Identifying the genetic associations among the psoriasis patients in eastern India.

Psoriasis is a multifactorial genetic disorder manifested by hyperproliferation and abnormal differentiation of epidermal keratinocytes, along with the infiltration of inflammatory cells into the skin. Although ~80 genetic susceptibility variants were reported in psoriasis, many loci showed population-specific associations, warranting the need for more population-specific association studies in psoriasis. We determined the association of forty single nucleotide polymorphisms (SNPs) among 2136 psoriasis patients and normal individuals from eastern India. We investigated the expression of corresponding genes and evaluated the protein structure stability for the genes with susceptible coding variants. We found fifteen SNPs significantly associated with psoriasis, while additional three SNPs showed significant association when we classified the patients based on the presence of HLA-Cw6 allele. Epistatic interaction between HLA-Cw6 and other associated loci showed significant association with the SNPs at PSORS1 region, along with other five SNPs outside PSORS1. Three genes showed significant differential expression in psoriatic tissues compared to the adjacent normal skin tissues but were not differential when classified the patients based on their genotypes. SNP rs495337 at SPATA2 (Spermatogenesis Associated 2) showed a 1.2-fold increased risk among the HLA-Cw6 patients compared to combined samples. We found significant downregulation of SPATA2 among the patients with risk genotypes and HLA-Cw6 allele compared to the non-risk genotypes. Protein structure stability analysis showed reduced structural stability for all the mutant residues caused by the associated coding variants. Our study evaluated the genetic associations of psoriasis-susceptible variants in India and evaluated the possible functional significance of these associated variants in psoriasis.

Serum miRNA profiling identified miRNAs associated with disease severity in psoriasis.

Psoriasis vulgaris is a chronic, autoimmune skin disease involving a complex interplay of epidermal keratinocytes, dermal fibroblast and infiltrating immune cells. Differential expressions of miRNAs are observed in psoriasis and the deregulated miRNAs are sometimes associated with disease severity. This study aims to identify miRNAs altered in the serum of psoriasis patients that are associated with the Psoriasis Area and Severity Index (PASI). In order to assess miRNA levels in the serum of psoriasis patients, we selected 24 differentially expressed miRNAs in the psoriatic skin are possibly derived from the skin and immune cells, as well as five miRNAs that are enriched in other tissues. We identified 16 miRNAs that exhibited significantly (p < 0.05) altered levels in the serum of psoriasis patients compared to healthy individuals. Among these, 13 miRNAs showed similar expression pattern in the serum of psoriasis patients as also observed in the psoriatic skin tissues. Ten miRNAs showed an accuracy of greater than 75% in classifying the psoriasis patients from healthy individuals. Further analysis of differential miRNA levels between the low PASI group and the high PASI group identified three miRNAs (miR-147b, miR-3614-5p, and miR-125a-5p) with significantly altered levels between the low severity and the high severity psoriasis patients. Our systematic investigation of skin and immune cell-derived miRNAs in the serum of psoriasis patients revealed alteration in miRNA levels to be associated with disease severity, which may help in monitoring the disease progression and therapeutic response.

Role of Trichoscopy in Evaluation of Alopecia Areata: A Study in a Tertiary Care Referral Centre in the Eastern India.

Background: Alopecia areata is an autoimmune disorder affecting the hair-bearing sites of the body. Trichoscopy has recently been practiced in the diagnosis of alopecia areata. Aim: To elicit trichoscopy patterns in alopecia areata and to find out any correlation of trichoscopic findings with disease severity. Methods: Trichoscopy was done on clinically diagnosed cases of alopecia areata and on age and sex-matched controls without hair disorders by using a DL1 dermoscope (magnification: ×10). Observed dermoscopic findings were analyzed to find the correlation with disease severity. Results: In total, 87 cases and 60 controls were included in the study with the mean age for cases being 25.47 ± 14.07 years. There was male predominance of cases (51; 58.62%). Alopecia in multiple patches was the most common type (42; 48.27%), and scalp was the most common site of involvement (79; 90.8%). Yellow dots (YD), black dots (BD), broken hairs (BH), circle hair (CH), and tapering hairs (TH) or exclamation hair (EH) were found to be statistically significant findings in alopecia areata as compared to controls. Circle hair was significantly associated with total severity of alopecia areata (P = 0.041). Yellow dots had a positive correlation with the number of episodes of alopecia areata (Spearman's rho = 0.273, P = 0.0106) and mean severity of alopecia tool (SALT) score (P = 0.0130). No significant association was noted between trichoscopic findings and disease activity, family history, disease associations, or nail involvement. Conclusion: A constellation of trichoscopic findings helps in establishing the diagnosis of alopecia areata obviating the need for biopsy.

