TABLE 1.
Copy number variant loci or genes related to autoimmune diseases.
| CNV-related genes or regions | Autoimmune diseases/syndromes | Populations (sample size) | CNV detection methods | Most common copies in healthy normal controls | Risk-associated CNVs (p-values) | Results | References |
|---|---|---|---|---|---|---|---|
| Beta-defensin gene | Psoriasis | Dutch and German population (179 Dutch patients and 272 controls; 319 German patients and 305 controls) | High-throughput paralogue ratio test (PRT) | 40% controls were four copies | Higher gnomic copy number (p = 0.01 for Dutch, p = 7.8E−5 for German) | Consistent | Hollox et al. (2008) |
| BMP8A | AS | Iranian (450 patients and 450 healthy controls) | TaqMan real‐time polymerase chain reaction (PCR) | Two copies | No significant association | – | Shahba et al. (2018) |
| C3 and C5 | BD | Han Chinese population (1,064 patients and 2,174 controls) | Real-time PCR | Two copies of C3 and C5 | More than two copies of C3 (p = 5.5E−3) and C5 (p = 1.1E−8) | – | Xu et al. (2015) |
| C4 and its two isotypes, C4A and C4B | SLE | Caucasians (Columbus): 1,241 European Americans (Yang et al. 2007) and Brazilian (427 patients and 301 controls) | TaqI southern blots (Yang et al. 2007); real-time PCR (Pereira et al. 2019) | Four copies of C4 genes (majority) | Lower copy number of C4 and C4A (p = 0.00002; Yang et al. 2007); low total copy number of C4 (p < 0.001), C4A (p < 0.001), and C4B (p = 0.03) | Consistent | Hauptmann et al. (1974), Yang et al. (2007), and Pereira et al. (2019) |
| 221 Caucasians (North American) | TaqMan-based real-time PCR and Southern blotting | Not reported | Higher copy number of C4B associated with hypertension and effective response to statin therapy in childhood-onset SLE patients (p = 0.016) and higher diastolic blood pressure (p = 0.015) | – | Mulvihill et al. (2019) | ||
| CD | Belgian population (770 patients and 345 controls) | Array comparative genomic hybridization | Not reported | Lower C4L (p = 7.68E−3) and higher C4S copies (p = 6.29E−3) | – | Cleynen et al. (2016) | |
| BD | Han Chinese population (905 patients and 1,238 controls) | Real-time PCR | Four copies of C4 genes, 2 copies of C4A genes | More than two copies of C4A (p = 1.65E−7) | – | Hou et al. (2013) | |
| T1DM | American population (cohort 1: 50 patients and 57 controls; cohort 2: 110 patients) | TaqMan quantitative PCR | Four copies of C4 genes; two copies of C4A gene | Fewer copies of C4A (p = 1.76E−5) and HERV-K (C4) (p = 4.59E−7) | – | Mason et al. (2014) | |
| GD | Chinese population (624 patients and 160 healthy individuals) | Quantitative real-time polymerase chain reaction | Four copies of C4 genes; two copies of C4A and C4B genes | Four copies of C4 (p = 0.001); copies of C4A (p = 0.008) and C4B (p = 2.42E-5) in GD | – | Liu et al. (2011) | |
| CCL3L1 | SLE | Caucasians (San Antonio), 1,084 subjects (469 cases of SLE and 615 matched controls) | 59-RACE and reverse transcription-PCR (RT-PCR) | Two copies | Lower than or greater than two copies (p = 0.032) | – | Mamtani et al. (2008) |
