Association Between the LCE3C_LCE3B Deletion Polymorphism and Susceptibility to Psoriasis: A Meta-Analysis of Published Studies

Abstract

Objective: To determine whether a deletion comprising the LCE3C and LCE3B genes (LCE3C_LCE3B-del) confers susceptibility to psoriasis. Methods: A meta-analysis was conducted to assess the association between the LCE3C_LCE3B-del polymorphism and psoriasis. Results: A total of 12,196 patients with psoriasis and 13,092 controls from 19 comparative studies were included in this meta-analysis. The meta-analysis showed a significant association between psoriasis and the LCE3C_LCE3B-del allele (odds ratio [OR], 1.220; 95% confidence interval [CI], 1.152-1.292; p<1.0×10⁻⁹). Stratification by ethnicity indicated an association between the LCE3C_LCE3B-del allele and psoriasis in Europeans and Asians (OR, 1.213; 95% CI, 1.130-1.302; p=8.0×10⁻⁹ and OR, 1.260; 95% CI, 1.135-1.398; p=1.4×10⁻⁶, respectively). Analysis using a recessive model, dominant model, and homozygote contrast showed the same pattern for the LCE3C_LCE3B-del allele. The analysis performed in a single Tunisian study showed no association between the LCE3C_LCE3B-del allele and psoriasis. Meta-analysis of the LCE3C_LCE3B-del allele showed no association between psoriatic arthritis and the LCE3C_LCE3B-del polymorphism (OR, 1.087; 95% CI, 0.870-1.359; p=0.464). Conclusion: Our meta-analysis demonstrates a significant association between psoriasis and the LCE3C_LCE3B-del polymorphism in Europeans and Asians, but no association with psoriatic arthritis.

Introduction

Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation and increased blood flow induced by the stimulation of tissue-resident immune cells with markedly altered cutaneous cytokine profiles (Bhalerao and Bowcock, 1998; Lee et al., 2010). Although its etiology is not fully understood, it has been established that psoriasis has a genetic component, and as of yet, the human leukocyte antigen (HLA) loci are the most powerful genetic factors identified (Nair et al., 2006). However, increasing evidence suggests that the non-HLA genes also contribute (Zhang et al., 2009).

Copy number variants are an important source of genetic variability and contribute to the susceptibility to several diseases. Recent studies have revealed an association between psoriasis and a 32.2-kb deletion of the LCE3C and LCE3B genes (LCE3C_LCE3B-del) (Nair et al., 2006). These genes encode the members of the late-confined envelope (LCE) and are in the region that contains the PSORS4 locus on chromosome 1q21, which was identified as a psoriasis-susceptibility locus in a genome-wide linkage analysis (de Cid et al., 2009). The mRNA for several LCE3 genes was absent in normal skin, but its expression was induced after skin barrier disruption and was high in psoriatic lesions (de Cid et al., 2009). Thus, it seems that the LCE3C_LCE3B-del polymorphism could play a role in the pathogenesis of psoriasis.

The LCE3C_LCE3B-del polymorphism has been reported to be associated with psoriasis by some, but not all, researchers, possibly due to small sample sizes, low statistical power, and/or clinical heterogeneity (Coto et al., 2010; Huffmeier et al., 2010a, 2010b; Docampo et al., 2011; Li et al., 2011; Riveira-Munoz et al., 2011; Xu et al., 2011; Ammar et al., 2012). Therefore, to overcome the limitations of individual studies, resolve inconsistencies, and reduce the likelihood that random errors are responsible for false-positive or false-negative associations, we performed a meta-analysis (Lee and Nath, 2005; Nath et al., 2005; Lee et al., 2006). The aim of the present study was to determine whether the LCE3C_LCE3B-del polymorphism confers susceptibility to psoriasis.