Evaluation of the Efficacy and Safety Profile of Long-Pulsed 1064 Neodymium:Yttrium-Aluminum-Garnet (Nd:YAG) Laser in Hemangioma and Vascular Malformation in Darker Skin Types.

Introduction A prospective, interventional study was conducted to evaluate the efficacy and safety profile of long-pulsed neodymium:yttrium-aluminum-garnet (Nd:YAG) laser in the treatment of vascular lesions in the darker skin patients of Fitzpatrick skin type IV and V. Materials and method The study was conducted at a tertiary care hospital. Institutional ethical committee permission was obtained before starting the study. Twenty-nine patients presenting with vascular lesions were enrolled in the study. The patients were called once a month for sessions for six months. Clinician Global Impression (CGI) scores were used for evaluation. We followed a "per protocol" analysis. Results Of the 29 patients we enrolled, three dropped out for various logistic reasons, and 26 patients completed their treatment. After six months of follow-up of the 26 patients who completed their treatment, 12 (46.15%) had shown complete healing (CGI = 4, 70%-100% improvement in lesions). The rest of the 14 (53.84%) patients showed good improvement (CG1 = 3, reduction of 50%-70% of lesions). No permanent side effects were noted. Conclusion Long-pulsed 1064 Nd:YAG laser proves to be an effective treatment for hemangioma and vascular malformation in darker skin patients with its major advantages of being a safe, well-tolerated, cost-effective procedure with minimal downtime and minimal side effects.

Could It be Wolf Isotopic Response?: Occurrence of Dermatophytoses on Vitiliginous Skin-Case Series of Five Cases from a Tertiary Care Centre in India.

Wolf isotopic response is the occurrence of new dermatoses on areas of the skin with previous but still active dermatoses. Vitiligo is an acquired disorder characterized by the loss of functional melanocytes which manifests as circumscribed depigmented macules and patches. Dermatophytoses are superficial fungal infections caused by three genera of fungi (Microsporum, Trichophyton, and Epidermophyton) that have the unique ability to invade and multiply within keratinized tissue (skin, hair, and nail). The appearance of dermatophyte infection on previously present vitiligo lesion is an uncommon example of Wolf response. We describe a case series of five vitiligo patients that presented to our OPD over 1 year period.

Nailfold Capillaroscopic Changes as a Marker of Interstitial Lung Disease in Systemic Sclerosis: A Cross-Sectional Study in a Tertiary Care Hospital in Eastern India.

Background: Systemic sclerosis (SSc) is an autoimmune connective tissue disorder causing microvascular abnormality leading to Raynaud's phenomenon, skin tightening, and nailfold capillary changes. The patient may have systemic involvement, among them interstitial lung disease (ILD) and pulmonary arterial hypertension are mainly associated with disease-related mortality. Aims: To find out an association between nailfold capillaroscopic changes with ILD severity. Materials and Methods: An institution based cross-sectional study was performed among the patients of SSc above 18 years. Detailed history was taken. Clinical examinations, nailfold capillaroscopy (NFC) with a dermatoscope and high-resolution computed tomography (HRCT) scan of thorax were done. Data were analyzed in MedCalc statistical software version 20. Results: Out of total 43 patients, 74.4% (n = 32) were female. Mean age was 35.05 ± 7.24 years and mean duration 4.28 ± 2.81 years. Diffuse SSc was found in 88.37% (n = 38). On NFC, early, active, and late patterns were found in 30.2% (n = 13), 25.6% (n = 11), and 44.2% (n = 19) cases, respectively. On HRCT, early, active, and late ILD were present in 18.6% (n = 8), 37.2% (n = 16), and 30.2% (n = 13) cases, respectively. ILD changes were absent in 14% (n = 6) though NFC changes were present in them. Respiratory symptoms were absent in 20.93% (n = 9) patients though all had features of early NFC and among them 9.3% (n = 4) showed early ILD changes on HRCT. Significant associations were found between NFC changes and ILD severity (P = 0.0003), NFC changes and respiratory symptoms (P < 0.0001) and between ILD changes and respiratory symptoms (P < 0.0001). Discussion: NFC, an inexpensive procedure, can be performed in all patients of SSc to detect development of early ILD even before appearance of respiratory symptoms to prevent further progression.