| RA | Caucasian (1,136 patients and 1,470 controls; McKinneyet al.2008), Tunisians and French (100 French patients and 200 controls; 166 Tunisian patients and 102 controls; Ben Kilani et al. 2016), United Kingdom population (657 patients and 192 controls), and United Kingdom (274 patients and 276 controls) | Reverse transcriptase (RT)-PCR (McKinney et al. 2008), droplet digital PCR (ddPCR) (Ben Kilani et al. 2016), PRT methodology (Carpenter et al. 2011) | Two copies | Higher than two in the New Zealand cohort (p = 0.009) but not the United Kingdom cohort; no association in the French study, a protective effect of five copies in the Tunisian population (p value not reported (Ben Kilani et al. 2016), no association (Carpenter et al. 2011) | Controversial | McKinney et al. (2008), Ben Kilani et al. (2016), and Carpenter et al. (2011) | |
| CD and psoriasis | United Kingdom (657 CD patients, 202 psoriasis patients, and 276 controls) | PRT methodology | Not reported | No association | – | Carpenter et al. (2011) | |
| AS | Algerian (81 patients and 119 controls) | Digital droplet PCR (ddPCR) | Two copies | No association | – | Dahmani et al. (2019) | |
| T1DM | Caucasian population (252 patients and 1,470 controls; McKinney et al. 2008) and 2,000 patients and 3,000 controls (Wellcome Trust Case Control Consortium et al. 2010) | Reverse transcriptase (RT)-PCR (McKinney et al. 2008) and the Agilent Comparative Genomic Hybridization (CGH) platform (Wellcome Trust Case Control Consortium et al. 2010) | Two copies | A copy number higher than 2 (p = 0.064) in the Caucasian population (McKinney et al. 2008); no association in the study (Wellcome Trust Case Control Consortium et al. 2010) | Consistent | McKinney et al. (2008) and Wellcome Trust Case Control Consortium et al. (2010) | |
| CD40, PTPN22, and CTLA-4 | GD | Caucasian (191 patients and 192 controls) | Quantitative-PCR (Q-PCR) assays | Two copies | No copy variation in the CD40, CTLA-4, and PTPN22 gene number variation in GD | – | Huber et al. (2011) |
| CFH, CFHR1, KIAA0125, UGT2B15, UGT2B17, TRY6, and CCL3L1 | GD | Chinese Han population (144 patients and 144 controls) | TaqMan quantitative polymerase chain reaction (TaqMan qPCR) | Two copies | No association | – | Song et al. (2017) |
| DEFA1 | BD | Korean population (55 patients and 35 controls) | A duplex TaqMan® real-time PCR assay | Most samples (31.1%) had a CN of five | A high CN associated with intestinal involvement in BD patients (p = 0.005) | – | Ahn et al. (2012) |
| DEFB4 | BD | Korean population (197 patients and 197 controls) | A novel comparative multiplex polymerase chain reaction (PCR): paralogue ratio test (PRT) | Median copy number was four | Lower copy number, but no statistical difference (p = 0.245) | – | Park et al. (2011) |
| DEFA1A3 | CD | Danes (240 patients) | Combined real-time quantitative PCR and pyrosequencing | Mean copy number was 6.7 | Higher copy number (p < 0.001) | – | Jespersgaard et al. (2011) |
| DEFB103 | AS | Chinese population (406 patients and 401 controls) | A multiplex fluorescence competitive polymerase chain reaction (PCR) | Ranged from 2 to 6 | No association | – | Cai et al. (2015) |
| FAS, caspase8, caspase3, and BCL2 | BD | Han Chinese population (1,014 patients and 2,076 controls) | TaqMan copy number assays and real-time PCR | Diploid 2 copy number carriers | High FAS copy number (>2) (p = 1.05E−3 in the first-stage study, p = 3.35E−8 in the replication and combined study) | – | Yu et al. (2015) |
| FCGR3A | SLE | Taiwanese population (846 patients with SLE and 1,420 healthy control subjects) | Custom TaqMan CNV real-time quantitative polymerase chain reaction (PCR) assays | Two copies | A low FCGR3A copy number (<2) (p = 5.06E−4) and a high (>2) FCGR3A copy number (p = 0.003) | – | Chen et al. (2014) |
