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Correlation of IL36RN and CARD14 mutations with clinical manifestations and laboratory findings in patients with generalised pustular psoriasis
Corresponding author: Dr. Nguyen Ngoc Trai, Department of Dermatology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam. bacsingoctrai2007@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Trai NN, Em DV, Van BT, My LH, Tro CV, Hao NT, et al. Correlation of IL36RN and CARD14 mutations with clinical manifestations and laboratory findings in patients with generalised pustular psoriasis. Indian J Dermatol Venereol Leprol 2023;89:378-84.
Abstract
Background
Generalized pustular psoriasis (GPP) is a chronic disease associated with genetic factors related to mutations of the interleukin 36 receptor antagonist gene (IL36RN) and the caspase recruitment domain 14 gene (CARD14). However, the relevance of these mutations to the clinical features and severity of GPP remains unclear.
Aims
Our objective was to correlate the presence of IL36RN and CARD14 mutations with the clinical and laboratory findings in patients with GPP.
Methods
This cross-sectional descriptive study was conducted in 64 subjects with GPP. Clinical manifestations were recorded and the severity was graded as mild, moderate, or severe. Routine laboratory tests were performed and blood samples were collected for Sanger sequencing. The clinical data of patients were compared among the different mutation groups.
Results
The two main variants of IL36RN were c.115+6T > C (p.Arg10ArgfsX1) and c.227C > T (p.Pro76Leu). The major CARD14 mutations were c.2458C > T (p.Arg820Trp), c.1641C > T (p.Arg547Ser), and c.1753G > A transitions.
Provocative factors were uncommon in the group with both IL36RN and CARD14 mutations. Drugs (unspecified), especially herbals, were the most common triggers. A history of psoriasis was frequent in patients with only CARD14 mutations, but fever was uncommon. The c.1641C > T mutation was associated with leukocytosis > 15000/mm3 and the c.1753G > A mutation was associated with hypoalbuminemia <3.8g/dL.
Both the c.115+6T > C and c.227C > T variants of IL36RN were associated with fever ≥38.5°C while the c.115+6T > C variant was also associated with geographic tongue.
No gene mutations were associated with the total severity and severity grades.
Limitations
Four patients without the two major IL36RN mutations were excluded from the study.
Conclusion
The presence of IL36RN and CARD14 mutations were associated with a history of psoriasis, various provocative factors, fever, leukocytosis, hypoalbuminemia, and geographic tongue. Further studies to explore the role of these mutations in therapeutic efficacy and disease outcomes are necessary.
Keywords
Gene mutation
IL36RN
CARD14
generalized pustular psoriasis
Plain Language Summary
Generalized pustular psoriasis (GPP) is a chronic disease associated with genetic factors related to IL36RN and CARD14 mutations. This study was conducted to investigate the effects of IL36RN and CARD14 mutations on the clinical appearance and laboratory findings in patients with GPP. Sixty-four patients with GPP participated in the study. Clinical manifestations and laboratory test results of the patients were recorded. Patients were graded according to the severity of GPP (mild, moderate or severe).
IL36RN and CARD14 mutations were associated with a history of psoriasis, trigger factors and clinical features such as geographic tongue, fever, leukocytosis and hypoalbuminemia.
Introduction
Generalized pustular psoriasis (GPP) is a chronic, refractory skin disease. However, some patients present with an acute, life-threatening, rapidly progressive generalized pustular rash accompanied by fever, erythema, oedema, hypoalbuminemia and leukocytosis. Genetic factors lead to a dysregulated inflammatory response and play a fundamental role in the pathogenesis of this disease. The frequency of mutations in IL36RN and CARD14 genes is significantly greater in patients with GPP than in healthy controls1,2,4-7 and these mutations are involved in the pathogenesis of GPP1-4
The IL36RN gene on the long arm of chromosome 2 in region 2q14 encodes for the protein interleukin-36 receptor antagonist (IL-36Ra).8 Excessive activation of the inflammatory pathway in keratinocytes has been implicated in the pathogenesis of pustular psoriasis. IL-36Ra prevents IL-36 from binding to its receptor impeding the activation of the inflammatory pathway in keratinocytes.