Clinicopathological Spectrum of Henoch-Schönlein Purpura Vasculitis: An Experience from a Tertiary Care Center.

Henoch-Schönlein purpura (HSP) is a small vessel vasculitis with multiorgan involvement. Renal involvement is the key factor predicting morbidity. We have aimed to analyze the clinicopathological spectrum of HSP vasculitis and HSP nephritis to assess the risk factors associated with kidney involvement. This retrospective study was performed in the department of pathology with collaboration of department of dermatology and department of nephrology of a tertiary care center. All clinical details along with biopsy findings were retrieved. Starting materials of the study were cases of leukocytoclastic vasculitis with only perivascular IgA deposit of more than ++ in the absence of other immunoglobulin and trace complements. To investigate the possible factors that are influential on the development of biopsy-proven HSP nephritis, we divided the whole study population in two groups -group 1: with and group 2: without biopsy-proven nephritis. One-way analysis of variance was carried out during comparative analysis between two groups using IBM SPSS statistics software, version 19 and MedCalc software, version 12.3.0.0. HSP vasculitis comprised 11.6% (n = 19) of total cutaneous vasculitis in 2 years (164 cases) with a mean age of 13.52 ± 8.10 (range: 4-33 years). Three cases developed de novo kidney disease (15.79%). A correlation analysis revealed that predictors were seasonal variation (P = 0.018), severe gastrointestinal involvement (P = 0.03), and subcutaneous edema (P = 0.005). Various clinical and laboratory parameters were associated with renal consequences. Occult nephritis was the most common presentation with crescent as a constant histopathological feature.

Genetic and acquired blistering disorders of pediatric age group: An experience from Eastern India.

INTRODUCTION: Blistering or vesiculobullous disorders in pediatric population are either immunobullous or mechanobullous. Spectrum was analyzed using demographic details, clinical features, histopathology, direct immunofluorescence (DIF) and Immunofluorescence mapping (IFM). METHODOLOGY: This was a single institution based observational study in children below 18 years. The demographic details were collected using proforma containing particulars of the patient, history, complaints, and other parameters. Punch biopsy of the skin lesion was done. Biopsy samples were examined under light microscope followed by DIF using fluorescent conjugated polyclonal antibody against immunoglobulins IgG, IgM, IgA, and complement C3. The salt-split technique was also used in particular cases. IFM was done using anticytokeratin (CK) 5 & 14, antilaminin 332, anticollagen VII, and anticollagen IV antibodies. RESULTS: Out of total 50 cases, linear IgA bullous dermatosis (LABD) was the commonest. The average concordance between clinical and final diagnosis (histopathological examination + DIF) was 87.5% and discordance was 12.5%. The agreement between histopathological examination and DIF was found to be substantially significant (κ = 0.6892). IFM depicted epidermolysis bullosa simplex with reduced CK 14 expression, dystrophic epidermolysis bullosa with reduced Collagen VII expression and junctional epidermolysis bullosa with absent laminin 5 expression. CONCLUSION: The spectrum of bullous lesions in childhood was properly delineated and subcategorization of EB was done. Histopathological examination showed the hallmarks that were conclusive in most of the cases except in LABD and EB. DIF and IFM proved indispensable in those cases. Thus, DIF is not a substitute for histopathology but complementary to it.

