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The association between the CASP5 rs7939842 polymorphism and the risk of rheumatoid arthritis in Chinese Han individuals
⁎Corresponding authors. liuruiping216@yahoo.com (Ruiping Liu), xunanwei@sina.com (Nanwei Xu)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Background
The association between inflammatory cysteinyl aspartate protease-5 (CASP5) and the susceptibility to rheumatoid arthritis (RA) remains unclear. This study examined whether the CASP5 rs7939842 polymorphism affects RA risk in Chinese Han individuals.
Methods
This study recruited 805 RA patients and 1095 healthy controls to investigate the association between the CASP5 rs7939842 polymorphism and RA risk. Genotype was examined using the 48-Plex SNPscan™ Kit. Plasma CASP5 levels were determined using enzyme-linked immunosorbent assays, and CASP5 gene expression was detected by quantitative polymerase chain reaction in 40 RA patients and 40 healthy controls.
Result
The CASP5 rs7939842 polymorphism G allele is a putative risk factor for RA. After stratified analyses, this polymorphism increased the risk of RA among CRP-, ACPA-, RF-, and ESR-positive individuals, as well as individuals with DAS28 ≥ 3.20 and functional class III + IV. Furthermore, the plasma CASP5 levels and CASP5 mRNA expression were higher in RA patients than in healthy controls.
Conclusion
The CASP5 rs7939842 polymorphism appears to be associated with an elevated risk of RA in Chinese Han individuals. Blood CASP5 protein and mRNA levels were significantly higher in RA patients than in healthy controls.
Keywords
Caspase-5
Polymorphisms
SNP
Rheumatoid arthritis
- RA
-
rheumatoid arthritis
- SNP
-
single nucleotide polymorphism
- caspases
-
cysteine-aspartic proteases
- CASP5
-
cysteinyl aspartate protease-5
- 95%CIs
-
95% confidence intervals
- ORs
-
odds ratios
Abbreviations
1 Introduction
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by chronic synovial inflammation, which causes joint destruction with irreversible cartilage degradation (Spel and Martinon 2020). Musculoskeletal defects attributed to RA gradually reduce physical function, affecting the quality of life (Smolen et al. 2016). The estimated prevalence of RA in the Chinese population was approximately 0.42% (i.e., more than 5 million RA patients) (Jin et al. 2017); Worldwide, nearly 5 in 1,000 adults have RA (Aletaha and Smolen 2018). Genetic and environmental factors (particularly smoking) are risk factors for RA (Sparks 2019). Many recent genome-wide association studies have revealed several novel loci associated with RA risk (Eyre et al. 2012; Leng et al. 2020; Stahl et al. 2010; Zhu et al. 2016).
Cysteine-aspartic proteases (caspases), encoded by the CASP gene family, are ancient intracellular proteases with ubiquitous distribution in multicellular organisms (Hong et al. 2020). The CASP gene family affects cell growth, differentiation, cytokine maturation and apoptosis (Zhang et al. 2013); Its members have three distinct effects as initiator (CASP 2/8/9/10), effector (CASP3/6/7), and inflammatory (CASP 1/4/5/11/12) caspases (Hong et al. 2020). With the aid of CASP1, CASP4 and CASP5 regulate inflammasome activation in monocytes (Vigano et al. 2015). Furthermore, animal studies and samples from RA patients have demonstrated that inflammasomes are involved in the pathogenesis of RA (Spel and Martinon 2020).
The CASP5 gene is located on chromosome 11q22.2. CASP5 polymorphisms are associated with the risks of various cancers (e.g., lung (Hosomi et al. 2003; Ulybina et al. 2009), ovarian (Quaye et al. 2009), renal (Dong et al. 2009), prostate (Mittal et al. 2012) and bladder (Mittal et al. 2011)). CASP5 gene polymorphisms are also presumably associated with susceptibility to autoimmune diseases (e.g., psoriasis vulgaris (He et al. 2015) and RA (Rui et al. 2018)). Of note, Rui et al. (2018) did not investigate the CASP5 rs7939842 polymorphism in RA (Rui et al. 2018). This polymorphism is located in the intervening region, which may affect gene expression and gene-selective splicing. However, no associations between the CASP5 rs7939842 polymorphisms and RA susceptibility have been reported. To our knowledge, this is the first study to investigate whether the CASP5 rs7939842 polymorphism is a risk factor for RA in Chinese Han individuals. This case-control study was conducted to examine the association between the CASP5 rs7939842 polymorphism and risk of RA in Chinese Han individuals; it examined CASP5 protein and gene expression in the blood of patients with RA and healthy controls.
