TNIP1/ANXA6 and CSMD1 variants interacting with cigarette smoking, alcohol intake affect risk of psoriasis

doi:10.1016/j.jdermsci.2013.02.006

Journal of Dermatological Science

Volume 70, Issue 2, May 2013, Pages 94-98

https://doi.org/10.1016/j.jdermsci.2013.02.006 Get rights and content

Abstract

Background

Psoriasis is a common multi-factorial skin disease, in which gene–gene and gene–environment interactions may affect the onset, manifestation and clinical course.

Objective

To investigate the underlying gene-environment interaction among several established susceptibility genes, cigarette smoking and alcohol intake.

Methods

Using a two-stage case–control design, we searched for pairwise interactions between cigarette smoking and alcohol intake respectively with 9 single nucleotide polymorphisms (SNPs) at ERAP1, PTTG1, CSMD1, GJB2, SERPINB8, ZNF816A and TNIP1/ANXA6 that have been associated with risk for psoriasis in 7,223 subjects. Multiple logistic regression analysis was used for data analysis.

Results

Significant interactions were found for alcohol intake with rs3762999 (p = 0.0257) and rs999556 (p = 0.0071) at TNIP/ANXA6; and for cigarette smoking with rs7007032 (p = 0.0023) and rs10088247 (p = 0.0023) at CSMD1.

Conclusion

This study provides empirical evidence for the gene–environment interactions between TNIP1/ANXA6 and alcohol use, CSMD1 and cigarette smoking, highlighting the importance of gene–environment interactions in the pathogenesis of psoriasis.

Introduction

Psoriasis is a common chronic, hyperproliferative, autoimmune skin disease. Numerous studies have indicated a strong genetic component and a multi-factorial etiology, in which gene–gene or gene–environment interactions may jointly affect the onset, manifestation and clinical course of psoriasis [1]. Over the past decade, a number of susceptibility loci have been identified, especially through recent genome-wide association studies (GWASs) [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. Recently, 9 SNPs at ERAP1, PTTG1, CSMD1, GJB2, SERPINB8, ZNF816A and TNIP1/ANXA6 have been associated with psoriasis through GWAS in Han Chinese population [7]. These findings contribute to further understanding of genetic architecture of psoriasis [12]. In addition, several environmental factors including alcohol intake, cigarette smoking, depression, stressful life events, overweight or obesity have been well established as risk factors for psoriasis [13], [14], [15], [16]. Although cigarette smoking and alcohol intake have consistently been identified as environmental risk factors for psoriasis [17], [18], [19], it is interesting to examine the interaction between these environmental risk factors and established genetic susceptibility loci for psoriasis. Hypothesizing that cigarette smoking and alcohol use interacting with these 9 established signals increased the risk of psoriasis, we performed the pair-wise interaction analysis using multiple logistic regression while adjusting for socio-demographics in two independent datasets.

Section snippets

Study subjects

Subjects used for this study included 7223 individuals of psoriasis cases and health controls recruited in two stages across China. Diagnosis, clinical assessment and recruitment of participants had been described elsewhere [7]. In brief, the diagnosis of cases with psoriasis and exclusion of normal controls was performed by two dermatologists independently.

Each participant, who had completed a standard questionnaire and socio-demographic information including age, sex, cigarette smoking status

Results

Totally 4122 psoriasis cases and 3101 healthy controls were included in this study. The first dataset included 1044 patients with psoriasis vulgaris with mean age of 33.08 years, 806 controls with mean age of 33.32 years. The second independent dataset, which was used for replication, included 3078 cases with mean age of 30.23 years, 2,295 controls with mean age of 33.48 years. The detailed sample information was provided in Table 1.

Cigarette smoking and alcohol intake were risk factors

Discussion

In this study we found through two independent case–control samples that genetic variants at genome-wide psoriasis associated loci CSMD1 interacting with cigarette smoking and TNIP1/ANXA6 with alcohol use affecting the risk for psoriasis. To our best knowledge, this was the first study for the gene–environment interaction of psoriasis in Chinese Han population. However, the biological mechanism underlying the gene–environment interaction is unclear. In order to fit for the previous two-stage

Acknowledgements

We are grateful to patients and their family members for participating in this study. This work was funded by the China Natural Science Foundation Youth Project (81000692, 31200939) and Normal Project (30971644, 81071285, 81101186, 81273301 and 81271747) of National Natural Science Foundation of China, Anhui High Education Project (KJ2010B402), Anhui Province Natural Science Foundation (1208085QH145), JRCC (JRCC2011-02) and Chinese Society of Dermatology LEO Foundation.

