Introduction: Vitiligo is a common depigmentation disorder characterized by defined white patches on the skin and affecting around 0.5% to 2% of the general population. Genetic association studies have identified several pre-disposing genes and single nucleotide polymorphisms (SNPs) for vitiligo pathogenesis; nonetheless, the reports are often conflicting and rarely conclusive. This comprehensive meta-analysis study was designed to evaluate the effect of the risk variants on vitiligo aetiology and covariate stratified vitiligo risk in the Asian population, considering all the studies published so far. Methods: We followed a systematic and comprehensive search to identify the relevant vitiligo-related candidate gene association studies in PubMed using specific keywords. After data extraction, we calculated, for the variants involved, the study-level unadjusted odds ratio, standard errors, and 95% confidence intervals by using logistic regression with additive, dominant effect, and recessive models using R software package (R, 3.4.2) “metafor.” Subgroup analysis was performed using logistic regression (generalized linear model; “glm”) of disease status on subgroup-specific genotype counts. For a better understanding of the likely biological function of vitiligo-associated variant obtained through the meta-analysis, in silico functional analyses, through standard publicly available web tools, were also conducted. Results: Thirty-one vitiligo-associated case-control studies on eleven SNPs were analysed in our study. In the fixed-effect meta-analysis, one variant upstream of TNF-α gene: rs1800629 was found to be associated with vitiligo risk in the additive (p = 4.26E−06), dominant (p = 1.65E−7), and recessive (p = 0.000453) models. After Benjamini-Hochberg false discovery rate (FDR) correction, rs1800629/TNF-α was found to be significant at 5% FDR in the dominant (padj = 1.82E−6) and recessive models (padj = 0.0049). In silico characterization revealed the prioritized variant to be regulatory in nature and thus having potential to contribute towards vitiligo pathogenesis. Conclusion: Our study constitutes the first comprehensive meta-analysis of candidate gene-based association studies reported in the whole of the Asian population, followed by an in silico analysis of the vitiligo-associated variant. According to the findings of our study, TNF-α single nucleotide variant rs1800629G>A has a risk association, potentially contributing to vitiligo pathogenesis in the Asian population.

1.
Majumder
S
,
Singha
B
,
Sarkar
A
,
Adhicari
P
.
Clinico-epidemiological profile of childhood vitiligo: experience from a tertiary care center of Northeast India
.
Asian J Med Sci
.
2022
;
13
(
12
):
203
7
. .
2.
Liu
J
,
Tang
R
,
Xiao
Y
,
Luo
M
,
Shi
Y
,
Deng
Q
, et al
.
Meta-analytic review of high anxiety comorbidity among patients with vitiligo
.
BioMed Res Int
.
2021
;
2021
:
6663646
. .
3.
Sarma
N
,
Chakraborty
S
,
Poojary
S
,
Shashi Kumar
BM
,
Gupta
LK
,
Budamakuntla
L
, et al
.
A nationwide, multicentric case-control study on vitiligo (MEDEC-V) to elicit the magnitude and correlates
.
Indian J Dermatol
.
2020
;
65
(
6
):
473
82
. .
4.
Kim
HJ
,
Ahn
HS
,
Kazmi
SZ
,
Kang
T
,
Kim
HS
,
Kang
MJ
, et al
.
Familial risk of vitiligo among first-degree relatives and spouses: a population-based cohort study in Korea
.
J Invest Dermatol
.
2021
;
141
(
4
):
921
4.e3
. .
5.
Mohr
N
,
Petersen
J
,
Kirsten
N
,
Augustin
M
.
Epidemiology of vitiligo: a dual population-based approach
.
Clin Epidemiol
.
2021
;
13
:
373
82
. .
6.
Ezzedine
K
,
Lim
H
,
Suzuki
T
,
Katayama
I
,
Hamvazi
I
,
Lan
C
, et al
.
Issues : the vitiligo global issues consensus conference
.
Pigment Cell Melanoma Rseearch
.
2013
;
25
(
3
):
1
28
.
7.
Dutta
T
,
Mitra
S
,
Saha
A
,
Ganguly
K
,
Pyne
T
,
Sengupta
M
.
A comprehensive meta-analysis and prioritization study to identify vitiligo associated coding and non-coding SNV candidates using web-based bioinformatics tools
.
Sci Rep
.
2022
;
12
(
1
):
14543
12
. .
8.
Sun
MC
,
Xu
XL
,
Lou
XF
,
Du
YZ
.
Recent progress and future directions: the nano-drug delivery system for the treatment of vitiligo
.
Int J Nanomedicine
.
2020
;
15
:
3267
79
. .
9.
Silverberg
JI
,
Silverberg
NB
.
Association between vitiligo and atopic disorders: a pilot study
.
JAMA Dermatol
.
2013
;
149
(
8
):
983
6
. .
10.
Liu
CY
,
Tung
TH
,
Lee
CY
,
Chang
KH
,
Wang
SH
,
Chi
CC
.
Association of multiple sclerosis with psoriasis: a systematic review and meta-analysis of observational studies
.
Am J Clin Dermatol
.
2019
;
20
(
2
):
201
8
. .
11.
Marrie
RA
,
Cohen
J
,
Stuve
O
,
Trojano
M
,
Sørensen
PS
,
Reingold
S
, et al
.
A systematic review of the incidence and prevalence of comorbidity in multiple sclerosis: overview
.
Mult Scler
.
2015
;
21
(
3
):
263
81
. .
12.
Avalos-Díaz
E
,
Pérez-Pérez
E
,
Rodríguez-Rodríguez
M
,
Pacheco-Tovar
MG
,
Herrera-Esparza
R
.
Autoimmune vitiligo in rheumatic disease in the Mestizo Mexican population
.