2 Patients and methods
2.1 Participants
This study recruited 805 RA patients and 1095 healthy controls from the Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University and the Changzhou First Hospital. The 2010 American College of Rheumatology/European League Against Rheumatism diagnostic criteria were used to identify RA patients (Aletaha et al. 2010). Healthy controls matched for age and sex were enrolled from Chinese Han individuals without RA during the study period, at each hospital. All RA patients were required to complete a demographic questionnaire. This study was approved by the Ethics Committee of Nanjing Medical University. All participants provided informed consent and this study adhered to the 1964 Declaration of Helsinki.
An additional 40 RA patients and 40 healthy controls were recruited based on the above inclusion and exclusion criteria. Plasma CASP5 levels were determined by enzyme-linked immunosorbent assays (Tongwei, Shanghai, China). CASP5 gene expression was quantified using the quantitative polymerase chain reaction method. Relative CASP5 gene expression was determined using the ΔΔCt method. All protocols were conducted in strict accordance with standard procedures.
2.2 Genotyping
QIAamp DNA Blood Mini Kits (Qiagen, Hilden, Germany) were used to extract DNA from 2 mL of peripheral blood from each participant. Subsequently, the CASP5 gene rs7939842 polymorphism was assessed with SsoAdvanced™ Universal® SYBR Green Supermix (Bio-Rad, Hercules, CA, USA) using a MX4000 Stratagene detection mechanism, in accordance with the manufacturer’s instructions (Zheng et al. 2013).
2.3 Statistical analysis
All statistical analyses were conducted using SPSS (ver. 21, SPSS, USA). Continuous demographic variables were tested to determine their adherence to a normal distribution. Normally distributed parameters were compared using t-tests. The genotype distribution and allelic frequencies of the CASP5 rs7939842 polymorphism were assessed using the chi-squared (χ2) test and logistic regression adjusted for age and sex. Crude 95% confidence intervals (95 %CIs) and odds ratios (ORs) were used to assess the correlations of the CASP5 rs7939842 polymorphism and RA susceptibility. In multiple comparison analyses, P-values were corrected using the Bonferroni method. Hardy–Weinberg equilibrium for healthy controls was examined using goodness-of-fit χ2 tests to verify that the individuals were representative of a healthy population. Stratified analyses were estimated using χ2 tests. Graphs were drawn using GraphPad Prism 8.0 (GraphPad, La Jolla, CA, USA).
2.4 CASP5 gene expression and protein levels
TRIzol reagent (Takara Biomedical Technology, Beijing, China) was used to extract RNA; the extracted RNA was stored at –80 °C. In combination with reverse transcription primers (Sangon Biotech, Shanghai, China) and reverse transcriptase (Vazyme Biotech, Nanjing, China), 1–5 μg RNA template was used to synthesize cDNA. Real-time polymerase chain reactions were performed using the Real-Time PCR System (Vazyme Biotech). Relative CASP5 expression was determined using the ΔΔCt method. GAPDH mRNA was used as a control to normalize CASP5 gene expression. The CASP5 primer sequences were 5´–CTTCACAGTCATCTGAGAACCT–3´ (forward) and 5´–GCCTGTGGAACTTCAAATGATT–3´ (reverse).
Serum CASP5 protein levels were measured using the human CASP5 ELISA Kit (Shanghai Tongwei Biological, Shanghai, China), in accordance with the manufacturer’s instructions. Serum CASP5 protein levels were calculated using a standard curve through the optical density value of the sample to be tested.
3 Results
3.1 Participant characteristics
This study recruited 805 RA patients and 1095 healthy controls. Table 1 summarizes the participant demographics and clinical characteristics. The RA patients and healthy controls were matched according to sex and age (P > 0.05). The mean ages of the cases and healthy controls were 55.92 and 55.01 years, respectively. Other clinical characteristics are listed in Table 1.