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Cigarette and electronic cigarette use are significant public health concerns across the United States. Tobacco use remains the single most preventable cause of morbidity and mortality in the world. Electronic cigarettes initially emerged as a better alternative to conventional cigarettes and for promoting smoking cessation; however, current evidence reveals similar deleterious health implications caused by both products on almost all organ systems, including the skin. Recognition of the cutaneous manifestations associated with cigarette and electronic cigarette use is essential for dermatologists in current clinical practice. Dermatologists play a vital role in educating and counseling patients on smoking cessation. We specifically highlight the cutaneous consequences of conventional cigarette smoking and electronic cigarettes on dermatologic disease.
Insights into interplay of immunopathophysiological events and molecular mechanistic cascades in psoriasis and its associated comorbidities
2021, Journal of Autoimmunity
Psoriasis is an inflammatory skin disease with complex pathogenesis and multiple etiological factors. Besides the essential role of autoreactive T cells and constellation of cytokines, the discovery of IL-23/Th17 axis as a central signaling pathway has unraveled the mechanism of accelerated inflammation in psoriasis. This has provided insights into psoriasis pathogenesis and revolutionized the development of effective biological therapies. Moreover, genome-wide association studies have identified several candidate genes and susceptibility loci associated with this disease. Although involvement of cellular innate and adaptive immune responses and dysregulation of immune cells have been implicated in psoriasis initiation and maintenance, there is still a lack of unifying mechanism for understanding the pathogenesis of this disease. Emerging evidence suggests that psoriasis is a high-mortality disease with additional burden of comorbidities, which adversely affects the treatment response and overall quality of life of patients. Furthermore, changing trends of psoriasis-associated comorbidities and shared patterns of genetic susceptibility, risk factors and pathophysiological mechanisms manifest psoriasis as a multifactorial systemic disease. This review highlights the recent progress in understanding the crucial role of different immune cells, proinflammatory cytokines and microRNAs in psoriasis pathogenesis. In addition, we comprehensively discuss the involvement of various complex signaling pathways and their interplay with immune cell markers to comprehend the underlying pathophysiological mechanism, which may lead to exploration of new therapeutic targets and development of novel treatment strategies to reduce the disastrous nature of psoriasis and associated comorbidities.
Endoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms and psoriasis susceptibility: A systematic review and meta-analysis
2020, Gene
Citation Excerpt :
Indeed, HLA-C*06 controls 35–50% of genetic susceptibility to the early-onset type psoriasis in Caucasian ethnicity (Asumalahti et al., 2002). In one study, non-synonymous polymorphisms at ERAP1 showed important disease susceptibility only in HLA-C*06 positive individuals (Das et al., 2017), which is in accordance with previous results in Caucasian and Chinese populations (Julià et al., 2012; Strange et al., 2010; Yin et al., 2013a,b; Tsoi et al., 2012). In a study performed in HLA-C*06-positive subjects from the Polish population, a statistically higher incidence of the rs26653C allele in ERAP1 was observed in the control group compared with psoriatic patients (Stawczyk-Macieja et al., 2018).
Psoriasis has a complex genetic background with a strong heritable component. Herein, the present meta-analysis aims to evaluate the association of ERAP1 polymorphisms with psoriasis susceptibility.
PubMed, Web of Sciences, Scopus, and Cochrane Library databases were examined with no time limits up to March 2019, without language, age, and sex restrictions. The odds ratio (OR) and 95% confidence interval (CI) were calculated by CMA 2.0 software in a dichotomous analysis using computed effect sizes and having OR and confidence limits for each study. The subgroup analysis based on ethnicity, type of study, and genotyping method was performed.