| RA | Taiwanese population (948 patients with RA and 1,420 healthy control subjects) | Custom TaqMan CNV real-time quantitative polymerase chain reaction (PCR) assays | Two copies | A low copy number (p = 5.83E−4) | – | Chen et al. (2014) | |
| AS | Algerian (81 patients and 119 controls; Dahmani et al.2019), Chinese population (402 patients and 399 controls; Wang et al.2016) | Digital droplet PCR (ddPCR) (Dahmani et al. 2019) and AccuCopy™ method (Wang et al. 2016) | Two copies | Less than two copies (<2) (p = 0.0001; Dahmani et al. 2019), a low copy number (p < 0.001; Wang et al. 2016) | Consistent | Dahmani et al. (2019) and Wang et al. (2016) | |
| FCGR3B | SLE | United Kingdom Caucasians (171 patients and 176 controls; Willcocks et al. 2008), Spanish ancestry (146 patients and 409 controls; Mamtani et al. 2010), Afro-Caribbean (134 patients and 589 controls; Molokhia et al. 2011), Taiwanese (846 patients and 1,420 controls; Chen et al. 2014), and Brazilian population (135 unrelated SLE patients and 200 healthy unrelated subjects; Barbosa et al. 2018) | qPCR (Willcocks et al. 2008), real-time PCR (Mamtani et al. 2010), paralogue ratio test (PRT) assay (Molokhia et al. 2011), custom TaqMan CNV real-time quantitative polymerase chain reaction (PCR) assays (Chen et al. 2014), and quantitative real-time PCR (Barbosa et al. 2018) | Two copies | A lower (<2) copy number in United Kingdom Caucasians (p = 0.027; Willcocks et al. 2008), copy number <2 or >2 in cases of Spanish ancestry (p = 0.001 and 0.013, respectively; Mamtani et al. 2010), Afro-Caribbean (p = 0.02; Molokhia et al. 2011), Taiwanese (p = 0.0032; Chen et al. 2014), and Brazilian population (p = 1.66E−3; Barbosa et al. 2018) | Consistent | Willcocks et al. (2008), Mamtani et al. (2010), Molokhia et al. (2011), Chen et al. (2014), and Barbosa et al. (2018) |
| RA | Spanish ancestry (158 patients and 409 controls; Mamtani et al. 2010), South Australia (197 patients and 162 controls; Graf et al. 2012), Taiwanese (948 patients and 1,420 controls; Chen et al. 2014), British population (480 patients; Rahbari et al. 2017), French population (Bai Kilani et al. 2019) | Real-time PCR (Mamtani et al. 2010), custom TaqMan® CN assay (Graf et al. 2012), custom TaqMan CNV real-time quantitative polymerase chain reaction (PCR) assays (Chen et al. 2014), a PRT/REDVR approach (Rahbari et al. 2017), and droplet digital PCR (Bai Kilani et al. 2019) | Two copies | No association in cases of Spanish ancestry (Mamtani et al. 2010), lower and higher copy number in South Australia (p = 0.017; Graf et al. 2012), no association in Taiwanese (Chen et al. 2014), deletion in British population (p = 2.9E−3; Rahbari et al. 2017), and without null allele (one–three copy numbers) in French population (Bai Kilani et al. 2019) | Controversial | Mamtani et al. (2010), Graf et al. (2012), Chen et al. (2014), Rahbari et al. (2017), and Bai Kilani et al. (2019) | |
| UC | Japanese population (752 patients and 2,062 controls) | TaqMan assay | Not reported | Abnormal copies (p = 0.02) | – | Asano et al. (2013) | |
| Psoriasis | Han Chinese population (343 patients and 574 controls) | TaqMan® copy number assays | Not reported | A higher copy number (p < 0.02) | – | Wu et al. (2014) | |
| BD | Iran (187 patients and 178 controls) | Quantitative real-time PCR | Two copies | No association | Black et al. (2012) | ||