Variable*
Cases (n = 805)
Controls (n = 1095)
P
Age (years)
55.92 (±15.10)
55.01 (±13.01)
0.169
Female/male
603/202
859/236
0.070
Age at onset, years, mean ± SD
45.97(±12.31)
—
—
Disease duration, years, mean ± SD
10.04(±9.66)
—
—
Treatment duration, years, mean ± SD
9.22(±9.10)
—
—
RF-positive, no. (%)
643(79.86%)
—
—
ACPA positive, no. (%)
451(56.02%)
—
—
CRP-positive, no. (%)
470(58.39%)
—
—
ESR, mm/h
35.90(±28.87)
—
—
DAS28
4.49(±1.55)
—
—
Functional class, no. (%)
—
—
I
79(9.81%)
—
—
II
353(43.85%)
—
—
III
314(39.01%)
—
—
IV
59(7.33%)
—
—
3.2 Association between the CASP5 rs7939842 polymorphism and RA risk
Table 2 lists the distributions of various genotypes and allelic frequencies of the rs7939842 polymorphisms in two groups. Hardy–Weinberg equilibrium analysis of the genotype distribution did not identify any difference from the healthy controls (P = 0.589). The AG + GG and GG genotypes significantly increased RA susceptibility (GG vs. AA, OR = 8.37, 95% CI = 1.01–69.68, P = 0.049; AG + GG vs. AA, OR = 1.56, 95% CI = 1.06–2.31, P = 0.026). However, this difference did not remain statistically significant after Bonferroni correction. The presence of the G allele was associated with a high risk of RA compared with the presence of the A allele (G vs. A, OR = 1.68, 95% CI = 1.15–2.45, P = 0.006). Bold values are statistically significant (P < 0.05). *After Bonferroni correction, the P < 0.017 indicates a statistically significant difference.
Genotype
Cases (n = 805)
Controls (n = 1095)
OR (95% CI)
P
n
%
n
%
CASP5 rs7939842
AA
749
93.0
1045
98.4
1.00
–
AG
50
6.2
49
1.6
1.42(0.95–2.13)
0.087*
GG
6
0.7
1
0.1
8.37(1.01–69.68)
0.049*
AG + GG
56
7.0
50
4.6
1.56(1.06–2.31)
0.026*
AG + AA
799
99.3
1094
99.9
1.00
–
GG
6
1.4
1
0.1
8.22(0.99–68.37)
0.051
G allele
62
3.9
51
2.3
1.68(1.15–2.45)
0.006
3.3 Stratified analyses of the CASP5 rs7939842 polymorphism and RA susceptibility
Stratified analysis suggested that the CASP5 rs7939842 polymorphism increases the risk of RA in CRP-, ACPA-, RF-, and ESR-positive individuals, as well as individuals with DAS28 ≥ 3.20 and functional class III + IV (Table 3). Bold values are statistically significant (P < 0.05); OR: odds ratios; CI: confidence intervals. *After Bonferroni correction, the P < 0.017 indicates a statistically significant difference.
Variable
AA
AG
GG
AG vs. AA
GG vs. AA
GG vs. AG + AA
GG + AG vs. AA
(Case/Control)
OR(95% CI); P
OR(95% CI); P
OR(95% CI); P
OR(95% CI); P
Sex
Male
189/224
11/12
2/0
1.09(0.47–2.52); 0.847*
NA
NA
1.28(0.52–2.88); 0. 445*
Female
560/821
39/37
4/1
1.55(0.97–2.45); 0.063*
5.86(0.65–52.61); 0.181*
5.73(0.64–51.39); 0.191
1.66(1.06–2.60); 0.026*
Age (years)
<55
335/504
18/19
2/0
1.43(0.74–2.76); 0.290*
NA
NA
1.75(0.93–3.29); 0.077*
≥55
414/541
32/30
4/1
1.39(0.83–2.33); 0.204*
5.23(0.58–46.94); 0.232*
5.12(0.57–45.98); 0.241
1.52(0.92–2.49); 0.098*
CRP status
Positive
429/1045
35/49
6/1
1.74(1.11–2.72); 0.014*
14.62(1.75–121.77); 0.004*
14.15(1.70–117.84); 0.005
2.00(1.30–3.06); 0.001*
Negative
320/1045
15/49
0/1
1.00(0.55–1.81); 0.999*
NA
NA
0.98(0.54–1.77); 0.946*
ACPA status
Positive
413/1045
33/49
5/1
1.70(1.08–2.69); 0.021*
12.65(1.47–108.62); 0.012*
12.26(1.43–105.28); 0.013
1.92(1.24–2.98); 0.003*
Negative
336/1045
17/49
1/1
1.08(0.61–1.90); 0.792*
3.11(0.19–49.86); 0.428*
3.10(0.19–49.67); 0.429
1.12(0.64–1.95); 0.688*
RF status
Positive
594/1045
43/49
6/1
1.54(1.01–2.35); 0.042*
10.56(1.27–87.89); 0.020*
10.30(1.24–85.79); 0.022
1.72(1.15–2.59); 0.008*
Negative
155/1045
7/49
0/1
0.96(0.43–2.16); 0.928*
NA
NA
0.94(0.42–2.12); 0.889*
ESR status
Positive
423/1045
36/49
4/1
1.82(1.16–2.83); 0.008*
9.88(1.10–88.67); 0.043*
9.53(1.06–85.53); 0.048