The CARD14 gene encode component 14 of the caspase recruitment domain family, which is a class of molecules that bind to proteins that regulate apoptosis or initiation of the nuclear factor-kappa B pathway. CARD14 mutations increase the caspase recruitment domain protein activity inducing keratinocyte activation of the nuclear factor-kappa B pathway and increased transcription of Interleukin 36 gamma; this leads to the development of inflammatory skin diseases, including pustular psoriasis. CARD14 mutations may be responsible for pustular psoriasis independent of IL36RN mutations both in children and adults.9,10
The precise relationship between these gene mutations and the clinical manifestations of GPP remains unclear. Two IL36RN mutations (c.115+6T > C and c.227C > T) are associated with severe clinical forms of pustular psoriasis, such as generalized, early-onset, or progressive pustular psoriasis with severe systemic symptoms.5,11-13 However, the relationship between CARD14 mutations and severity of pustular psoriasis has not yet been investigated.
In this study we explore the relationship between IL36RN and CARD14 mutations and the clinical characteristics of patients with GPP.
Material and Methods
Subjects
This cross-sectional descriptive study included 64 patients with GPP hospitalized for treatment at the Ho Chi Minh City Dermatology Hospital, South Vietnam and the Hanoi Central Institute of Dermatology, North Vietnam between October 2019 and October 2020. All recruited patients met the diagnostic criteria of the Japanese Dermatological Association.14
Ethical approval
All participants were provided with a detailed description of the study and signed a consent form. The study was approved by the Ethics Committee of the Institute of Clinical Research and Medicine in Hanoi, Vietnam (approval number: 6302/HDDD) and complied with the principles of the Declaration of Helsinki.
Study design
Data collection
Clinical data collected for all patients included age, sex, age of onset, personal and family history of psoriasis and GPP, precipitating factors, medication history and clinical symptoms and clinical features. Skin lesions were photographed for later comparison. Peripheral blood samples were collected for routine tests (total blood cell analysis, blood glucose, liver, and renal function, electrolytes, urinalysis), for monitoring parameters (white blood cell count, C-reactive protein and serum albumin concentration) and for sequencing.
Severity grading was performed in accordance with the Japanese Dermatological Association criteria.14 Severity of erythema, pustulosis and oedema were scored from 0 to 3 and white blood cell count, C-reactive protein, serum albumin, and body temperature were scored from 0 to 2. The final score of each patient determined the grading as mild (score 0-6), moderate (score 7-10), or severe (score 11-17).14
Mutation analysis
Peripheral blood (2 mL) was collected in test tubes containing 1.5 mg/mL EDTA and sent to the Centre for Molecular Biomedicine, University of Medicine and Pharmacy, Ho Chi Minh City for sequencing. DNA was extracted using a GeneJET Genomic DNA purification kit (Thermo Scientific, Waltham, MA, USA) and stored at −30°C. DNA samples were quantified for purity and concentration using a nanodrop (Thermo Scientific).
Primers for PCR and sequencing of exons and flanking introns were designed using the CLC Main Workbench v.5.5(Quiagen, USA). The National Center for Biotechnology Information Consensus CDS (https://www.ncbi.nlm.nih. gov/projects/CCDS/CcdsBrowse.cgi) was used to obtain information regarding the attributed genomic and coding structures of CARD14 (NG_032778.1 and NM_024110.4) and IL36RN (NG_031864.1 and NM_012275.3). The PCR process was conducted in 25-μL reactions containing 1X PCR buffer, 0.1 μM of forward and reverse primers each, 25-50 ng genomic DNA, and other essential chemicals. The temperature was set based on the phase of the process.