| AS | Algerian (81 patients and 119 controls; Dahmani et al. 2019) and Chinese population (402 patients and 399 controls; Wang et al. 2016) | Digital droplet PCR (ddPCR) (Dahmani et al. 2019) and AccuCopy™ method (Wang et al. 2016) | Two copies | No association in Algerian population (Dahmani et al. 2019) and a low (≤3) FCGR3B copy number (p = 0.001; Wang et al. 2016) | Controversial | Dahmani et al. (2019) and Wang et al. (2016) | |
| pSS | Spanish ancestry (61 patients and 409 controls), Australian (174 patients and 162 controls; Nossent et al. 2012), and Swedish and Norwegian population (124 patients and 139 controls; Haldorsen et al. 2013) | Real-time PCR (Mamtani et al. 2010), a quantitative real-time polymerase chain reaction assay (Nossent et al. 2012), TaqMan copy number assay (Haldorsen et al. 2013) | Two copies | Copy number <2 or >2 in cases of Spanish ancestry (p = 0.074 and 0.048, respectively; Mamtani et al. 2010), low FCGR3B CN (<2 copies) in Australian population (p = 0.016; Nossent et al. 2012), and no association in Swedish and Norwegian population Haldorsen et al. (2013) | Controversial | Mamtani et al. (2010), Nossent et al. (2012), and Haldorsen et al. (2013) | |
| GPC5, B9D2, and ASB11 | AITD | Chinese Han population (158 patients and 181 controls) | Chromosome microarray on the Affymetrix CytoScan™ HD platform, then identified by RTPCR | Not reported | The frequency of CNV loss for GPC5, B9D2, and ASB11 genes was higher in AITD (p < 0.05) | – | Guan et al. (2020) |
| GSTM1 | RA | Swedish (2,426 cases and 1,257 controls) and Tunisian population (165 cases and 102 controls) | TaqMan copy number assays (Lundstrom et al. 2011) and digital droplet PCR (ddPCR) (Achour et al. 2018) | 51.8% for 0 copies and 40.1% for 1 copy | No association in Swedish population (Lundstrom et al. 2011) and lack of association (Achour et al. 2018) | Consistent | Lundstrom et al. (2011) and Achour et al. (2018) |
| HBD-2 | CD | German | Genome-wide DNA copy number profiling by array-based comparative genomic hybridization and quantitative polymerase-chain reaction analysis | Median of 4 (range 2–10) copies | The copy number distribution shifted to lower numbers (p = 0.002) | – | Fellermann et al. (2006) |
| HSP90 and its two major isoforms | SLE | Han Chinese population (419 patients and 538 controls) | A custom-by-design Multiplex AccuCopy™ method | Two copies | Abnormal copies of HSP90AB1 (p = 0.02) | – | Zhang et al. (2019) |
| KIR3DL1 and KIR3DS1 | T1DM | White European ancestry (6,744 cases and 5,362 controls) | A hybrid qPCR/SNP array | Two copies of KIR3DL1 and 0 copy of KIR3DS1 | No evidence of association | – | Pontikos et al. (2014) |
| LCE3B and LCE3C | Psoriasis | The Dutch population (1,039 cases and 759 controls) | Array comparative genomic hybridization and a polymerase chain reaction: TaqMan SNP genotyping assay | Not reported | Absence (p < 0.0001) | Bergboer et al. (2012) | |
| IL17F, IL23A, IL17A, and IL23R | BD | Han Chinese population (1,036 patients and 2,050 controls) | TaqMan real-time polymerase chain reaction assay | Not reported | More than two copies of IL17F (p = 4.17E−8) and IL23A (p = 2.86E−11) associated with BD and no association between CNV of IL17A and IL23R | – | Hou et al. (2015) |
| IL-22 gene exon1 | Psoriasis | Estonian (290 patients and 263 controls) | Quantitative RT-PCR | Not reported | Abnormal copies associated with psoriasis severity (p < 0.0001) | – | Prans et al. (2013) |
