptor for adenosine triphosphate (ATP) and uridine triphosphate (UTP) that acts as a sensor for the release of nucleotides by apoptotic cells. It is also known to induce CCL2 secretion in macrophages. |
Sheng, et al. 2017 [50] | FLJ25996 | rs9866504 | Chinese 3 (MG) | G<A | 0.85 (0.79–0.92) | 6.44×10-2 | No information |
Sheng, et al. 2017 [50] | GPM6A | rs997779 | Chinese 3 (MG) | G<A | 1.17 (1.08–1.26) | 4.48×10-2 | GPM6A gene is abundant in all rat hippocampal subregions, and it localized to membrane protrusions (filopodia/spines) of primary hippocampal neurons. This gene has a role in neurite/filopodium outgrowth and synapse formation. |
Lessard, et al. 2017 [39] | GTF2IRD1 | rs2267828 | Asian 2 (MG) | G<A | 0.81 (0.76–0.88) | 6.46×10-8 | The protein encoded by this gene contains 5 GTF2I-like repeats and each repeat possesses a potential helix-loop-helix (HLH) motif. It may interact with other HLH-proteins and function as a transcription factor or as a positive transcriptional regulator under the control of Retinoblastoma protein. This gene plays a role in craniofacial and cognitive development. [38] |
Morris, et al. 2016 [42] | GTF2IRD1-GTF2I | rs73135369 | Overall 3 (MG) | C<T | 1.32 (1.23–1.42) | 8.77×10-14 | This gene encodes a phosphoprotein containing 6 characteristic repeat motifs. The encoded protein binds to the initiator element (Inr) and E-box element in promoters and functions as a regulator of transcription. [38] |
Zhang, et al. 2015 [57] | HCFC1 | rs17422 | Asian 2 (MG) | T<C | 0.75 (0.71–0.80) | 1.47×10-15 | This gene is a member of the host cell factor family and encodes a protein with 5 Kelch repeats, a fibronectin-like motif, and 6 HCF repeats, each of which contains a highly specific cleavage signal. It is involved in control of the cell cycle and transcriptional regulation during herpes simplex virus infection. [38] |
Niu, et al. 2015 [58] | HLA-DR3 | Overall 17 (MO) | DR3 | 1.88 (1.58–2.23) | <0.001 | Major histocompatibility complex, class II, DR beta 1 (HLA-DRB1 gene). | |
The HLA-DRB1 locus is ubiquitous and encodes a very large number of functionally variable gene products (HLA-DR1 to HLA-DR17). HLA-DRB1 belongs to the HLA class II beta chain paralogs. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen-presenting cells (APC: B lymphocytes, DCs, macrophages). [38] | |||||||
Niu, et al. 2015 [58] | HLA-DR11 | Overall 15 (MO) | DR11 | 0.72 (0.60–0.85) | <0.0001 | ||
Castaño-Rodríguez, et al. 2008 [59] | HLA-DR2 | Latin American 9 (MO) | DR2 | 1.754 (1.404–2.191) | 0 | ||
Lee, et al. 2015 [60] | HLA-G | rs1063320 | Overall 4 (MO) | G vs. C | 1.367 (1.158–1.613) | 2.2×10-5 | HLA-G belongs to the HLA class I heavy chain paralogs. [38] Nonclassic HLA-G class I molecules inhibit natural killer cell function. [61] |
Kim, et al. 2012 [62] | ICAM1–ICAM4–ICAM5 | rs3093030 | Overall 4 (MO) | A vs. G | 1.16 (1.11–1.22) | 4.88×10-10 | ICAM1 gene encodes a cell-surface glycoprotein which is mainly expressed in the vascular endothelium, macrophages and lymphocytes, and plays a role in immunological events including extravasation and T-cell-mediated responses. ICAM4 gene encodes the Landsteiner-Wiener blood group antigen(s) that belongs to the immunoglobulin (Ig) superfamily. It contains 2 Ig-like C2-type domains and binds to the leukocyte adhesion LFA-1 protein. ICAM5 is preferentially expressed in brain. |