PCR reaction products were checked by electrophoresis (30 min at 100 V) on 1.5% agarose gel with 0.5X Tris- Borate-EDTA buffer. Samples were analyzed with a 1 kb plus DNA scale for size comparison. The products were clarified with the ExoSAP-IT reagent (Thermo Scientific). BigDye™ Terminator v3.1 Cycle Sequencing Kit was used for sequencing. The nucleotide sequence of the gene was determined by the automatic sequencing machine ABI 3500 Genetic Analyzer (Applied Biosystems). The CLC Main Workbench v5.5 software was used to align the target gene sequences in the samples and the mitochondrial DNA sequences on the National Center for Biotechnology Information to detect mutations in the gene, and the PolyPhen-2 software was used to predict the potential pathogenicity of the variations.
Statistical methods
Data were analyzed using the SPSS 20.0 software (version 20.0; SPSS Inc., Chicago, IL, USA). The results were presented as mean (standard deviation), median (range) or proportion. For normally distributed data, comparisons between groups were performed by the independent sample t-test or the one-way analysis of variance. For skewed data, we applied the Mann-Whitney U rank-sum test while for numeric data the Pearson’s χ2 test or the Fisher’s exact test was used. A P < 0.05 was considered significant.
Results
Mutation analysis
There were 28 (43.8%) patients with CARD14 mutations alone and 10 (15.6%) with IL36RN mutations alone. Mutations in both CARD14 and IL36RN were present in 22 (34.4%) patients. The remaining 4 (6.3%) patients had no mutations in either gene and they were excluded from subsequent analysis.
IL36RN mutations
The two main variants of IL36RN identified on sequencing were c.115+6T > C and c.227C > T. Homozygous c.115+6T > C was the most prevalent type, present in 21 (32.8%) patients. Both heterozygous and homozygous c.115+6T > C variants together accounted for 29 (45.3%) of the mutations observed while heterozygous and homozygous c.227C > T variants were present in 11 (17.2%) patients.
A novel heterozygous c.96T > G (p.His32Gln) variation was found in exon 3 in 2 (3.1%) cases. Using the PolyPhen-2 software this variant had a score of 0.00 and was predicted to be benign. Two heterozygous variants (c.304C > T and c.386A > G) were detected in exon 5 in 1 patient each. The PolyPhen-2 score of 0.473 for c.304C > T and 0.962 for c.386A > G indicated that these variants were potentially pathogenic.
None of these mutations were noted in the control group. The two variants c.115+6T > C and c.227C > T represented the majority of IL36RN mutations, while other detected mutations formed a very small proportion; thus, we only considered these two mutations for subsequent analysis.
CARD14 mutations
The c.2458C > T (p.Arg820Trp) transition was detected in 41 (64.1%) of the 64 patients with GPP. Other CARD14 mutations included c.1641C > T (p.Arg547Ser) in 25 (39.1%) patients and c.1753G > A in 18 (28.2%) patients.
Two new mutations in exon 16 and exon 18 were also noted in one case each. These were heterozygous c.1717G > A (p.Ala573Thr and c.2113G > A (p.Val705Ile) mutations with Polyphen-2 scores of 0.911and 0.983 respectively which indicated potential pathogenicity.
Only the three most frequent CARD14 mutations (c.2458C > T, c.1641C > T and c.1753G > A) were included in subsequent analyses.
Epidemiology, history, and triggering factors
The 60 patients (after excluding 4 patients with uncommon mutations) were classified into three groups based on their genotype:
Mutations in IL36RN only
Mutations in CARD14 only
Mutations in both IL36RN and CARD14.
The sociodemographic profiles of the patients are shown in Table 1.