Functional Mapping of Genetic Interactions between HLA-Cw6 and LCE3A in Psoriasis.

Functional studies to delineate the molecular mechanisms of causal genetic variants are the main focus in the post-GWAS era. Previous GWASs have identified >50 susceptibility loci associated with psoriasis. Functional understanding of the biology underlying the disease risk of most of these associated loci is unclear. In this study, we identified a regulatory SNP at the putative enhancer of the LCE3A gene within the epidermal differentiation complex that showed epistatic interaction with HLA-Cw6. The variant allele disrupted signal transducer and activator of transcription 3 binding to the region, thereby regulating the expression of the downstream LCE3A gene. Electrophoretic mobility shift and pulldown assay confirmed the preferential binding of signal transducer and activator of transcription 3 to the DNA with a wild-type allele compared with the DNA with a variant allele. The reporter assay further validated the IL-6‒stimulated phosphorylated signal transducer and activator of transcription 3‒mediated LCE3A activation in the presence of the wild-type allele. Interestingly, the presence of the HLA-Cw6 allele leads to IL-6‒mediated phosphorylation of signal transducer and activator of transcription 3, followed by its nuclear localization in the epidermal keratinocytes of psoriatic skin, suggesting indirect interaction of the HLA-Cw6 allele and a regulatory SNP upstream of the LCE3A gene. This study reflects an interesting approach to dissecting the molecular mechanism underlying the genetic interaction observed between HLA-Cw6 and LCE3A in psoriasis pathogenesis.

A Quality of Life Study of Patients with Leprosy Attending the Dermatology OPD of a Tertiary Care Center of Eastern India.

BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae affecting the skin, peripheral nervous system, and other tissues. The disease is associated with social stigma, and the patients sometimes suffer social discrimination because it often leads to visible physical deformities. Hence, leprosy may have severe impact on the quality of life (QoL) of patients. AIMS AND OBJECTIVES: The aim of this study was to assess the effect of leprosy on the QoL of the affected patients and to find out whether there is some association with certain demographic and clinical factors. MATERIALS AND METHODS: The Dermatology Life Quality Index (DLQI) questionnaire was used to assess the QoL of 114 patients with leprosy who attended dermatology outpatient department of a tertiary care center of eastern India. This was a cross-sectional study. RESULTS: Among a total of 114 patients, leprosy had no impact on the QoL of 15 (13.16%) patients. There was a mild impact in 23 (20.18%) of the patients. There was moderate impact in 37 (32.46%) of the patients. The disease had severe impact in the QoL of 39 (34.21%) patients. None of the patients had a very severe impact. Several of the clinical aspects such as nerve involvement, systemic features, deformity, disability grade, and type of leprosy have significant impact on QoL. Among the demographic factors, gender had some effects on QoL. CONCLUSION: Leprosy adversely affects the QoL of those affected. Although it is considered a social disease, at least in our part of the country, demographics have minimal effect on the QoL. Rather, important clinical aspects such as systemic features, nerve involvement, reaction, deformity, and disability have profound impact on the QoL of the patients.

Clinico-Etiological Evaluation of Chronic Leg Ulcer in a Tertiary Care Center of Eastern India.

BACKGROUND: A chronic leg ulcer (CLU) is a significant public health problem. It has various etiologies. Racial, familial, occupational, and social factors may also have an impact on the prevalence of different causes of leg ulcers. Though there are western data on the epidemiology of leg ulcer, similar data are largely unavailable from our part of the world. AIMS: We undertook a study in a tertiary care center in eastern India to determine the clinical and etiological pattern of patients with CLU. MATERIALS AND METHODS: Hundred consecutive patients presenting with CLU, fulfilling the criteria, were included after informed consent. Patients were subjected to proper history taking, clinical examination, routine blood test, and pus for culture and sensitivity test (where needed) along with Ankle Brachial Index (ABI). RESULTS: Among the 100 patients, venous ulcer (34%) was predominant followed by arterial ulcer (14%), mixed arterial and venous ulcer (11%). History of smoking (56%) and obesity (BMI >25) (32%) were the common risk factors in leg ulcer patients. Fifty nine percent of the total CLU were infected and out of this, 86.4% showed growth of microorganisms. Staphylococcus aureus (39%) was the most commonly isolated organism, followed by Pseudomonas aeruginosa (15%). Eleven (24.44%) clinically diagnosed venous ulcer patients showed significantly lower ABI (<0.9) and were diagnosed as mixed ulcer (a venous ulcer with a peripheral arterial disease). CONCLUSION: Venous ulcer and mixed ulcer are the most common type of CLU.