Bentham, et al. 2015 [35] | IFIH1 | rs2111485 | European 2 (MG) | C<G | 1.15 (1.11–1.20) | 1.27×10-11 | IFIH1 gene encodes a DEAD box protein that is upregulated in response to treatment with beta-interferon and a protein kinase C-activating compound, mezerein. |
The encoded protein participates in the activation of apoptosis in viral dsRNA infected cells, modulating type 1 interferon (IFN) response, production of proinflammatory cytokines and apoptotic processes. [63] | |||||||
Morris, et al. 2016 [42] | IKBKE | rs2297550 | Overall 3 (MG) | G<C | 1.16 (1.11–1.21) | 1.31×10-11 | IKBKE is a noncanonical I-kappa-B kinase that is essential for regulating antiviral signaling pathways. |
Bentham, et al. 2015 [35] | IKZF1 | rs4917014 | European 2 (MG) | G<T | 1.18 (1.13–1.24) | 6.39×10-14 | IKZF1 gene encodes a transcription factor associated with chromatin remodeling. It functions as a regulator of lymphocyte differentiation. [38] |
Bentham, et al. 2015 [35] | IKZF2 | rs3768792 | European 2 (MG) | G<A | 1.24 (1.17–1.31) | 1.21×10-13 | IKZF2 gene encodes a member of the Ikaros family of zincfinger proteins that is involved in the regulation of lymphocyte development. [38] |
Bentham, et al. 2015 [35] | IKZF3 | rs2941509 | European 2 (MG) | T<C | 1.35 (1.22–1.49) | 7.98×10-9 | IKZF3 gene encodes a member of the Ikaros family of zincfinger proteins. This gene product is a transcription factor that is important in the regulation of B-lymphocyte proliferation and differentiation. [38] |
Bentham, et al. 2015 [35] | IL-10 | rs3024505 | European 2 (MG) | A<G | 1.17 (1.11–1.24) | 4.64×10-9 | Interleukin (IL)-10 is produced primarily by monocytes and to a lesser extent by lymphocytes. It down-regulates the expression of Th1 cytokines, major histocompatibility complex (MHC) class II Ags, and costimulatory molecules on macrophages. It enhances B-cell survival, proliferation, and antibody production. It can block NF-kappa B activity, and is involved in the regulation of the Janus kinase (JAK)-STAT signaling pathway. [38] |
Bentham, et al. 2015 [35] | IL-12A | rs564799 | European 2 (MG) | C<T | 1.14 (1.09–1.18) | 1.54×10-9 | IL-12A acts on T and natural killer cells. It is required for the T-cell-independent induction of IFN-gamma, and is important for the differentiation of both Th1 and Th2 cells. [38] |
Qi, et al. 2015 [64] | IL-21 | rs907715 | Overall 7 (MO) | GG+GA vs. AA | 1.20 (1.09–1.31) | 0 | IL-21 plays a role in both the innate and adaptive immune responses by inducing the differentiation, proliferation and activity of multiple target cells including macrophages, natural killer cells, B cells and cytotoxic T cells. [38] |
Ryan, et al. 2009 [65] | IL-21R | rs3093301 | Overall 2 (MO) | A vs. G | 1.16 (1.08–1.25) | 1.0×10-4 | IL-21R gene encodes a cytokine receptor for IL-21. It transduces the growth promoting signal of IL21, and is important for the proliferation and differentiation of T cells, B cells, and NK cells. [38] |