| Group |
IL36RN (n = 10) |
CARD14 (n = 28) |
IL36RN + CARD14 (n = 22) |
P-value |
|---|---|---|---|---|
| Age | 43.9 ± 22.97 | 34.71 ± 17.65 | 35.82 ± 17.69 | 0.4* |
| Gender (male/female) | 6/4 | 13/15 | 8/14 | 0.45** |
| Region (HCMC/Hanoi) | 6/4 | 21/7 | 16/6 | 0.658** |
| Personal history | ||||
| PV (without/with) | 7/3 | 8/20 | 14/8 | 0.016** |
| PsA (without/with) | 10/ 0 | 23/5 | 19/3 | 0.361** |
| EP (without/with) | 7/3 | 24/4 | 20/2 | 0.304** |
| Family history | ||||
| GPP (without/with) | 10/0 | 25/3 | 22/0 | 0.165** |
| PV (without/with) | 10/0 | 25/3 | 21/1 | 0.447** |
| Age of onset | 32.36 ± 21.9 | 29.27 ± 15.91 | 25.31 ± 16.83 | 0.528* |
| Provocative factors (without/with) | 3/7 | 10/18 | 15/7 | 0.038** |
| Unspecified drugs (without/with) | 4/6 | 20/8 | 17/5 | 0.098** |
| Herbal medicine (without/with) | 9/1 | 21/7 | 19/3 | 0.445** |
| Stress (without/with) | 6/4 | 24/4 | 20/2 | 0.084** |
| Infection (without/with) | 8/2 | 23/5 | 20/2 | 0.613** |
PV: psoriasis vulgaris, GPP: generalized pustular psoriasis, EP: erythrodermic psoriasis, PsA: psoriatic arthritis, HCMC: Ho Chi Minh City, *Statistically analyzed by one-way ANOVA test, ** Statistically analyzed by Pearson’s chi-square test
No significant differences were noted between the subgroups with regard to the age, sex, region or age of onset. A history of psoriasis was frequently seen in patients with CARD14 mutations alone (P = 0.016). Provocative factors include: corticosteroids, herbal medicines, stress, pregnancy, infection and drugs. Provocative factors were less commonly noted in patients with both IL36RN and CARD14 mutations (P = 0.038).
Drugs were the most common trigger (19 patients; 29.7%) and herbal medicines were involved in 13 (20.3%) of these cases. Other triggers included stress (11 patients; 17.2%) and infections (9 patients; 14.1%).
Clinical manifestations [Table 2]
| Clinical symptoms |
IL36RN (n = 10) |
CARD14 (n = 28) |
IL36RN + CARD14 (n = 22) |
P-value |
|---|---|---|---|---|
| Itching (without/with) | 6/4 | 16/12 | 9/13 | 0.442** |
| Skin pain (without/with) | 1/9 | 7/21 | 7/15 | 0.418** |
| Fever (without/with) | 2/8 | 17/11 | 8/14 | 0.050** |
| Malaise (without/with) | 6/4 | 20/8 | 17/5 | 0.603** |
| Chills (without/with) | 3/7 | 13/15 | 11/11 | 0.561** |
| Arthralgia (without/with) | 8/2 | 23/5 | 16/6 | 0.718** |
| Erythroderma (without/with) | 7/3 | 21/7 | 19/3 | 0.49** |
| Nail involvement (without/with) | 5/5 | 14/14 | 12/10 | 0.944** |
| Mucosal involvement (without/with) | 5/5 | 14/14 | 12/10 | 0.944** |
| Geographic tongue (without/with) | 5/5 | 21/7 | 13/9 | 0.278** |
| Palmoplantar pustulosis (without/with) | 9/1 | 21/7 | 19/3 | 0.445** |
| Acropustulosis (without/with) | 9/1 | 27/1 | 18/4 | 0.232** |
* Statistically analyzed by one-way ANOVA test, ** Statistically analyzed by Pearson’s chi-square test
The common findings in descending order of frequency were skin pain, fever, chills, itching and mucosal involvement. Acropustulosis was present in 10% of patients.