Clinicopathological Study of Primary Cutaneous Amyloidosis in a Tertiary Care Center of Eastern India Reveals Insignificant Association with Friction, Scrubbing, and Photo-Exposure: How valid is the "Keratinocyte Hypothesis"?

INTRODUCTION: Primary cutaneous amyloidosis (PCA) can be classified into four principal categories: macular amyloidosis, lichen amyloidosis, biphasic, and nodular amyloidosis. Some unusual variants such as widespread diffuse hyperpigmentation without papules, poikiloderma like involvement, lesions following Blaschko's line, etc., have also been reported. However, not much data are available regarding the demography, epidemiology, clinical patterns, and distribution and histopathological findings, especially from the eastern part of India. AIMS: We conducted a cross-sectional, institution-based study to evaluate clinicopathological pattern and factors of PCA in eastern India. MATERIALS AND METHODS: We recorded clinical and histopathological findings of 100 consecutive patients of PCA presenting to a tertiary care institution of Kolkata in eastern India. RESULTS: We found female patients of PCA outnumber male (M:F =1:1.9) with majority of patients being young adults (56%) between 20 and 40 years of age. More than half (54%) of the patients were pruritic. The severity of pruritus is significantly more associated with lichenoid and biphasic variants over macular amyloidosis. Positive family history was recorded in 17% of cases. Macular variant was the most common variant constituting 48% of the total PCA. We also found that the association with history of friction and scrubbing and photo-exposure were statistically insignificant. However, duration of the disease has statistically significant association with the disease morphology. Congo red stain showed these deposits as reddish orange substance in 28 patients out of 64 patients' samples on which Congo red could be performed. CONCLUSION: Our study revealed that many concepts of pathogenesis of PCA including friction and photoexposure might have lesser importance. However, morphological types were significantly associated with the duration of the disease and symptom severity.

Epigenome-wide DNA methylation regulates cardinal pathological features of psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory autoimmune skin disorder. Several studies suggested psoriasis to be a complex multifactorial disease, but the exact triggering factor is yet to be determined. Evidences suggest that in addition to genetic factors, epigenetic reprogramming is also involved in psoriasis development. Major histopathological features, like increased proliferation and abnormal differentiation of keratinocytes, and immune cell infiltrations are characteristic marks of psoriatic skin lesions. Following therapy, histopathological features as well as aberrant DNA methylation reversed to normal levels. To understand the role of DNA methylation in regulating these crucial histopathologic features, we investigated the genome-wide DNA methylation profile of psoriasis patients with different histopathological features. RESULTS: Genome-wide DNA methylation profiling of psoriatic and adjacent normal skin tissues identified several novel differentially methylated regions associated with psoriasis. Differentially methylated CpGs were significantly enriched in several psoriasis susceptibility (PSORS) regions and epigenetically regulated the expression of key pathogenic genes, even with low-CpG promoters. Top differentially methylated genes overlapped with PSORS regions including S100A9, SELENBP1, CARD14, KAZN and PTPN22 showed inverse correlation between methylation and gene expression. We identified differentially methylated genes associated with characteristic histopathological features in psoriasis. Psoriatic skin with Munro's microabscess, a distinctive feature in psoriasis including parakeratosis and neutrophil accumulation at the stratum corneum, was enriched with differentially methylated genes involved in neutrophil chemotaxis. Rete peg elongation and focal hypergranulosis were also associated with epigenetically regulated genes, supporting the reversible nature of these characteristic features during remission and relapse of the lesions. CONCLUSION: Our study, for the first time, indicated the possible involvement of DNA methylation in regulating the cardinal pathophysiological features in psoriasis. Common genes involved in regulation of these pathologies may be used to develop drugs for better clinical management of psoriasis.