Thirteen articles were involved in the meta-analysis, in details eight were cohort studies and five were case-control studies. The results showed an association between rs27524 [OR = 1.179; 95%CI: 1.081, 1.286; p < 0.001] and rs30187 [OR = 1.237; 95%CI: 1.133, 1.351; p < 0.001] polymorphisms and psoriasis susceptibility; whereas no association was detected with rs26653 [OR = 1.013; 95%CI: 0.798, 1.286; p = 0.914] and rs27044 [OR = 1.164; 95%CI: 0.982, 1.381; p = 0.080] polymorphisms. Psoriasis susceptibility in both Caucasian and Asian ethnicities was related to rs27524 polymorphism, while rs30187 and rs27044 polymorphisms were over-represented in patients belonging to Caucasian ethnicity. In addition, in cohort studies, psoriasis susceptibility was related to rs27524 polymorphism, while the associated polymorphisms were rs26653 and rs27044 in case-control studies, and rs30187 in both cohort and case-control studies.
These findings showed an association between rs27524 and rs30187 polymorphisms and susceptibility to psoriasis, while lack of association was obtained for rs26653 and rs27044 polymorphisms. In order to confirm our results, further studies are needed, also considering different factors, such as type of psoriasis and ethnicity.
Multi-omics study in monozygotic twins confirm the contribution of de novo mutation to psoriasis
2020, Journal of Autoimmunity
Citation Excerpt :
The ELISA results showed that the concentration of C3 and C3b of TW2_Pso were significant higher than other samples (C3 p-value = 3.45e-14, C3b p-value = 1.57e-10) (Fig. 4). The influence of genetic factors in psoriasis has been widely reported [3]. In the last decades, as the price of genotyping array and next generation sequence became lower and lower, several large scale GWAS have been achieved.
Genome-wide association studies have identified over 120 risk loci for psoriasis. However, most of the variations are located in non-coding region with high frequency and small effect size. Pathogenetic variants are rarely reported except HLA-C*0602 with the odds ratio being approximately 4.0 in Chinese population. Although rare variations still account for a small proportion of phenotypic variances in complex diseases, their effect on phenotypes is large. Recently, more and more studies focus on the low-frequency functional variants and have achieved a certain amount of success.
Whole genome sequencing and sanger sequencing was performed on 8 MZ twin pairs discordant for psoriasis to scan and verified the de novo mutations (DNMs). Additionally, 665 individuals with about 20 years' medical history versus 2054 healthy controls and two published large population studies which had about 8 years’ medical history (including 10,727 cases versus 10,582 controls) were applied to validate the enrichment of rare damaging mutations in two DNMs genes. Besides, to verify the pathogenicity of candidate DNM in C3, RNA-sequencing for CD4⁺, CD8⁺ T cells of twins and lesion, non-lesion skin of psoriasis patients were carried out. Meanwhile, the enzyme-linked immunosorbent assay kit was used to detect the level of C3, C3b in the supernatant of peripheral blood.
A total of 27 DNMs between co-twins were identified. We found six of eight twins carry HLA-C∗0602 allele which have large effects on psoriasis. And it is interesting that a missense mutation in SPRED1 and a splice region mutation in C3 are found in the psoriasis individuals in the other two MZ twin pairs without carrying HLA-C*0602 allele. In the replication stage, we found 2 loss-of-function (LOF) variants of C3 only in 665 cases with about 20 years' medical history and gene-wise analysis in 665 cases and 2054 controls showed that the rare missense mutations in C3 were enriched in cases (OR = 1.91, P = 0.0028). We further scanned the LOF mutations of C3 in two published studies (about 8 years’ medical history), and found one LOF mutation in the case without carrying HLA-C*0602. In the individual with DNM in C3, RNA sequencing showed the expression level of C3 in skin was significant higher than healthy samples in public database (TPM fold change = 1.40, P = 0.000181) and ELISA showed protein C3 in peripheral blood was higher (~2.2-fold difference) than the other samples of twins without DNM in C3.
To the best of our knowledge, this is the first report that DNM in C3 is the likely pathological mutations, and it provided a better understanding of the genetic etiology of psoriasis and additional treatments for this disease.
Recent advances in atopic dermatitis and psoriasis: Genetic background, barrier function, and therapeutic targets
2015, Journal of Dermatological Science
Citation Excerpt :
Variation at IL12B, IL23R, and IL23A would contribute not only to psoriasis susceptibility but also to risk of developing type 2 diabetes in the Caucasian population [28]. Genetic variants at CSMD1 were associated with cigarette smoking and those at TNIP1/ANXA6 were associated with alcohol use, affecting the risk for psoriasis, in the Han Chinese population [29]. This study provided an empirical evidence that these genes and environmental factors interacting together contributed to the increased risk for psoriasis.