1.98(1.28–3.04); 0.002*
Negative
326/1045
14/49
2/1
0.92(0.50–1.68); 0.777*
6.41(0.58–70.93); 0.117*
6.44(0.58–71.19); 0.116
1.03(0.58–1.83); 0.931*
DAS28
<3.20
170/1045
9/49
1/1
1.13(0.54–2.34); 0.744*
6.15(0.38–98.75); 0.227*
6.11(0.38–98.16); 0.228
1.23(0.61–2.47); 0.561*
≥3.20
579/1045
41/49
5/1
1.51(0.99–2.31); 0.057*
9.02(1.05–77.43); 0.045*
8.82(1.03–75.69); 0.049
1.66(1.10–2.51); 0.015*
Functional class
I + II
413/1045
17/49
2/1
0.88(0.50–1.54); 0.650
5.06(0.46–55.96); 0.169
5.09(0.46–56.26); 0.168
0.96(0.56–1.65); 0.887*
III + IV
336/1045
33/49
4/1
2.09(1.32–3.31); 0.001
12.44(1.39–111.69); 0.018
11.86(1.32–106.44); 0.022
2.30(1.48–3.58); <0.001*
3.4 CASP5 protein levels and mRNA expression in RA patients and healthy individuals
Next, we measured CASP5 protein and mRNA levels in 40 RA patients and 40 healthy controls. Statistical analysis revealed that CASP5 mRNA expression was significantly higher in RA patients than in healthy controls (P < 0.001; Fig. 1). The means ± standard deviations of CASP5 mRNA levels in the cases and controls were 3.21 ± 2.89 and 1.00 ± 1.52, respectively. The serum CASP5 levels were significantly higher in RA patients than in healthy controls (P < 0.001; Fig. 2). The means ± standard deviations of CASP5 protein levels in cases and controls were 36.53 ± 22.28 and 15.18 ± 11.77 ng/mL, respectively. Plasma CASP5 protein and mRNA levels were significantly higher in CRP-positive individuals (Table 4). Stratified analyses revealed that the CASP5 protein and mRNA levels in RA patients remained significantly elevated in men, women, and individuals aged ≥ 55 or < 55 years (Table 5). RF: rheumatoid factor; ACPA: anti-cyclic citrullinated peptide antibodies; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; DAS28: disease activity score in 28 joints. Bold values are statistically significant (P < 0.05). RA: rheumatoid arthritis; HC: healthy control. Bold values are statistically significant (P < 0.05).
Comparison of relative CASP5 mRNA expression between RA patients and healthy controls.
Comparison of CASP5 plasma levels between RA patients and healthy controls.
Variable
Case
CASP5 protein levels(Mean ± SD) (ng/mL)
P
CASP5 expression(Mean ± SD)
P
RF status
0.212
0.069
Negative
9
28.30 ± 22.04
1.68 ± 1.90
Positive
31
38.92 ± 22.13
3.66 ± 3.00
ACPA
0.735
0.727
Negative
23
37.57 ± 22.07
3.07 ± 2.88
Positive
17
35.12 ± 23.16
3.40 ± 2.98
CRP status
0.013
0.004
Negative
16
26.04 ± 18.67
1.78 ± 1.82
Positive
24
43.52 ± 22.07
4.17 ± 3.10
ESR (mm/h)
0.066
0.056
< 25.00
17
29.01 ± 19.19
2.20 ± 2.43
≥ 25.00
23
42.09 ± 23.16
3.96 ± 3.02
DAS28
0.204
0.416
< 3.20
13
30.03 ± 24.76
2.67 ± 3.45
≥ 3.20
27
39.66 ± 20.75
3.47 ± 2.61
Functional class
0.731
0.887
I + II
23
35.47 ± 23.81
3.16 ± 3.14
III + IV
17
37.96 ± 20.66
3.29 ± 2.61
Case
CASP5 protein level (Mean ± SD) (ng/mL)
P
CASP5 mRNA level (Mean ± SD)
P
Female
RA
31
36.66 ± 23.08
<0.001
3.19 ± 2.90
0.002
HC
30
16.86 ± 11.60
1.17 ± 1.67
Male
RA
9
36.08 ± 20.55
0.006
3.30 ± 3.03
0.025
HC
10
10.13 ± 11.34
0.50 ± 0.83
Age ≥ 55
RA
24
35.51 ± 21.76
<0.001
3.01 ± 2.55
0.003
HC
24
15.04 ± 11.82
1.03 ± 1.75
Age < 55
RA
16
38.07 ± 23.68
0.002
3.52 ± 3.40
0.010
HC
16
15.38 ± 12.08
0.95 ± 1.15
4 Discussion
To our knowledge, this is the first study to explore the association between the CASP5 rs7939842 polymorphism and RA susceptibility in Chinese Han individuals. It revealed that the CASP5 rs7939842 polymorphism might elevate RA risk among CRP-, ACPA-, RF-, and ESR-positive individuals, as well as individuals with DAS28 ≥ 3.20 and functional class III + IV. The CASP5 gene expression and plasma CASP5 levels were significantly higher in RA patients than in healthy controls.