"Turban PUVAsol:" A Simple, Novel, Effective, and Safe Treatment Option for Advanced and Refractory Cases of Alopecia Areata.

BACKGROUND: Alopecia areata (AA) is an autoimmune characterized by nonscarring loss of scalp and/or body hairs. Topical PUVA has been reported to have good effect in AA. The modification of topical PUVA which we call, "Turban PUVA-sol," is a method of localized immunotherapy using psoralen solution followed by sun exposure. AIMS: We aim to study the therapeutic role and side effect profile of turban PUVA in the treatment of advanced and refractory AA. METHODOLOGY: Fifteen consecutive patients of alopecia subtotalis (at least 70% of scalp hair loss), totalis, and universalis, attending the dermatology outpatient department of a tertiary care hospital in eastern India were subjected to "Turban PUVA-sol" after duly signed consent. Alternate day therapy was given. RESULTS: At the end of 10 months of study, 2 (13%) out of fifteen patients were lost to follow-up for some unknown reasons. The severity of alopecia tool scores showed a significant (P = 0.0002) decrease posttreatment. Correlation between the severity of alopecia and grade of improvement showed a rho value of -0.453. In the remaining thirteen patients, using physician global assessment (PGA), 4 (26%) showed good response, 4 (26%) showed moderate response, 3 showed mild (20%) response, and 2 patients (13%) showed negligible response. Three out of four patients who showed good improvement in PGA showed more than 80% of new hair growth. Side effects are minimal with some patients complaining of mild irritation and scaling. CONCLUSION: We found topical Turban PUVAsol to be a very cost-effective and safe treatment option for AA.

Clinico-epidemiological Study of Congenital Ichthyosis in a Tertiary Care Center of Eastern India.

BACKGROUND: Congenital ichthyoses comprises various specific genetic diseases and can range from mild to very severe presentation. Furthermore, these may be associated with various syndromes. There is scanty data regarding the demographic profile and clinical features of patients with congenital ichthyosis in India. AIMS AND OBJECTIVES: The aim is to evaluate the epidemiology and clinical characteristics of various types of congenital ichthyoses. MATERIALS AND METHODS: The study was conducted for 1 year from April 2013 to March 2014. Patients were evaluated for epidemiological profile and clinical features. RESULTS: During the study of 1 year, 106 patients of congenital ichthyoses were identified. The most common of the various ichthyoses was ichthyosis vulgaris, followed by lamellar ichthyosis, X-linked recessive ichthyosis. One case of Netherton syndrome and one of ichthyosis hystrix were also identified. CONCLUSION: Various types of congenital ichthyoses present with different clinical features which range from mild to severe. These present with significant psychological stress to both patients and their families. Furthermore, all these diseases have significant implications of transmission to their offspring.

Use of Fine Needle Aspirate from Peripheral Nerves of Pure-neural Leprosy for Cytology and Polymerase Chain Reaction to Confirm the Diagnosis: A Follow-up Study of 4 Years.

BACKGROUND: Pure neural leprosy (PNL) still remains a diagnostic challenge because of the absence of sine qua non skin lesions of leprosy and a confirmatory diagnostic method. The authors had earlier described a simple yet objective technique of combining fine needle aspiration cytology (FNAC) coupled with a multiplex polymerase chain reaction (PCR) in a pilot study, wherein the technique showed promise of a reliable diagnostic tool. In the pursuit of further evidence, the authors carried out a 4-year study with PNL cases to find the efficacy and reliability of the said method in a larger sample size. AIM: This study was conducted to find the efficacy, reliability, and reproducibility of FNAC coupled with multiplex PCR and Ziehl-Neelsen (ZN) staining in identifying the cases of PNL. MATERIALS AND METHODS: All cases that were suspected to be suffering from PNL, following evaluation by two independent observers were included in the study and were subjected to FNAC from the affected nerve, and the aspirates were evaluated for cytology, ZN staining, and multiplex PCR for Mycobacterium leprae genome. In addition, serum anti-PGL1 levels were also performed in all the study subjects. Fifteen non-PNL cases were also included in the control arm. RESULTS: A total of 47 cases were included in the test arm and subjected to FNAC. Conventional ZN staining could demonstrate acid-fast bacilli (AFB) in only 15 out of 47 cases (31.91%) while M. leprae DNA could be elicited in 37 (78.72%) cases by the multiplex PCR. Only 13 (27.65%) out of 47 cases showed anti-PGLI-1 antibody positivity. On cytological examination of the nerve aspirates, only 11 (23.40%) cases showed epithelioid cells whereas nonspecific inflammation was seen in 26 (75.60%) cases. CONCLUSION: The results of this study conducted over a larger sample size corroborate with the findings of our pilot study. In a resource poor set up, FNAC in combination with ZN staining and multiplex PCR is a rapid, simple, and easily performed test, which can give a reproducible and objective diagnosis in cases of PNL.