Katkam, et al. 2017 [66] | IL-6 | rs1800797 | Overall 13 (MO) | G vs. C | 1.36 (1.22–1.53) | 0.00 | IL-6 functions in inflammation and the maturation of B cells. In addition, it has been shown to be an endogenous pyrogen capable of inducing fever in people with autoimmune diseases or infections. [38] |
Zhang, et al. 2015 [57] | IRAK1 | rs1059702 | Asian 2 (MG) | C<T | 0.71 (0.67–0.76) | 2.40×10-18 | IRAK1 gene encodes the interleukin-1 receptor-associated kinase 1. It is partially responsible for IL1-induced upregulation of the transcription factor NF-kappa B. [38] |
Bentham, et al. 2015 [35] | IRF5 | rs10488631 | European 2 (MG) | C<T | 1.92 (1.81–2.03) | 9.37×10-110 | Proteins of the interferon regulatory factor (IRF) family bind to the IFN-stimulated response element and regulate expression of genes stimulated by type I IFNs, namely IFN-alpha and IFN-beta. IRF family proteins also control expression of IFNalpha and IFN-beta-regulated genes that are induced by viral infection. [38] |
Lee, et al. 2012 [47] | IRF5 | rs729302 | European 2 (MG) | C<A | 0.774 (0.707–0.848) | 3.93×10-8 | |
Bentham, et al. 2015 [35] | IRF7 | rs12802200 | European 2 (MG) | A<C | 1.23 (1.15–1.31) | 8.81×10-10 | |
Bentham, et al. 2015 [35] | IRF8 | rs11644034 | European 2 (MG) | A<G | 1.25 (1.19–1.32) | 9.58×10-18 | |
Sheng, et al. 2015 [50] | IRF8 | rs2934498 | Chinese 2 (MG) | G<A | 1.25 (1.16–1.34) | 4.97×10-9 | |
Bentham, et al. 2015 [35] | ITGAM | rs34572943 | European 2 (MG) | A<G | 1.71 (1.61–1.81) | 3.39×10-76 | ITGAM gene encodes the integrin alpha M chain. It is important in the adherence of neutrophils and monocytes to stimulated endothelium, and also in the phagocytosis of complement coated particles. [38] |
Morris, et al. 2016 [42] | JAK2 | rs1887428 | Overall 3 (MG) | G<C | 1.16 (1.12–1.20) | 2.19×10-17 | JAK2 encodes a tyrosine kinase involved in a specific subset of cytokine receptor signaling pathways. It has been found to be associated with the prolactin receptor and is required for responses to gamma interferon. [38] |
Bentham, et al. 2015 [35] | JAZF1 | rs849142 | European 2 (MG) | C<T | 1.14 (1.10–1.19) | 8.61×10-11 | JAZF1 gene encodes a nuclear protein that functions as a transcriptional repressor. [38] |
Zhang, et al. 2015 [57] | L1CAM | rs4898457 | Asian 2 (MG) | G<A | 0.87 (0.82–0.92) | 2.84×10-6 | L1CAM gene encodes an axonal glycoprotein belonging to the immunoglobulin supergene family. This cell adhesion molecule plays an important role in nervous system development, including neuronal migration and differentiation. [38] |
Morris, et al. 2016 [42] | LBH | rs17321999 | Overall 3 (MG) | A<C | 0.83 (0.79–0.87) | 2.22×10-16 | LBH (limb bud and heart development) is a key gene regulator which could act as a transcriptional coactivator in the mitogen ‐activated protein kinase signaling pathway to mediate cellular functions. Several SNP within LBH are associated with rheumatoid arthritis and SLE. [67] |
Morris, et al. 2016 [42] | LBH | rs7579944 | Overall 3 (MG) | C<T | 0.90 (0.87–0.93) | 1.41×10-9 | |
Morris, et al. 2016 [42] | LPP-TPRG1-AS1 | rs6762714 | Overall 3 (MG) | C<T | 1.16 (1.12–1.20) | 4.00×10-15 | LPP gene encodes a protein localizes to the cell periphery in focal adhesions and may be involved in cell-cell adhesion and cell motility. It also functions as a transcriptional coactivator. [38] |
