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  Table of Contents  
Year : 2021  |  Volume : 12  |  Issue : 1  |  Page : 181-182  

FOK 1 (rs10735810 id) variants in pemphigus vulgaris: A pilot investigation in North Indians

1 Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Dermatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission06-May-2020
Date of Decision02-Jul-2020
Date of Acceptance22-Aug-2020
Date of Web Publication16-Jan-2021

Correspondence Address:
Seema Chhabra
Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh - 160 012
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/idoj.IDOJ_349_20

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How to cite this article:
Priyanka K, Minz RW, Chhabra S, Handa S. FOK 1 (rs10735810 id) variants in pemphigus vulgaris: A pilot investigation in North Indians. Indian Dermatol Online J 2021;12:181-2

How to cite this URL:
Priyanka K, Minz RW, Chhabra S, Handa S. FOK 1 (rs10735810 id) variants in pemphigus vulgaris: A pilot investigation in North Indians. Indian Dermatol Online J [serial online] 2021 [cited 2021 Feb 26];12:181-2. Available from: https://www.idoj.in/text.asp?2021/12/1/181/307167


Pemphigus vulgaris (PV) is a blistering autoimmune, potentially life-threatening disease. It is characterized by intraepithelial acantholysis due to pathogenic desmoglein-3 (DSG3) autoantibodies.[1] Vitamin D, as an immunoregulator has a variety of anti-inflammatory or regulatory effects and several reports have linked vitamin D deficiency with PV predisposition.[1],[2] Furthermore, vitamin D has been shown to reduce DSG3 expression in keratinocyes.[3] Vitamin D facilitates several immuno-modulatory functions through vitamin D receptor (VDR), a ligand-activated transcription factor that controls or triggers expression of a variety of genes which impart stimulatory and protective effects on keratinocytes thereby signifying implication of VDRs in skin diseases[1],[2],[3],[4],[5] Single-nucleotide polymorphisms (SNPs) in VDR (12q12-14) have been extensively studied in various dermatological disorders[4],[5]; however, SNPs remain neglected in PV. Therefore, a pilot case-control study was conducted with 204 North Indian subjects (recruited over a period of 9 months) including PV patients (n = 74, after a detailed medical and family history) and age- and sex-matched healthy controls (n = 130), to investigate the genetic association of VDR-Fok1 variants in PV patients.

Sample size was calculated using EPI Info 7 online calculator at an alpha error of 0.05, power of 80% and ratio of controls and cases of 1.75:1, taking the expected odds ratio of 5.71 for FOK1 gene polymorphisms and assumption that proportion of controls and cases with FOK1 gene polymorphisms 85% and 97%, respectively. Total sample size calculated (Fleiss with continuity correction) was 178 with 65 cases and 113 controls. For possible dropouts it was decided to include extra subjects so the final sample size was 74 cases and 130 healthy controls.

Under all aseptic precautions, peripheral blood samples were obtained consecutively from patients presenting to the dermatology outpatient clinics, with histopathology and/or direct immunofluorescence proven PV and from healthy unrelated voluntary controls. An informed consent was obtained from all the enrolled cases and healthy controls.

Genomic DNA was isolated from collected venous blood (3 ml) and quantified. Using primers,[2] polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays were performed for the identification of FOK1 variants. Fok1 being functional and important polymorphism of VDR gene results in different translation initiation sites due to thymine (T) to cytosine (C) substitution in the first translation initiation codon ATG which generates long and short forms of VDR. The Fok1 polymorphism affects function of VDR resulting in altered efficiency of binding to vitamin D. Individuals with the C allele initiate translation at the second ATG site and lack the three NH2-terminal amino acids of the full-length VDR protein. In contrast, individuals with the T allele initiate translation at the first ATG site and synthesize a full-length VDR protein. The short and long protein forms are associated with a different ability to induce transcription of vitamin D-dependent genes.

