| Mailis A 1994 [10] | Candidate gene study; Serologic HLA typing | 15 cases with RSD | Caucasian female patients were diagnosed using detailed protocols and scoring systems used in the Toronto hospital. This study used inclusion and exclusion criteria for specific patients (arbitrarily called “psychogenic RSD”) with a painful and homogeneous complex of signs and symptoms arising from derangement of sudomotor, vasomotor, and trophic (superficial and deep) tissue mechanisms. | Class I MHCClass II MHC (HLA-A3 HLA-B7 HLA-DR15 HLA-DR4) | MHC antigens with varying frequencies compared with controls were HLA A3, B7, DR15, and DR4.None of the MHC antigen frequencies in the patient group (due to the small sample size) was statistically different when compared with the control frequencies using Fisher’s exact test.Remarkably, five of six patients positive for HLA-DR15 resisted treatment, while only one of six patients with HLA-DR15 responded well to the treatment. These results did not reach statistical significance.The principal finding of this pilot study was the clustering of DR15 antigen in patients with RSD who indicated a poor outcome to treatment (high resistance to treatment). |
| Kemler MA 1999 [8] | Candidate gene study; Serologic HLA typing | 52 unrelated Dutch CRPS patients | Patients with a definite diagnosis of RSD according to the criteria of the International Association for the Study of Pain. | Class I MHCClass II MHC (HLA-DQ1) | The frequency of HLA-DQ1 was found to be increased from 42% in the average population to 69% in patients with RSD (Bonferroni corrected x2, p=0.02). All other MHC antigens did not significantly differ from control frequencies.The association with DR15 was found in a previous study on a small number of patients (Mailis A et al. 1994 [10]). The association was compatible with this study as DQ1 is closely associated with DR15. |
| van de Beek WJT 2000 [9] | Correspond / Letter to previous study | | | Class I MHCClass II MHC (HLA-DQ1) | The study of Kemler et al. [8] indicated an insignificant increase in DQ1 frequency compared with the frequencies in a much more extensive Dutch database. The control group they used in the study significantly differs from that in the more extensive Dutch database. Possible erroneous analysis or publication data or a cohort bias can cause this. |
| van Hilten JJ 2000 [11] | Candidate gene study; HLA-SSO typing | 26 patients with a distinct phenotype of CRPS that progressed toward multifocal or generalized tonic dystonia.A panel of 2,355 healthy blood donors was used for comparison. | Tonic dystonia was observed in all patients. In 12 patients, dystonia occurred together with sensory and autonomic symptoms at the time of onset, although in 14 patients, dystonia developed at a later phase of the disease. In all except one patient, dystonia of the hands resulted in flexor postures of the fingers. Patients were diagnosed according to the International Association for the Study of Pain criteria. | HLA-DRB1HLA-DQA1HLA-DQB1 polymorphism(HLA-DR13) | A significant association of HLA-DR13 and HLA-DR13 genes with CRPS was present in 46% of the patients and 27% of the control group individuals (p<0.03). No differences between patients and control individuals reached statistical significance for any other alleles tested.Although DQ1 frequency seemed to be increased in the patients, this increase was not significant.As a result, this distinct phenotype of CRPS with progressive tonic dystonia is associated with HLA-DR13. |
| van de Beek WJ 2003 [13] | Subsequent candidate gene study; Typing of microsatellite loci | 26 CRPS patients;Control values were obtained from a panel of 324 healthy blood donors. | 26 Caucasian patients fulfilled the criteria of CRPS patients who presented with tonic dystonia in at least two of the affected extremities (van Hilten et al. 2000 [11]). | Microsatellite markers(DS61014, D6S273, TNFα, MIB, C1_2_5, C1_3_2)(HLA-DR13) | Significantly increased frequencies of alleles D6S1014*134, D6S1014*137, C1_2_5*204, C1_3_2*342, and C1_3_2*354 were found in patients as compared with those of controls. Additionally, the frequency of alleles D6S1014*140 and C1_3_2*345 was significantly decreased in the patients. For D6S273, TNFα, and MIB, no differences emerged between patients and controls.The significantly higher frequencies of D6S1014*134, and D6S1014*137 strengthen the previous finding of an association of HLA-DR13 with CRPS with multifocal or generalized tonic dystonia. |
| de Rooij AM 2009 [14] | Candidate gene study; SSO-HLA class I, SSP-HLA class II, Both with PCR | 150 cases (CRPS patients), 2440 Healthy controls (previously published group of healthy Dutch Caucasian blood donors) | CRPS-related fixed dystonia of at least one extremity. CRPS criteria of International Association for the Study of Pain. Dutch–Caucasian patients were recruited at the Leiden University Medical Center. | MHC class I (HLA-A HLA-B)MHC class II (HLA-DRB1 HLA-DQB1) (HLA-B62, HLA-DQ8) | Genetic associations of HLA-A, HLA-B, HLA-DR, and HLA-DQ alleles were determined in CRPS patients with fixed dystonia. Initial uncorrected association analyses revealed four HLA alleles that appeared to be associated with the disease: HLA-A23 (OR = 2.63 [95% CI 1.29–5.31], p=0.017), HLA-B62 (OR = 2.05 [95% CI 1.41–2.99] p=0.001), HLA-DR4 (1.55 [95% CI 1.11–2.18] p=0.016), and HLA-DQ8 (1.75 [95% CI 1.20–2.57] p=0.005).After correction for comparisons of multiple HLA alleles (Pc), HLA-B62 (Pc = 0.02) and HLA-DQ8 (Pc = 0.04) remained significantly associated. |