CASP5 is involved in the inflammatory response in inflammatory diseases via caspase-1 independent pyroptosis (Man et al. 2017). Initially, CASP5 recognizes cytosolic lipopolysaccharide, leading to gasdermin D cleavage and pyroptosis; Subsequently, the NLRP3 inflammasome and caspase-1-dependent maturation of IL-1β and IL-18 are activated by the N-terminal fragment after CASP5 binds to lipopolysaccharide (Man et al. 2017; Matikainen et al. 2020). CASP5 is associated with the release of inflammatory markers, including IL-1β and IL-18, which are linked to inflammasome activation (Chadha et al. 2020). The NLRP3 inflammasome is critical to RA (Guo et al. 2018; Shen et al. 2018). In addition, the maturation and release of IL-18 and IL-1β are involved in the pathology of RA (Spel and Martinon 2020). To our knowledge, CASP5 expression and the plasma CASP5 protein level have rarely been studied in RA patients. In this study, the CASP5 expression and plasma CASP5 levels appeared to be higher in RA patients and significantly higher in CRP-positive individuals, than in healthy controls. Therefore, CASP5 may have a role in the pathogenesis of RA.
Associations have been identified between CASP5 polymorphisms and autoimmune diseases. According to He et al., the rs507879, rs518604, and rs523104 CASP5 gene polymorphisms were not associated with the risk of psoriasis vulgaris in Chinese populations (He et al. 2015). Rui et al. investigated the associations between some CASP5 polymorphisms and RA; Only one locus (rs9651713) was associated with the risk of RA—it was associated with an elevated risk of RA in Chinese Han individuals (Rui et al. 2018). Here, we found a new locus associated with RA risk: the CASP5 rs7939842 polymorphism was linked to RA risk in Chinese Han individuals such that the AG + GG and GG genotypes significantly increased RA susceptibility. However, this difference did not remain statistically significant after Bonferroni correction. The G allele of the rs7939842 polymorphism was associated with a higher risk of RA. Subgroup analysis indicated that the CASP5 rs7939842 polymorphism was associated with an elevated risk of RA in CRP-, ACPA-, RF-, and ESR-positive individuals, as well as individuals with DAS28 ≥ 3.20 and functional class III + IV. Further analysis indicated that the CASP5 expression and plasma CASP5 levels were increased in RA patients, particularly in CRP-positive individuals (Table 4). The levels of both CASP5 expression and plasma CASP5 increased in parallel. These levels remained significantly elevated in stratified analyses of men, women, and individuals aged ≥ 55 or < 55 years. Therefore, the rs7939842 locus may be involved in the pathogenesis of RA.
There were several limitations in this study. First, unavoidable selection bias among the cases and healthy controls might have caused the sample to be under-representative of the general population, although participants were recruited from two hospitals. Second, gene–gene and gene–environment interactions were not considered. Third, this study investigated only a single nucleotide polymorphism (SNP), thus ignoring synergy among SNPs. Fourth, this study did not explore the association between RA treatment and the CASP5 rs7939842 polymorphism. Fifth, this study did not analyze the effect of the CASP5 rs7939842 polymorphism on CASP5 mRNA expression and protein levels because all 80 individuals carried the AA genotype (Supplementary Material), which hindered further effective analysis.
In conclusion, the CASP5 rs7939842 polymorphism appears to be associated with an increased risk of RA in Chinese Han individuals. Compared with healthy controls, CASP5 protein and CASP5 gene expression levels were increased significantly in blood. The findings should be validated in larger studies involving multiple populations and functional analyses.
Acknowledgements
This work was supported by the Changzhou Sci&Tech Program (CJ20210064) and the Changzhou High-Level Medical Talents Training Project (2016CZLJ011).
Declaration of Competing Interest
The authors declare no conflict of interest.
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Appendix A
Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.arabjc.2021.103667.
Appendix A
Supplementary data
The following are the Supplementary data to this article:Supplementary Data 1
Supplementary Data 1