Although no significant differences in the frequency of clinical symptoms in the subgroups, the incidence of fever was significantly higher in the group with IL36RN mutations alone as compared with the group with CARD14 mutations alone (χ2 test, P = 0.027) [Table 3]. The c.115+6T > C gene variant was associated with geographic tongue (P = 0.033, odds ratio = 3.15) [Table 3].
| Clinical and laboratory findings | Mutation | P-value | ||
|---|---|---|---|---|
| Fever (≥37.5°C) | IL36RN alone10 | CARD14 alone28 | ||
| No | 2 | 17 | 0.027** | |
| Yes | 8 | 11 | ||
| Fever (°C) | c.115+6T > C (IL36RN) | |||
| Without35 | With29 | |||
| <38.5 | 32 | 20 | 0.022** | |
| ≥38.5 | 3 | 9 | ||
| Geographic tongue | c.115+6T > C (IL36RN) | |||
| Without35 | With29 | |||
| Without | 27 | 15 | 0.033** | |
| With | 8 | 14 | ||
| Fever (°C) | c.227C > T (IL36RN) | |||
| Without53 | With11 | |||
| <38.5 | 46 | 6 | 0.025** | |
| ≥38.5 | 7 | 5 | ||
| WBC (K/mm3 ) | c.1641C > T (CARD14) | |||
| Without39 | With25 | |||
| <15 | 30 | 13 | 0.038** | |
| ≥15 | 9 | 12 | ||
| Serum albumin (g/dL) | c.1753G > A (CARD14) | |||
| Without45 | With19 | |||
| ≥3.8 | 26 | 16 | 0.042** | |
| <3.8 | 19 | 3 | ||
WBC: white blood cell count, ** Statistically analysed by Pearson’s chi-square test
Assessment of disease severity
The various clinical and laboratory parameters for disease severity are summarized in Table 4. The severity scores for individual parameters, severity grades, total severity and severity classification did not differ between the groups. However, when the IL36RN variants were analyzed separately, the c.115+6T > C and c.227C > T variants were found to be associated with fever (temperature ≥38.5C) [Table 3].
| Evaluation of clinical symptoms (score) |
IL36RN (n = 10) |
CARD14 (n = 28) |
IL36RN + CARD14 (n = 22) |
P-value |
|---|---|---|---|---|
| Erythema (<3/≥3) | 3/7 | 14/14 | 14/8 | 0.205** |
| Pustules (<3/≥3) | 5/5 | 13/15 | 13/9 | 0.669** |
| Edema (<3/≥3) | 6/4 | 13/15 | 13/9 | 0.604** |
| Fever (<2/≥2) | 7/3 | 25/3 | 16/6 | 0.239** |
| Evaluation of laboratory findings | ||||
| WBC (K/mm3 ) (<15/≥15) | 7/3 | 18/10 | 14/8 | 0.935** |
| CRP (mg/dL) (<7/≥7) | 2/8 | 11/17 | 9/13 | 0.484** |
| Serum albumin (g/dL) (≥3,8/<3,8) | 5/5 | 21/7 | 15/7 | 0.345** |
| Total severity score | 12.2 ± 2.34 | 11.14 ± 2.92 | 11 ± 3.2 | 0.546* |
| Severity classification (mild-moderate/severe) |
3/7 | 10/18 | 9/13 | 0.83** |
WBC: white blood cell count, CRP: C-reactive protein, * Statistically analyzed by one-way ANOVA test, ** Statistically analyzed by Pearson’s chi-square test
The c.1641C > T mutation of CARD14 was associated with leukocytosis >15000/mm3 (P = 0.038, OR = 3.077, 95% CI: 1.043-9.078) and the c.1753G > A variant was associated with a hypoalbuminemia <3.8 g/dL (P = 0.042, OR = 0.257) [Table 3].
Discussion
The role of IL36RN and CARD14 mutations in pustular psoriasis has been studied exhaustively.2 We detected IL36RN mutations in 32 of 64 (50%) patients with GPP, similar to the incidence (46.8%) in a report on 62 patients from China.6 The c.115+6T > C variant was present in 29 (45.3%) of 64 patients and accounted for the majority of IL36RN mutations. This is similar to that reported from China (Zhu et al. 52.5%; Li et al. 38.7%)13,15,16 but much higher than in studies from Japan (Farooq 14%; Sugiura 19.3%).1,17
Few studies have addressed the prevalence of CARD14 mutations in pustular psoriasis.3 CARD14 mutations were noted in 50 (78.1%) of our 64 patients with GPP but were seen in only 21% in a study of 19 patients from Japan.3 The two most common CARD14 mutations observed were c.2458C > T (41 patients; 64.1%) and c.1641C > T (25 patients; 39.1%). These two variants have earlier been observed in patients with psoriasis vulgaris.9,18 The mutation c.526G > C (p.Asp176His) reported from Japan was not detected in our study.4
Drugs (unspecified) were frequent triggers of GPP (19 patients; 29.7%). Traditional medicines triggered the onset of GPP in 13 (20.3%) patients. Provocative factors played a significant role in triggering GPP in patients with IL36RN or CARD14 mutations alone, but not in patients with both mutations together.