Atopic dermatitis (AD) and psoriasis are common inflammatory skin diseases. Although clinical pictures of these two diseases are quite different, they share some common pathological backgrounds such as barrier dysfunction and enhanced IL-22 expression. To explain the clinical differences of the diseases, it has been proposed that Th2/Th22-polarized immune status together with an attenuated Th17 axis may cause insufficient induction of antimicrobial peptides and more severe barrier dysfunction in AD. While skin barrier dysfunction is commonly seen in AD and psoriasis, a Th2-dominant cytokine milieu down-regulates immunity against infections, which are commonly seen in lesional skin of AD. In the era of biologics, increase in the understanding or new discoveries of molecules involved in the development of various diseases will instantly lead to a new therapeutic strategy. In this review, we give an overview of recent advances in AD and psoriasis, especially on genetic background, barrier function, and therapeutic targets.
Combined effect between CHRNB3-CHRNA6 region gene variant (rs6474412) and smoking in psoriasis vulgaris severity
2014, Gene
Citation Excerpt :
The psoriasis risk of smokers with HLA-Cw6 increased by about 11-fold compared with nonsmokers without HLA-Cw6 in Chinese (Jin et al., 2009). The interaction between CSMD1 (rs7007032 and rs10088247) and smoking was evident in another Chinese study (Yin et al., 2013). In principle, these studies provide possible interactions between smoking and psoriasis.
Many factors associated with causing psoriasis have been reported, such as the genetic and environmental factors. Smoking is one of the well-established environmental risk factors for psoriasis and also associated with the disease severity. In addition, several studies of psoriasis and psoriatic arthritis have documented gene–environment interactions involving smoking behavior. Although gene polymorphisms on nicotinic acetylcholine receptor subunits CHRNB3–CHRNA6 region gene have been found to correlate with smoking behavior and lung cancer susceptibility in Chinese Han population, the combined effect between the smoking-related genetic variants and smoking behavior on psoriasis vulgaris (PV) has been unreported.
To evaluate the combined effect of the smoking-related (rs6474412-C/T) polymorphism on CHRNB3–CHRNA6 region gene and smoking behavior on PV risk and clinic traits in Chinese Han population.
A hospital-based case–control study including 672 subjects (355 PV cases and 317 controls) was conducted. The variant of rs6474412 was typed by SNaPshot Multiplex Kit (Applied Biosystems Co., USA).
The higher body mass index (BMI ≥ 25), smoking behavior and alcohol consumption were risk factors for PV, and the estimated ORs were 1.55 (95% CI, 1.09–2.29), 1.74 (95% CI, 1.22–2.49) and 1.81 (95% CI, 1.25–2.62) respectively. The smoking patients had more severe conditions than non-smokers (OR = 1.71, 95% CI, 1.08–2.70, P = 0.020). The alleles and genotypes of rs6474412 were not associated with risk of PV, but the combined effect of rs6474412 genotype (TT) and smoking behavior increased severity of PV (OR = 5.95; 95% CI, 1.39–25.31; P < 0.05; adjusted OR = 2.20; 95% CI, 1.55–3.14; P < 0.001).
Our results demonstrate that the combined effect of rs6474412-C/T polymorphism in smoking-related CHRNB3–CHRNA6 region gene and smoking behavior may not confer risk to PV, but may have impact on PV severity in Chinese Han population.

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¹: These authors contributed equally to this work.

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TNIP1/ANXA6 and CSMD1 variants interacting with cigarette smoking, alcohol intake affect risk of psoriasis

Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Study subjects

Results

Discussion

Acknowledgements

Am. J. Hum. Genet.

J. Invest. Dermatol.

Immunol. Lett.

J. Invest. Dermatol.

HLA-C, CSTA and DS12346 susceptibility alleles confer over 100-fold increased risk of developing psoriasis: evidence of gene interaction

J. Hum. Genet.

Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21

Nat. Genet.

Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways

Nat. Genet.

Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene

Hum. Mol. Genet.

A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci

PLoS Genet.

Association analyses identify six new psoriasis susceptibility loci in the Chinese population

Nat. Genet.

Genome-wide association analysis identifies three psoriasis susceptibility loci

Nat. Genet.

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

Nat. Genet.

Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis

Nat. Genet.

Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2

Nat. Genet.