Methods

Identification of eligible studies and data extraction

We searched for studies that examined associations between the LCE3C_LCE3B-del allele polymorphism and psoriasis using the MEDLINE and EMBASE citation database to identify the available articles in which the LCE3C_LCE3B-del allele polymorphism was analyzed in psoriasis patients. Combinations of keywords, such as LCE3C, LCE3B, polymorphism, and psoriasis, were entered as the Medical Subject Heading (MeSH) component and as text words. References in identified studies were also investigated to identify additional studies not indexed by MEDLINE and EMBASE. Genetic association studies that determined the distributions of the LCE3C_LCE3B-del allele polymorphism in psoriasis and in normal controls were included. Reports were included in this meta-analysis if they (1) were published before August 2012, (2) contained original data (to ensure independence among studies), and (3) provided sufficient genotype data to calculate the odds ratio (OR). The following were excluded: (1) reports containing overlapping data, (2) reports in which the number of null and wild genotypes could not be ascertained, and (3) reports in which family members had been studied, such as those involving transmission disequilibrium studies, because analyses were based on linkage considerations. The following information was extracted from each identified study: author, year of publication, ethnicity of the study population, demographics, number of cases and controls, and the frequencies of the genotypes and alleles of the LCE3C_LCE3B-del polymorphism.

Evaluation of publication bias

Funnel plots are used to detect publication bias, but they require a range of studies of varying sizes and subjective judgments. Thus, we evaluated the publication bias using the Begg's adjusted rank correlation test and Egger's linear regression test (Egger et al., 1997a), which measure the funnel plot asymmetry on a natural logarithm scale of ORs. The Chi-square test was used to determine if the observed genotype frequencies in controls conformed to the Hardy-Weinberg (H-W) expectations.

Evaluations of statistical associations

We performed meta-analyses using (1) allelic contrast, (2) recessive model, (3) dominant model, and (4) homozygote contrast. Point estimates of risks, ORs, and 95% confidence intervals (CIs) were estimated for each study. In addition, within- and between-study variation and heterogeneity were assessed using Cochran's Q-statistic. This heterogeneity test assesses the null hypothesis that all studies evaluated the same effect. The effect of heterogeneity was quantified using I², which ranges between 0% and 100% and represents the proportion of study variability attributable to heterogeneity rather than chance (Higgins and Thompson, 2002). I² values of 25%, 50%, and 75% were nominally defined as low, moderate, and high estimates, respectively. The fixed-effect model assumes that a genetic factor has a similar effect on disease susceptibility across all studies investigated, and that observed variations among studies are caused by chance alone (Egger et al., 1997b). The random-effect model assumes that different studies show substantial diversity and assesses both within-study sampling error and between-study variance (DerSimonian and Laird, 1986). When the study groups are homogeneous, the two models are similar; however, if this is not the case, the random-effect model usually provides wider CIs than the fixed-effect model. The random-effect model is best used in the presence of significant between-study heterogeneity (DerSimonian and Laird, 1986). Statistical manipulations were undertaken using a Comprehensive Meta-Analysis computer program (Biosta, Englewood, NJ).

Results

Studies included in the meta-analysis

Thirty-nine studies were identified by electronic and manual searches, and 10 were selected for a full-text review based on the title and abstract details (de Cid et al., 2009; Coto et al., 2010; Huffmeier et al., 2010a, 2010b; Docampo et al., 2011; Li et al., 2011; Riveira-Munoz et al., 2011; Xu et al., 2011; Ammar et al., 2012; Bergboer et al., 2012). Three of these 10 studies were excluded because they contained duplicated data (de Cid et al., 2009; Huffmeier et al., 2010b; Bergboer et al., 2012). One of the eligible studies contained data on 13 different ethnic groups, and these groups were treated independently (Riveira-Munoz et al., 2011). Thus, a total of 19 separate comparisons were considered in the meta-analysis (6-8, 10-13), containing a total of 12,196 patients and 13,092 controls (Table 1) (Guan et al., 1997; Sato et al., 1998; Tassiulas et al., 1998; Akai et al., 1999; Pullmann et al., 1999; Molad et al., 2000; Kaufman et al., 2001; Prkacin et al., 2001; Uhm et al., 2002; Douglas et al., 2004; Sprovieri et al., 2005; Al-Awadhi et al., 2007; Rabbani et al., 2008; Abbas et al., 2012). These 19 studies encompassed 13 European, 5 Asian, and 1 Tunisian population. The LCE3C_LCE3B-del polymorphism was examined in 17 studies of psoriasis and 2 studies of psoriatic arthritis. Selected details from the individual studies are summarized in Table 1.