The issue of whether the age at onset of GPP is related to gene mutations remains controversial. Mutations in IL36RN were observed to be related to GPP occurrence early in life,13,15 but Korber et al. did not note any relationship to age at onset.5 We, too, did not observe any difference in the age at onset between the groups. It is likely that the age of onset is influenced by gene-environment interactions and immune responses rather than genetic factors alone.
Many studies have suggested that the mutant genotype is associated with the phenotypic expression of GPP.11,12 In 233 patients with GPP, Hussain et al. found an association between the IL36RN mutations and severe clinical features (i.e., early onset, systemic inflammation).12 Distinct IL36RN genotypes were appraised for the effect on phenotypic manifestations, such as diffuse or localized GPP. Null mutations were thought to be related to serious clinical symptoms because of completely loss of function of IL36Ra while hypomorphic mutations with partially altered the structure and function of IL36Ra could result in diverse clinical manifestations.11
We studied the role of different gene mutations in giving rise to the variation in forms and severity of GPP. The total severity score of patients with GPP did not differ between the three groups of gene mutations (IL36RN, CARD14 and IL36RN + CARD14). Zhu et al. also found no difference in severity scores between groups with and without IL36RN mutations.13 It is likely that GPP severity is not related to a single gene mutation or a combination of IL36RN and CARD14 mutations, suggesting that additional factors influence severity. This is further supported by the occurrence of severe GPP in heterozygous variants 5 and the presence of homozygous variants with mild or no symptoms.16 Gene modification, other mutated genes, interactions between gene mutations, polyallelic inheritance, and the impact of environmental factors have been proposed to explain these observations.11,17
The group with only IL36RN mutations had fever more frequently than the group with only CARD14 mutations (P = 0.027). Both c.115+6T > C and c.227C > T variants were associated with high fever (≥38.5°C).
The c.115+6T > C variant was associated with geographic tongue in our patients, as has been previously observed by Liang et al.19
Leukocytosis and hypoalbuminemia are indicators of severity in patients with GPP.14 Zhu et al. found CARD14 mutations to be associated with leukocytosis and hypoalbuminemia but not IL36RN mutations.13 We found the c.1641C > T to be associated with leukocytosis and the c.1753G > A with hypoalbuminemia. However, the most frequent CARD14 mutation (c.2458C > T) was not significant correlated with either clinical symptoms or laboratory parameters.
Limitations
There were few GPP patients without both mutations and these patients were excluded from analysis.
Conclusion
Our study showed that mutations in IL36RN and CARD14 are associated with triggering factors and some clinical features of GPP, such as fever ≥38.5°C, geographic tongue, leukocytosis and hypoalbuminemia.
There were statistical differences in some clinical and laboratory findings in GPP patients with and without gene mutations that could aid genetic diagnosis. The mechanism by which these gene mutations influence the progression of GPP is only partly understood. GPP should not be viewed as a single-gene disease, but as the combined result of genetic factors, immune responses and environmental influences. Larger studies to clarify the role of mutations in the varied clinical presentation of patients with GPP need to be planned. Future randomized controlled clinical studies may provide more data and to establish standard treatments for generalized pustular psoriasis based on the genetic profile.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Abbreviations:
IL36RN - Interleukin-36 receptor antagonist gene
IL-36Ra - Interleukin-36 receptor antagonist protein
CARD14 - caspase recruitment domain 14
GPP - generalized pustular psoriasis
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