Wang, et al. 2013 [54] | LRRC18-WDFY4A | rs1913517 | Caucasian 3 (MG) | A<G | 1.16 (1.08 –1.23) | 7.8×10-6 | Both LRRC18 and WDFY4 are of unknown function. |
Bentham, et al. 2015 [35] | LYST | rs9782955 | European 2 (GWAS) | T<C | 1.16 (1.11–1.22) | 1.25×10-9 | LYST gene encodes a protein that regulates intracellular protein trafficking in endosomes, and may be involved in pigmentation. [38] No known immune function. Studies have revealed that LYST functions in lysosomal trafficking in many immune cells, a process that is also crucial in the activation of TLRs by self-nucleic acids in SLE. [68] |
Lee, et al. 2012 [69] | MBL2 | rs1800450 | Overall 21 (MO) | B vs. A | 1.298 (1.154–1.459) | 1.49×10-5 | MBL2 gene encodes the soluble mannose-binding lectin or protein. It recognizes mannose and N-acetylglucosamine on many microorganisms, and is capable of activating the classical complement pathway. [38] |
Bentham, et al. 2015 [35] | MECP2 | rs1734787 | European 2 (MG) | C<A | 1.31 (1.22–1.40) | 1.78×10-15 | MECP2 is a dichotomous transcriptional regulator that either activates or represses gene expression. [70] |
Zhang, et al. 2015 [57] | MECP2 | rs2734647 | Asian 2 (MG) | C<T | 0.72 (0.67–0.76) | 5.22×10-18 | |
Bentham, et al. 2015 [35] | miR-146a | rs2431697 | European 2 (MG) | C<T | 1.26 (1.21–1.31) | 8.01×10-28 | MicroRNA 146a can repress type 1 IFN pathway through targeting TNF receptor-associated factor 6, IL-1 receptorassociated kinase, IFN regulator factor 5 (IRF5), and STAT-1. [71] |
Molineros, et al. 2017 [41] | MYNN | rs10936599 | Overall 9 (MG) | C<T | 1.14 (1.10–1.18) | 1.92×10-13 | MYNN encodes the zinc-finger transcription factor myoneurin, which regulates neuromuscular junctions and telomere length. [41] |
Zhang, et al. 2015 [57] | NAA10 | rs1557501 | Asian 2 (MG) | C<T | 0.83 (0.79–0.88) | 7.84×10-10 | NAA10 gene encodes an N-terminal acetyltransferase that functions as the catalytic subunit of the major amino-terminal acetyltransferase A complex. [38] |
Zhang, et al. 2015 [57] | NAA10 | rs2071128 | Asian 2 (MG) | G<A | 0.81 (0.77–0.86) | 2.19×10-13 | |
Bentham, et al. 2015 [35] | NADSYN1 | rs3794060 | European 2 (MG) | T<C | 1.23 (1.18–1.29) | 1.32×10-20 | This gene encodes a synthetase that catalyzes the final step in the biosynthesis of Nicotinamide adenine dinucleotide. |
Zhang, et al. 2015 [57] | Near-VCX2 | rs5978830 | Asian 2 (MG) | A<G | 0.84 (0.80–0.89) | 1.00×10-8 | This gene belongs to the VCX/Y gene family, which has multiple members on both X and Y chromosomes that are expressed exclusively in male germ cells. The VCX gene cluster is polymorphic in terms of copy number; different individuals may have a different number of VCX genes. This gene contains 2 copies of a 30 nt tandem repeat. Deletion of a nearby member of this family was implicated in cognitive disability. [38] |
Sheng, et al. 2015 [50] | NRXN1 | rs2048979 | Chinese 3 (MG) | G/A | 0.87 (0.82–0.91) | 1.35×10-3 | Neurexins are cell-surface receptors that bind neuroligins to form Ca(2+)-dependent neurexin/neuroligin complexes at synapses in the central nervous system. This complex is required for efficient neurotransmission and is involved in the formation of synaptic contacts. [38] |