Table 1.

Characteristics of the Individual Studies Included in the Meta-Analysis

			Numbers		Case			Control
Study name	Country	Ethnicity	Case	Control	II	ID	DD	II	ID	DD	Association p-value	HWE p-value
Ammar (2012)	Tunisia	Tunisian	180	208	25	83	72	31	87	90	0.745	0.226
Xu (2011)	China	Asian	970	1064	126	453	391	161	543	360	0.005	0.065
Li (2011)	China	Asian	464	761	49	246	169	122	380	259	0.054	0.409
Riveira-Munoz-1 (2011)	Spain	European	176	382	15	95	66	69	206	107	0.003	0.098
Riveira-Munoz-2 (2011)	Italy	European	423	450	63	201	159	93	198	159	0.088	0.034
Riveira-Munoz-3 (2011)	France	European	141	164	13	60	68	26	65	73	0.177	0.088
Riveira-Munoz-4 (2011)	Netherlands	European	204	280	18	91	95	48	130	102	0.003	0.537
Riveira-Munoz-5 (2011)	Germany	European	1342	936	121	543	678	112	433	391	0.000	0.667
Riveira-Munoz-6 (2011)	UK	European	941	1021	72	415	454	111	450	460	0.031	0.943
Riveira-Munoz-7 (2011)	Ireland	European	392	947	33	164	195	99	385	463	0.459	0.169
Riveira-Munoz-8 (2011)	Finland	European	135	335	13	50	72	49	136	150	0.046	0.054
Riveira-Munoz-9 (2011)	USA	European	596	294	41	263	292	29	152	113	0.004	0.041
Riveira-Munoz-10 (2011)	USA	European	2123	1913	224	963	936	244	860	809	0.058	0.515
Riveira-Munoz-11 (2011)	Japan	Asian	550	537	77	257	216	93	257	187	0.064	0.789
Riveira-Munoz-12 (2011)	Mongolia	Asian	100	168	10	46	44	46	78	44	0.000	0.357
Riveira-Munoz-13 (2011)	China	Asian	1995	1897	258	956	781	347	926	624	0.000	0.914
Coto (2010)	Spain	European	405	400	52	204	149	60	196	144	0.544	0.675
Docampo (2011)	Italy	European	424^a	450	58	204	162	93	198	159	0.036	0.034
Huffmeier (2010^b)	Germany	European	635^a	885			825^b			1159^b	0.767	>0.05

Psoriatic arthritis.

D allele.

HWE, Hardy-Weinberg equilibrium; I, insertion allele of the LCE3C_LCE3B-del polymorphism; D, deletion allele of the LCE3C_LCE3B-del polymorphism.

Meta-analysis of the association between the LCE3C_LCE3B-del polymorphism and psoriasis

Meta-analysis showed a significant association between psoriasis and the LCE3C_LCE3B-del allele (OR 1.220, 95% CI 1.152-1.292, p<1.0×10⁻⁹) (Table 2, Fig. 1). Stratification by ethnicity indicated an association between the LCE3C_LCE3B-del allele and psoriasis in Europeans and Asians (OR, 1.213; 95% CI, 1.130-1.302; p=8.0×10⁻⁹ and OR, 1.260; 95% CI, 1.135-1.398; p=1.4×10⁻⁶, respectively) (Table 2, Fig. 2). Analysis using the recessive, dominant model, and homozygote contrast showed the same pattern for the LCE3C_LCE3B-del allele, a significant association between the LCE3C_LCE3B-del polymorphism and psoriasis (Table 2). The analysis performed in the single Tunisian study showed no association between the LCE3C_LCE3B-del allele and psoriasis (Table 2).

FIG. 1.

Odds ratios (ORs) and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between the D allele of the LCE3C_LCE3B-del polymorphism and psoriasis in all study subjects.

FIG. 2.

ORs and 95% CIs of individual studies and of pooled data for the associations between the D allele of the LCE3C_LCE3B-del polymorphism and psoriasis in each ethnic group.

Table 2.