| van Rooijen DE 2012 [15] | Subsequent candidate gene study; SSO-HLA class I, SSP-HLA class II, Both with PCR | 131 cases; 150 cases; 5,604 healthy controls | 131 Dutch–Caucasian CRPS patients without dystonia. Patients were recruited at three different medical centers. 150 Dutch–Caucasian CRPS patients with dystonia, previously published group of Dutch–Caucasian CRPS patients.The study was performed on a homogeneous group of CRPS patients, and homogenization of clinical diagnoses was done by including only CRPS patients who fulfilled the Budapest Research Criteria. | MHC class I (HLA-A, HLA-B, HLA-C)MHC class II (HLA-DR, HLA-DQ)(HLA-B62, HLA-DQ8) | For 131 patients without dystonia, initial (uncorrected) analysis of the two target HLA alleles revealed a significant association with HLA-DQ8 (OR = 1.65 [95% CI 1.12–2.42], p=0.014), whereas no association with HLA-B62 was found (OR = 1.22 [95% CI 0.78–1.92], p=0.458).Re-analyzed data of 150 CRPS patients with dystonia, the two alleles indicated a significant association, similar to the original study’s findings (de Rooje AM et al. 2009 [14]).The study provided genetic clues that CRPS with and without dystonia are genetically different, but overlapping, phenotypes.In exploratory analysis, 6 HLA alleles indicated an association with the disease (CRPS without dystonia) when uncorrected for multiple testing: HLA-B13, HLA-B37, HLA-Cw4, HLA-Cw6, HLA-DR4, HLA-DR11. However, after correction for comparisons of various HLA alleles, according to Edwards, none of the associations remained significant. |
| Jin EH 2013 [6] | Candidate gene study; Genome-wide expression profiling followed by qRT-PCR | 24 cases 18 controls (healthy Korean controls) | 24 Korean CRPS patients diagnosed using Budapest criteria.(13 CRPS type I patients. 11 CRPS type II patients) A clinical diagnosis of CPRS was performed according to the Budapest Criteria published by the International Association for the Study of Pain (IASP) in 2007. | 80 DEGs for microarray analysis;14 genes for qRT-PCR(HLA-DRB1, HLA-A29.1, HLA-DRB6, MMP9, PTGS2, ANPEP, HDC, G-CSF3R, STAT3, ARHGEF10) | The microarray analysis was conducted for four (2 CRPS I and 2 CPRS II) of 24 patients and five of 18 controls. The qRT-PCR was conducted on all cases and controls.In microarray, 69 genes were up-regulated, and 11 were down-regulated among 80 DEGs. Of 80 DEGs, the researchers selected 12 specific genes through a literature review: HLA-DRB1, HLA-A29.1, HLA-DRB6, MMP9, PTGS2, IL-8, MMP25, ANPEP (CD13), HDC, G-CSF3R, STAT3, and ARHGEF10. All the selected genes were found to be up-regulated using microarray analysis, except ARHGEF10. They validated the microarray result using qRT-PCR; all genes indicated concordant results, except ARHGEF10, which was up-regulated in qRT-PCR. The most substantial finding of this study was the MMP9 gene, which indicated significantly different levels of expression in CRPS patients compared with that in the controls, which is suggested to play an important role in the pain progression of CRPS patients. |
| Tan W 2017 [7] | Subsequent bioinformatics study, DEGs analysis, protein-protein interaction (PPI) analysis, and functional enrichment study | 4 cases and 5 controls (healthy Korean controls) | 2 CRPS type I patients, 2 CRPS type II patients(4 Korean CRPS patients); A clinical diagnosis of CRPS was performed according to the Budapest Criteria published by the International Association for the Study of Pain (IASP) in 2007. | 257 DEGs(HLA-DRB1, HLA-DQB1, HLA-DRB4) EP300, CREBBP, STAT3, STAT5 | They used GSE47603 microarray data from a previous study (Jin EH et al. 2013 [6]).In DEGs analysis, 257 DEGs were identified (243 up-regulated, 14 down-regulated); the most significantly up-regulated and down-regulated genes were HLA-DRB1 and HLA-DQB1, respectively. In the functional enrichment analysis, those identified DEGs were enriched in immune response, cell motion, adhesion, and angiogenesis. Therefore, these signaling pathways were associated with CRPS.In PPI analysis, genes with a higher degree included adenovirus early region 1A binding protein p300 (EP300), CREB-binding protein (CREBBP), signal transducer and activator of transcription (STAT)3, and STAT5 of the STAT protein family. As a result, immune reactions and critical genes may have an essential role in CRPS development. |
| Piotr KJ 2016 | Genome-wide association study | 230 cases, 230 controls | Males and females > 18 years, fulfilling the criteria of Budapest Criteria published by the International Association for the Study of Pain (IASP) 2007 | 83% of all common SNPs in the human genome | In this study, the investigated common SNPs may be associated with the CRPS phenotype. |
| Escolano-Lozano F 2021 [16] | Specific protein expression study; ELISA of skin and serum biopsies | 31 cases, 19 pain controls, 17 controls (healthy subjects) | 31 CRPS patients diagnosed by Budapest Research Criteria. Some patients who visited the University Medical Center Mainz were recruited; 19 pain controls with post-traumatic or diabetic neuropathic limb pain without CRPS | Protein expression (MMP9 MMP2) | |