Lee, et al. 2017 [72] | OPN | rs11229919 | Asian 2 (MO) | C vs. T | 2.070 (1.570–2.730) | 2.5×10-7 | The protein encoded by this gene is involved in the attachment of osteoclasts to the mineralized bone matrix. It is also a cytokine that upregulates expression of interferon-gamma and interleukin-12. [38] |
Zhang, et al. 2014 [52] | PHLDB1 | rs11603023 | Asian 3 (MG) | T<C | 1.20 (1.12–1.27) | 1.25×10-8 | PHLDB1 is an insulin responsive protein that enhances AKT activation. AKT signaling pathway plays an important role in cellular proliferation and growth signaling. Abnormal activation of the AKT signaling pathway was found in peripheral blood T cells from individuals with SLE. [52] |
Bentham, et al. 2015 [35] | PLD2 | rs2286672 | European 2 (MG) | T<C | 1.25 (1.16–1.35) | 2.93×10-9 | The protein encoded by this gene catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid and choline. This protein localizes to the peripheral membrane and may be involved in cytoskeletal organization, cell cycle control, transcriptional regulation, and/or regulated secretion. [38] |
Tan, et al. 2011 [73] | PPP2CA | rs10491322 | Overall 4 (MO) | G vs. A | 1.2 (1.07–1.27) | 3.8×10-4 | PPP2CA gene encodes the phosphatase 2A catalytic subunit. Protein phosphatase 2A is implicated in the negative control of cell growth and division. [38] |
Tan, et al. 2011 [73] | PPP2CA | rs7704116 | Overall 4 (MO) | A vs. G | 1.3 (1.14–1.31) | 3.8×10-7 | |
Bentham, et al. 2015 [35] | PRDM1-ATG5 | rs6568431 | European 2 (MG) | A<C | 1.21 (1.15–1.27) | 5.04×10-14 | PRDM1 gene encodes a protein that acts as a repressor of beta-interferon gene expression. [38] The encoded protein by ATG5 gene is involved in several cellular processes, including autophagic vesicle formation, mitochondrial quality control after oxidative damage, negative regulation of the innate antiviral immune response, lymphocyte development and proliferation, MHC II antigen presentation, adipocyte differentiation, and apoptosis. [38] |
Bentham, et al. 2015 [35] | PTPN22 | rs2476601 | European 2 (MG) | T<C | 1.43 (1.34–1.53) | 1.10×10-8 | PTPN22 gene encodes a lymphoid-specific intracellular phosphatase that associates with the molecular adapter protein CBL and may be involved in regulating CBL function in the T-cell receptor signaling pathway. [38] |
Morris, et al. 2016 [42] | PTPRC | rs34889541 | Overall 3 (MG) | A<G | 0.81 (0.76–0.86) | 2.44×10-12 | The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitosis, and oncogenic transformation. PTP is also an essential regulator of T- and B-cell antigen receptor signaling. [38] |
Ramos, et al. 2011 [74] | PXK | rs6445975 | Overall 4 (MG) | G<T | 1.20 (1.13–1.27) | 5.27×10-9 | This gene encodes a phox (PX) domain-containing protein which may be involved in synaptic transmission and the ligand-induced internalization and degradation of epidermal growth factors. [38] |
Bentham, et al. 2015 [35] | RAD51B | rs4902562 | European 2 (MG) | A<G | 1.14 (1.09–1.19) | 6.15×10-10 | RAD51 family members are evolutionarily conserved proteins essential for DNA repair by homologous recombination. Overexpression of this gene was found to cause cell cycle G1 delay and cell apoptosis, which suggested a role of this protein in sensing DNA damage. [38] |