Meta-Analysis of the Association Between the LCE3C_LCE3B-del Polymorphism and Psoriasis

			Test of association			Test of heterogeneity
Polymorphism	Population	No. of studies	OR	95% CI	p-value	Model	p-value	I ²
D vs. I allele	Overall	17	1.220	1.152-1.292	<1.0×10⁻⁹	R	0.023	45.0
	European	11	1.213	1.130-1.302	8.0×10⁻⁹	R	0.094	38.2
	Asian	5	1.260	1.135-1.398	1.4×10⁻⁶	R	0.061	55.5
	Tunisian	1	0.952	0.710-1.277	0.745	NA	NA	NA
DD+ID vs. II (Dominant)	Overall	17	1.408	1.300-1.526	<1.0×10⁻⁹	F	0.328	10.7
	European	11	1.397	1.254-1.557	<1.0×10⁻⁹	F	0.578	0
	Asian	5	1.469	1.203-1.795	1.6×10⁻⁵	R	0.276	52.7
	Tunisian	1	1.086	0.615-1.919	0.777	NA	NA	NA
DD vs. ID+II (Recessive)	Overall	17	1.232	1.140-1.331	1.1×10⁻⁸	R	0.037	41.6
	European	11	1.220	1.105-1.346	7.3×10⁻⁶	R	0.075	41.1
	Asian	5	1.291	1.181-1.411	2.0×10⁻⁹	F	0.202	32.8
	Tunisian	1	0.874	0.583-1.311	0.515	NA	NA	NA
DD vs. II	Overall	17	1.519	1.394-1.656	<1.0×10⁻⁹	F	0.100	32.0
	European	11	1.481	1.320-1.661	<1.0×10⁻⁹	F	0.260	18.6
	Asian	5	1.638	1.315-2.040	1.0×10⁻⁶	R	0.074	53.1
	Tunisian	1	0.992	0.538-1.828	0.979	NA	NA	NA

OR, odds ratio; CI, confidence interval; R, random-effect model; F, fixed-effect model; NA, not available.

Meta-analysis of the association between the LCE3C_LCE3B-del polymorphism and psoriatic arthritis

Two studies were included in the meta-analysis of the association between the LCE3C_LCE3B-del polymorphism and psoriatic arthritis (Table 3). Meta-analysis showed no association between psoriatic arthritis and the LCE3C_LCE3B-del polymorphism (OR for the allele, 1.087; 95% CI, 0.870-1.359; p=0.464). Excluding the study not in the H-W equilibrium did not affect our result (OR, 0.977; 95% CI, 0.840-1.137; p=0.285) (Table 3, Fig. 3).

FIG. 3.

ORs and 95% CIs of individual studies and of pooled data for the associations between the D allele of the LCE3C_LCE3B-del polymorphism and psoriatic arthritis.

Table 3.

Meta-Analysis of the Association Between the LCE3C_LCE3B-del Polymorphism and Psoriatic Arthritis

			Test of association			Test of heterogeneity
Polymorphism	Population	No. of studies	OR	95% CI	p-value	Model	p-value	I ²
D vs. I allele	European	2	1.087	0.870-1.359	0.464	R	0.067	70.2
D vs. I allele	HWE	1	0.977	0.840-1.137	0.285	NA	NA	NA

Heterogeneity and publication bias

The distributions of genotypes of the LCE3C_LCE3B-del polymorphism in 3 of the 19 control groups were not consistent with the H-W equilibrium (Docampo et al., 2011; Riveira-Munoz et al., 2011). Deviation from the H-W equilibrium among the controls implies the possibility of selection bias or genotyping errors. However, when the affected studies were excluded, the results were not substantially affected. No between-study heterogeneity was found during the analysis of the dominant model, the homozygote contrast in overall and Europeans, or during the analysis of the recessive model in Tunisians. Thus, these meta-analyses were performed using a fixed-effect model, and the others were performed using a random-effect model (Table 2). Publication bias causes a disproportionate number of positive studies and poses a problem for meta-analyses, but Egger's regression test showed no evidence of publication bias in these meta-analyses (Egger's regression test p-values>0.1) (Fig. 4).

FIG. 4.

Funnel plot of studies on the association between the D allele of the LCE3C_LCE3B-del polymorphism and psoriasis in all study subjects (Egger's regression p-values=0.189).