The disease was commoner in females compared to males (male:female = 1:1.47). The mean age of patients was 46.68 ± 12.9 years. The most common clinical subtype of PV was mucocutaneous (70%). Forty-two patients presented with active disease at enrolment. Distribution followed Hardy-Weinberg equilibrium [Table 1] and “CC” genotype (mutant) was observed to be significantly associated with the risk of PV in patients (58.1% vs. 30.7% controls; OR = 3.12;C.I. = 1.7-5.60; P = 0.000). TT genotype (wild) did not show any significant difference (P = 0.98) between the groups. 61.2% controls were heterozygous (TC) carriers (P = 0.0000*). The allelic distribution showed “C” allele was the most abundant in patients vs. healthy controls (77% vs. 63.84%; OR = 1.89; CI = 1.2- 3.0; P = 0.008) whereas T allele occurred more frequently in healthy controls (OR = 0.53;CI = 0.33-0.83; P = 0.008). The carriage rate of “C” allele was more than 90% in all the subjects but controls possessed a significantly higher proportion of heterozygous “TC” genotype with the protective allele “T” (69.23%, P = 0.0002) compared with patients. These findings indicate that individuals with mutant allele “C” were more susceptible to develop PV, indicating that “C” allele might be a risk factor. Meanwhile, presence of T allele might prevent synthesis of transcriptionally more active truncated VDR (protein) in their skin, thereby generating a protective response in the keratinocytes and modulating the disease. The absence of data on serum vitamin D precluded a confirmation of our findings. However, a previous study[1] on low vitamin D levels among North Indian PV strengthens our observations. Lacking data on VDR mediation in PV pathogenesis, we compared our healthy population data with that of the other studies and found concordance with Hasan et al.[4] and incongruity with Itu Singh et al.[5] A meta-analysis of FOK1 variations across different Indian populations indicates genetic evidence of disease susceptibility in different ethnicities.[6] In conclusion, our analysis highlights that “C” allele carriers are more susceptible to develop PV. Further studies can support this correlation if a corresponding decrease in Vitamin D levels is observed.
Table 1: Representative frequency distribution of FOK1 genotypes and alleles in Pemphigus vulgaris Patients and healthy controls

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Ethical clearance

The study has been approved by the Institute extramural ethics committee, PGIMER, Chandigarh, India (PGI/IEC/2013/P-400) dated 26/02/2013.


Special thanks to Prof. Sunil Dogra for valuable suggestions regarding the VDR-FOK1 SNPs in pemphigus and to Dr Neha Joshi for her technical support and valuable inputs during the study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Joshi N, Minz RW, Anand S, Parmar NV, Kanwar AJ. Vitamin D deficiency and lower TGF-β/IL-17 ratio in a North Indian cohort of pemphigus vulgaris. BMC Res Notes 2014;7:536.  Back to cited text no. 1
El-Komy MH, Samir N, Shaker OG. Estimation of vitamin D levels in patients with pemphigus vulgaris. J Eur Acad Dermatol Venereol 2014;28:859-63.  Back to cited text no. 2
Yamamoto C, Tamai K, Nakano H, Matsuzaki Y, Kaneko T, Sawamura D. Vitamin D3 inhibits expression of pemphigus vulgaris antigen desmoglein 3: Implication of a partial mechanism in the pharmacological effect of vitamin D3 on skin diseases. Mol Med Rep 2008;1:581-3.  Back to cited text no. 3
Hassan I, Bhat YJ, Majid S, Sajad P, Rasool F, Malik RA, et al. Association of vitamin D receptor gene polymorphisms and serum 25-Hydroxy vitamin D levels in vitiligo-a case-control study. Indian Dermatol Online J 2019;10:131-8.  Back to cited text no. 4
[PUBMED]  [Full text]  
Singh I, Lavania M, Pathak VK, Ahuja M, Turankar RP, Singh V, et al. VDR polymorphism, gene expression and vitamin D levels in leprosy patients from North Indian population. PLoS Negl Trop Dis 2018;12:e0006823.  Back to cited text no. 5
Bid HK, Mittal RD. Study of vitamin-D receptor (VDR) gene start codon polymorphism (Fok I) in healthy individuals from North India. Indian J Human Genet 2003;9;51-4.  Back to cited text no. 6


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