| miR-143, miR-146a, miR-9-3, miR-205, miR-301a, and miR-23a | AS | Chinese Han population (768 patients and 660 controls) | TaqMan PCR | Two copies | Low copy numbers of miR-143 (p = 1.126E−7), miR-146a (p = 3.716E−8), miR-9-3 (p = 2.566E−5), and miR-205 (p = 7.187E−6) and high copy numbers of miR-301a (p = 3.725E−5) and miR-23a (p = 8.033E−9) AAU+, AS+; additionally, a low copy number of miR-146a (p = 0.001) and a high copy number of miR-23a and miR-205 (p = 0.002) in AAU+, AS− | – | Yang et al. (2017) |
| miR-23a, miR-146a, and miR-301a | BD | Han Chinese population (377 patients and 2,291 controls) | TaqMan PCR | Two copies | No association | – | Hou et al. (2016) |
| NCF1 | RA | The middle and southern parts of Sweden (494 patients and 480 controls) | A multiplex qPCR assay | Two copies | RA less likely to have an increased copy number (p = 0.037) | – | Olsson et al. (2012) |
| SIRPB1 and TMEM91 | AITD | Chinese Han population (15 patients and 15 controls) | Chromosome microarray | Not reported | The frequency of CNV gain for SIRPB1 was higher in AITD (p = 0.001) and no association of TMEM91 CNV and AITD | – | Jin et al. (2018) |
| T-Bet, GATA-3, RORC, and FOXP3 | AS | Chinese Han population (676 patients with AAU, including 298 patients with AAU+, AS+; 378 patients with AAU+, AS−; and 596 unrelated healthy controls) | Real-time PCR | Two copies | A high copy number (CN) of T-bet in AAU+, AS− and AAU+, AS+ (p = 4.3E−5 and 1.2E−8, respectively), a high CN of GATA-3 in AAU+, AS+ (p = 1.8E−7), a higher frequency of CN of FOXP3 in female AAU+, AS+ and female AAU+, AS− (p = 0.005 and 0.004, respectively), and no association between RORC CNVs and AS | – | Bai et al. (2016) |
| TBX21, GATA3, Rorc, and Foxp3 | BD | Han Chinese population (1,048 patients and 2,236 controls) | TaqMan real-time PCR | Two copies of these four genes | High Rorc CNV in BD (p = 8.99E−8) and low Foxp3 CNV (p = 1.92E−5) in female BD | – | Liao et al. (2015) |
| TLR7 | BD | Chinese Han population (400 patients and 600 controls) | Real-time PCR | One copy for male and two copies for female | A high copy number of TLR7 (p = 0.021 for males and p = 0.048 for females) | – | Fang et al. (2015) |
| AS | Chinese Han population (649 patients and 628 controls) | AccuCopyTM method | Not reported | Lower copy number (=1), especially in males (p = 0.009 for TLR7_1 fragment and p = 0.01 for TLR7_2 fragment) | – | Wang et al. (2018) | |
| GD and GO | Chinese population (196 controls and 484 GD patients, including 203 patients with GO) | Real-time polymerase chain reaction (PCR) | Not reported | A protective effect of lower than normal CNV for TLR7 (CNV <2 for females and CNV <1 for males) but no statistical significance and no association in GO | – | Liao et al. (2014) | |
| TSHR | GD and GO | Chinese population (196 controls and 484 GD patients, including 203 patients with GO) | Real-time polymerase chain reaction (PCR) | Two copies | Copy number <2 or >2 in GD, not in GO (p = 0.01) | – | Liao et al. (2014) |
| UGT2B17 | AS | Newfoundland (298 patients and 299 controls) | Built-in DNA analytics aberration detection method-2 (ADM-2) algorithm | Two copies | The frequency of two copies higher in cases (p < 0.05) | – | Uddin et al. (2013) |
CNVs, copy number variations; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; IBD, inflammatory bowel disease; BD, Behcet’s disease, AS, ankylosing spondylitis (AS); pSS, primary Sjogren’s syndrome; T1DM, type 1 diabetes mellitus; AITD, autoimmune thyroid disease