Discussion

The two genes of the LCE gene family, LCE3B and LCE3C, are located in the epidermal differentiation complex. The LCE cluster, which encodes the stratum corneum proteins, shows a wide range of expression in various epithelia, responds to different environmental conditions, and may play a key role when the skin barrier functions as a physiological stimulus (Nair et al., 2006). Expression studies have shown that carriers of LCE3C_LCE3B-del have a compromised repair response or induce an inappropriate repair response after barrier disruption, triggering compensation by the other LCE genes (de Cid et al., 2009).

In this meta-analysis, we combined data from published studies to evaluate the genetic associations between the LCE3C_LCE3B-del polymorphism and psoriasis. Our meta-analysis showed a significant association between psoriasis and the LCE3C_LCE3B-del polymorphism in Europeans and Asians. However, we did not find an association between the LCE3C_LCE3B-del polymorphism and psoriatic arthritis. LCE expression was induced by skin barrier disruption in normal epidermis, and LCE was expressed strongly in psoriatic lesions. Thus, this meta-analysis suggests that the LCE3C_LCE3B-del polymorphism plays a role in psoriasis susceptibility in Europeans and Asians, and it might not contribute to the development of psoriatic arthritis in Europeans. Our data indicate that the LCE3C_LCE3B-del polymorphism may be associated with only skin manifestations of psoriasis and contribute differently to susceptibility to skin and joint diseases. This finding may suggest that there are different contributions of genetic factors to the skin and joint diseases of psoriasis. The result of this meta-analysis suggests that carriers of the LCE3C_LCE3B-del have a compromised repair response after barrier disruption in the skin.

However, our results for psoriatic arthritis should be interpreted with caution because of the limited number of studies included in this meta-analysis. There were only two studies on psoriatic arthritis. The relative importance of the LCE3C_LCE3B-del polymorphism during the development of psoriatic arthritis may depend on ethnicity. However, we were unable to perform an ethnicity-specific meta-analysis due to limited data.

This meta-analysis differs from a previous meta-analysis on the relationship between the LCE3C_LCE3B-del polymorphism and psoriasis risk performed by Riveira-Munoz et al. (Prahalad, 2006; Riveira-Munoz et al., 2011), because in the present study, there were six more studies, 2019 more psoriasis patients, and 3768 more controls, and our meta-analysis was conducted on psoriasis and psoriatic arthritis. However, the results of our meta-analysis with regard to the association of the LCE3C_LCE3B-del polymorphism with the development of psoriasis in Europeans and Asians are in agreement with the results from the previous study.

To our knowledge, this is the most comprehensive meta-analysis of the relationships between the LCE3C_LCE3B-del polymorphism and psoriasis and psoriatic arthritis. Nonetheless, the present study has some limitations that should be considered. First, heterogeneity and confounding factors may have distorted the analysis. Publication bias may also have affected the analysis, because studies that produced negative results may not have been published or may have been missed, despite the performance of Egger's regression test. Second, the LCE3C_LCE3B-del polymorphism could also be associated with psoriasis severity. However, the limited amount of data available prevented a meta-analysis of the association between the LCE3C_LCE3B-del polymorphism and disease severity. Third, we included data from European and Asian patients in our ethnic-specific meta-analysis, and thus our ethnicity-associated results are applicable to only the ethnic groups analyzed.

In conclusion, this meta-analysis of the association between the LCE3C_LCE3B-del polymorphism and psoriasis, based on a total sample of 12,196 patients with psoriasis and 13,092, confirms that the LCE3C_LCE3B-del polymorphism is associated with psoriasis susceptibility in Europeans, and Asians. However, the LCE3C_LCE3B-del polymorphism is not associated with the development of psoriatic arthritis in Europeans. Our meta-analysis suggests that different genetic risk factors contribute to skin and joint disease of psoriasis. Larger-scale studies in populations with different ethnicities are required to explore the relationship between polymorphisms of the LCE3C_LCE3B gene and the pathogenesis of psoriasis and psoriatic arthritis.

Footnotes

Acknowledgments

This study was supported by a grant from the Korea University.

Author Disclosure Statement

The authors declare that they have no vested interest that could have inappropriately influenced this study.

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