Associations of ERAP1 coding variants and domain specific interaction with HLA-C∗06 in the early onset psoriasis patients of India.

Interferon-γ-induced aminopeptidase ERAP1 trims peptides within the endoplasmic reticulum so that they can be loaded onto MHC class I and presented to the CD8+ T-cells. ERAP1 association and its interaction with HLA-C∗06 is controversial across different populations. We have investigated the association and possible functional role of non-synonymous SNPs at different exons of ERAP1 (rs26653: Arg127Pro, rs30187: Lys528Arg and rs27044: Gln730Glu) and their interactions with HLA-C∗06 in psoriasis. Significant associations of HLA-C∗06 (OR=5.47, P<2.2×10-16), rs30187 (OR 1.35, P=7.4×10-4) and rs27044 (OR=1.24, P=5.8×10-3) were observed. All three ERAP1 SNPs showed significant association only for HLA-C∗06 positive patients, while rs30187 and rs27044 showed significant association only for early onset patients (rs30187: OR=1.47, P=9.6×10-5; rs27044: OR=1.36, P=3.3×10-4). No differential expression of ERAP1 was observed either between paired uninvolved and involved skin tissues of psoriasis patients or between non-risk and risk variants in the involved skin. Significant epistatic interaction was observed between HLA-C∗06 and the SNP (rs27044) located at the peptide-binding cavity of ERAP1. Evolutionary conservation analysis among mammals showed confinement of Lys528 and Gln730 within highly conserved regions of ERAP1 and suggested the possible detrimental effect of this allele in ERAP1 regulation.

Association of IL12B risk haplotype and lack of interaction with HLA-Cw6 among the psoriasis patients in India.

Psoriasis is a complex multifactorial chronic inflammatory skin disorder involving both genetic and environmental susceptibility factors. It is strongly associated with HLA-Cw6, but several studies suggested that further genetic factors may confer additional risk. We investigated the association of two single-nucleotide polymorphisms (SNPs), rs3212227 at the 3'-untranslated region and rs7709212 located at ~6.7 kb upstream from the transcription start site of IL12B gene in a case-control study comprising 1702 individuals from India. We found both SNPs were significantly associated with psoriasis (rs7709212: odds ratio (OR)=1.37, P-value=1.09 × 10-5; rs3212227: OR=1.38, P-value=8.88 × 10-6). IL12B gene was significantly upregulated in involved skin of psoriasis patients with risk genotype carriers (rs7709212_TT and rs3212227_TT) compared with non-risk genotype carriers (rs7709212_CC and rs3212227_GG). Significantly higher serum protein concentration of IL12 was also observed among risk allele carriers compared with non-risk allele carriers irrespective of the presence of HLA-Cw6 allele. Haplotype analysis suggested significant increased risk (OR=1.50, P-value=5.01 × 10-8) to the disease when both risk alleles of IL12B were present. IL12 serum protein concentration of risk haplotype (TT-TT) carriers showed significant upregulation compared with the non-risk carriers independent of HLA-Cw6 alleles. Our data suggested the association of IL12B with the psoriasis, however no evidence was observed for the epistatic effect of IL12B with HLA-Cw6 among the psoriasis patients in India.