Molineros, et al. 2017 [41] | RNASEH2C | rs1308020 | Overall 9 (MG) | T<C | 0.84 (0.81–0.88) | 2.96×10-19 | RNASEH2C encodes subunit C of the human ribonuclease H2 enzyme complex that trims RNA-DNA duplexes. |
Morris, et al. 2016 [42] | RNASEH2C | rs494003 | Overall 3 (MG) | A<G | 1.14 (1.09–1.19) | 5.81×10-9 | |
Bentham, et al. 2015 [35] | SH2B3 | rs10774625 | European 2 (MG) | A<G | 1.13 (1.08–1.18) | 4.09×10-9 | The encoded protein is a key negative regulator of cytokine signaling and plays a critical role in hematopoiesis. [38] Functional analysis indicated that it inhibits the activation of NFAT in stimulated T cells. [75] |
Bentham, et al. 2015 [35] | SLC15A4 | rs1059312 | European 2 (MG) | G<A | 1.17 (1.12–1.21) | 1.48×10-13 | SLC15A4 belongs to a superfamily of proton-coupled oligopeptide transporters. [76] Kobayashi et al. [77] (2014) found that B-cell-derived Slc15a4 was crucial for Tlr7 (300365)-triggered type I interferon (e.g., IFNA) and autoantibody production in a mouse model of lupus (SLE). |
Bentham, et al. 2015 [35] | SMG7-NCF2 | rs17849501 | European 2 (MG) | T<C | 2.10 (1.95–2.26) | 3.45×10-88 | SMG7 gene encodes a protein that is essential for nonsensemediated mRNA decay; a process whereby transcripts with premature termination codons are targeted for rapid degradation by a mRNA decay complex. NCF2 gene encodes neutrophil cytosolic factor 2, the cytosolic subunit of the multiprotein nicotinamide adenine dinucleotide phosphate oxidase complex found in neutrophils. It produces a burst of superoxide which is delivered to the lumen of the neutrophil phagosome. [38] |
Lee, et al. 2012 [47] | STAT4 | rs10931481 | European 2 (MG) | A<G | 1.312 (1.194–1.442) | 1.74×10-8 | STAT4 encodes a member of the STAT family of transcription factors. In response to cytokines and growth factors, it acts as transcription activator. This protein is essential for mediating responses to IL12 in lymphocytes, and regulating the differentiation of T helper cells. [38] |
Bentham, et al. 2015 [35] | STAT4 | rs11889341 | European 2 (MG) | T<C | 1.73 (1.65–1.81) | 5.59×10-122 | |
Lee, et al. 2012 [47] | STAT4 | rs7574865 | European 2 (MG) | T<G | 1.477 (1.335–1.634) | 4.06×10-14 | |
Bentham, et al. 2015 [35] | TCF7-SKP | rs7726414 | European 2 (MG) | T<C | 1.45 (1.32–1.58) | 4.44×10-16 | TCF7 is a T-cell-specific transcription factor that regulates the expression of CD3. plays a critical role in natural killer cell and innate lymphoid cell development. [38] |
Lee, et al. 2016 [78] | TLR7 | rs3853839 | Asian 3 (MO) | allele 2 vs. allele 1 | 0.773 (0.725–0.823) | <1.0×10-9 | The protein encoded by this gene is a member of the Toll-like receptor family which plays a fundamental role in pathogen recognition and activation of innate immunity. [38] |
Zhang, et al. 2015 [57] | TMEM187 | rs2266888 | Asian 2 (MG) | G<A | 0.76 (0.72–0.81) | 8.20×10-15 | This gene consists of 2 exons and encodes a multipass membrane protein. An alternatively spliced transcript variant encoding the same protein has been found, but its biological validity is not determined. [38] |
Zhang, et al. 2015 [57] | TMEM187 | rs6571303 | Asian 2 (MG) | C<T | 0.80 (0.76–0.84) | 3.06×10-13 | |
Sheng, et al. 2015 [50] | TMEM39A | rs12494314 | Chinese 3 (MG) | C<T | 0.84 (0.80–0.89) | 1.01×10-9 | The TMEM39A-associated coding SNP (rs1132200) results in an amino acid change from alanine to threonine at position 487 of the protein. Although almost no biological data have been published suggesting its relevance to SLE, it has been found to be associated with multiple sclerosis. [79] |
Bates, et al. 2009 [80] | TNFAIP3 | rs5029939 | Caucasian 2 (MG) | G<T | 2.09 (1.68–2.60) | 1.67×10-14 | The tumor necrosis factor alpha inducible protein 3 (TNFAIP3) encodes the ubiquitin-modifying enzyme A20 and is an inhibitor of nuclear factor-kB activity in several signaling pathways, including those of TNF and Toll-like receptors. Also, it is required for the negative regulation of inflammatory responses. [81] |
Bentham, et al. 2015 [35] | TNFAIP3 | rs6932056 | European 2 (MG) | C<T | 1.83 (1.65–2.02) | 1.97×10-31 | |
Ramos, et al. 2011 [74] | TNFSF4 | rs10798269 | Overall 4 (MG) | A<G | 0.83 (0.78–0.88) | 4.04×10-10 | TNFSF4 gene encodes a cytokine of the TNF ligand family. The encoded protein functions in T-cell APC interactions and mediates adhesion of activated T cells to endothelial cells. [38] |
Sheng, et al. 2015 [50] | TNFSF4 | rs1418190 | Chinese 2 (MG) | C<T | 0.81 (0.75–0.87) | 1.08×10-8 | |
Sheng, et al. 2015 [50] | TNFSF4 | rs4916219 | Chinese 2 (MG) | A<G | 0.80 (0.75–0.86) | 7.77×10-9 | |
Bentham, et al. 2015 [35] | TNFSF4 | rs704840 | European 2 (MG) | G<T | 1.22 (1.17–1.27) | 3.12×10-9 | |
Yang, et al. 2017 [82] | TNF-α | rs1800629 | Overall 41 (MO) | A vs. G | 1.70 (1.46–1.98) | <0.001 | TNF is a pleiotropic cytokine that produces different stimuli in various physiological and pathological conditions. TNF contributes importantly to the development of T cells, B cells, and DCs. [47] |
Bentham, et al. 2015 [35] | TNIP1 | rs10036748 | European 2 (MG) | C<T | 1.38 (1.32–1.45) | 1.27×10-45 | TNIP1 gene encodes an A20-binding protein which plays a role in autoimmunity and tissue homeostasis through the regulation of nuclear factor kappa-B activation. [38] |
Wang, et al. 2013 [54] | TNIP1 | rs7708392 | Caucasian 3 (MG) | C/G | 1.29 (1.17–1.44) | 1.2×10-6 | |
Lee, et al. 2012 [47] | TNPO3 | rs12531711 | European 2 (MG) | G<A | 1.593 (1.403–1.808) | 6.41×10-13 | TNPO3 is a nuclear import receptor for serine/argininerich (SR) proteins, which are essential precursor-mRNA splicing factors. [83] |
Kurreeman, et al. 2010 [84] | TRAF1-C5 | rs10818488 | Overall 3 (MG) | A | 1.22 (1.12–1.31) | 1.02×10-6 | TRAF1 is involved in the negative regulation of T-cell proliferation and serves as an essential effector of the TNF signaling cascade. C5 is known to be a factor in the complement cascade and may increase susceptibility to autoimmune and inflammatory disease. [85] |
Namjou, et al. 2012 [86] | TRAF6 | rs4755453 | Overall 4 (MO) | C vs. G | 0.88 (0.83–0.94) | 4.73×10-5 | TRAF6 encodes an adaptor molecule that has a central role in the nuclear factor NF-κB activation pathway. It regulates inflammation, DC development, thymic selection and regulatory T-cell production as well as osteoclast formation. |
Namjou, et al. 2012 [86] | TRAF6 | rs5030437 | Overall 4 (MO) | A vs. G | 0.88 (0.83–0.94) | 7.85×10-5 | |
Namjou, et al. 2012 [86] | TRAF6 | rs5030445 | Overall 4 (MO) | A vs. G | 0.88 (0.83–0.94) | 1.31×10-4 | |
Namjou, et al. 2012 [86] | TRAF6 | rs5030472 | Overall 4 (MO) | A vs. G | 0.85 (0.77–0.92) | 4.75×10-4 | |
Bentham, et al. 2015 [35] | TYK2 | rs2304256 | European 2 (MG) | A<C | 1.24 (1.17–1.31) | 3.50×10-13 | TYK2 gene encodes a member of the tyrosine kinase and, more specifically, the JAKs protein families. This protein associates with the cytoplasmic domain of type I and type II cytokine receptors and promulgate cytokine signals by phosphorylating receptor subunits. It is also component of both the type I and type III interferon signaling pathways. [38] |
Diaz-Gallo, et al. 2013 [87] | UBASH3a | rs9976767 | Overall 2 (MO) | G vs. A | 1.23 (1.11–1.37) | 2.4×10-4 | UBASH3 gene encodes one of 2 family members belonging to the T-cell ubiquitin ligand family. Both family members can negatively regulate T-cell signaling. [38] |
Ramos, et al. 2011 [74] | UBE2L3 | rs181359 | Overall 4 (MG) | T<C | 1.23 (1.15–1.33) | 1.15×10-9 | The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or shortlived proteins for degradation. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. It participates in the ubiquitination of p53, c-Fos, and the NF-kB precursor p105 in vitro. [38] UBE2L3 participates in ubiquitylation and has a key role in the regulation of innate and adaptive immune systems. [88] |
Bentham, et al. 2015 [35] | UBE2L3 | rs7444 | European 2 (MG) | T<C | 1.27 (1.21–1.33) | 1.84×10-22 | |
Bentham, et al. 2015 [35] | UHRF1BP1 | rs9462027 | European 2 (MG) | A<G | 1.14 (1.09–1.19) | 7.55×10-9 | UHRF1 binding protein 1 |
Sheng, et al. 2015 [50] | ULK3 | rs881536 | Chinese 2 (MG) | A/C | 1.16 (1.07–1.23) | 5.78×10-3 | The kinase domain of ULK3 was required for reporter activation. ULK3 showed autophosphorylation activity, and it showed serine/threonine kinase activity toward GLI2, with lower kinase activity toward GLI1 and GLI3. [89] |
Zhou, et al. 2014 [90] | VDRr | rs2228570 | Overall 6 (MO) | F vs. F | 0.75 (0.65–0.86) | <0.0001 | VDRr gene encodes vitamin D3 receptor, which is a member of the nuclear hormone receptor superfamily of ligand-inducible transcription factors. Downstream targets of vitamin D3 receptor are principally involved in mineral metabolism, though this receptor regulates a variety of other metabolic pathways, such as those involved in immune response and cancer. [38] |
Bentham, et al. 2015 [35] | WDFY4 | rs2663052 | European 2 (MG) | G<A | 1.16 (1.10–1.22) | 5.25×10-9 | WDFY4 is a huge protein with unknown function but is predominantly expressed in primary and secondary immune tissues. |
Zhang, et al. 2015 [91] | YDJC | rs2298428 | Overall 3 (MG) | T<C | 1.23 (1.16–1.3) | 1.31×10-11 | The role of the YDJC gene is currently largely unknown. [88] |
Morris, et al. 2016 [42] | ZFP90 | rs1170426 | Overall 3 (MG) | C | 1.12 (1.08–1.17) | 2.24×10-8 | ZFP90 gene encodes a member of the zinc-finger protein family that modulates gene expression. The encoded protein derepresses the transcription of certain fetal cardiac genes and may contribute to the genetic reprogramming that occurs during the development of heart failure. [38] |
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