Biomed Rep
.
2016
;
5
(
2
):
176
80
. .
13.
Franks
AL
,
Slansky
JE
.
Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer
.
Anticancer Res
.
2012
;
32
(
4
):
1119
36
.
14.
Asilian
A
,
Momeni
I
,
Khosravani
P
.
Vitiligo associated with esophageal adenocarcinoma
.
Int J Prev Med
.
2013
;
4
(
4
):
489
90
.
15.
Roberts
GHL
,
Santorico
SA
,
Spritz
RA
,
Genetics
M
,
Program
G
,
Medical
A
.
The genetic architecture of vitiligo
.
HHS Public Access
.
2020
;
33
(
1
):
8
15
. .
16.
Zhang
Z
,
Xiang
LF
.
Genetic susceptibility to vitiligo: recent progress from genome-wide association studies
.
Dermatologica Sin
.
2014
;
32
(
4
):
225
32
. .
17.
Tang
XF
,
Zhang
Z
,
Hu
DY
,
Xu
AE
,
Zhou
HS
,
Sun
LD
, et al
.
Association analyses identify three susceptibility loci for vitiligo in the Chinese han population
.
J Invest Dermatol
.
2013
;
133
(
2
):
403
10
. .
18.
Saumya
P
,
Shyam
V
.
The menace of dermatophytosis in India: the evidence that we need
.
Indian J Dermatol Venereol Leprol
.
2018
;
84
(
1
):
6
15
. .
19.
Srivastava
DSL
,
Mittal
RD
.
Genetic polymorphism of the N-acetyltransferase 2 gene, and susceptibility to prostate cancer: a pilot study in north Indian population
.
BMC Urol
.
2005
;
5
:
12
6
. .
20.
Vatsis
KP
,
Weber
WW
,
Bell
DA
,
Dupret
JM
,
Evans
DAP
,
Grant
DM
, et al
.
Nomenclature for N-acetyltransferases
.
Pharmacogenetics
.
1995
;
5
(
1
):
1
17
. .
21.
Ahmed
R
,
Sharif
D
,
Jaf
M
,
Amin
DM
.
Effect of tnf-α −308g/a (Rs1800629) promoter polymorphism on the serum level of tnf-α among iraqi patients with generalized vitiligo
.
Clin Cosmet Investig Dermatol
.
2020
;
13
:
825
35
. .
22.
Alkhateeb
A
,
Qarqaz
F
,
Al-Sabah
J
,
Al Rashaideh
T
.
Clinical characteristics and PTPN22 1858CT variant analysis in jordanian arab vitiligo patients
.
Mol Diagn Ther
.
2010
;
14
(
3
):
179
84
. .
23.
Birlea
SA
,
Jin
Y
,
Bennett
DC
,
Herbstman
DM
,
Wallace
MR
,
McCormack
WT
, et al
.
Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP
.
J Invest Dermatol
.
2011
;
131
(
2
):
371
81
. .
24.
Viechtbauer
W
.
Conducting meta-analyses inRwith themetaforPackage
.
J Stat Softw
.
2010
;
36
(
3
):
1
48
. .
25.
Borenstein
M
,
Hedges
LV
,
Higgins
JPT
,
Rothstein
HR
.
A basic introduction to fixed-effect and random-effects models for meta-analysis
.
Res Synth Methods
.
2010
;
1
(
2
):
97
111
. .
26.
Noble
WS
.
How does multiple testing correction work
.
Nat Biotechnol
.
2009
;
27
(
12
):
1135
7
. .
27.
Huedo-Medina
TB
,
Sánchez-Meca
J
,
Marín-Martínez
F
,
Botella
J
.
Assessing heterogeneity in meta-analysis: Q statistic or I 2 Index
.
Psychol Methods
.
2006
;
11
(
2
):
193
206
. .
28.
Jiang
Y
,
Zhang
R
,
Zheng
J
,
Liu
P
,
Tang
G
,
Lv
H
, et al
.
Meta-analysis of 125 rheumatoid arthritis-related single nucleotide polymorphisms studied in the past two decades
.
PLoS One
.
2012
;
7
(
12
):
e51571
8
. .
29.
Sterne
JAEM
,
Egger
M
.
Funnel plots for detecting bias in meta-analysis: guidelines on choice. of axis
.
J Clin Epidemiol
.
2001
;
54
(
10
):
1046
55
. .
30.
Laddha
NC
,
Dwivedi
M
,
Begum
R
.
Increased Tumor Necrosis Factor (TNF)-α and its promoter polymorphisms correlate with disease progression and higher susceptibility towards vitiligo
.
PLoS One
.
2012
;
7
(
12
):
e52298
. .
31.
Prashant
S
.
Giri a, Rasheedunnisa Begum b MD. Meta-analysis for association of TNFA-308(G > A) SNP with vitiligo susceptibility
.
Gene
.
2022
;
809
:
146027
. .
32.
Gianfaldoni
S
,
Tchernev
G
,
Wollina
U
,
Lotti
J
,
Satolli
F
,
França
K
, et al
.
Vitiligo in children: a better understanding of the disease
.
Open Access Maced J Med Sci
.
2018
;
6
(
1
):
181
4
. .
33.
An
I
,
Harman
M
,
Ibiloglu
I
.
Topical ciclopirox olamine 1%: revisiting a unique antifungal
.
Indian Dermatol Online J
.
2017
;
10
(
4
):
481
5
. .
34.
Baldini
E
,
Odorisio
T
,
Sorrenti
S
,
Catania
A
,
Tartaglia
F
,
Carbotta
G
, et al
.
Vitiligo and autoimmune thyroid disorders
.
Front Endocrinol
.
2017
;
8
(
OCT
):
290
6
. .
35.
Stanca A. Birlea1, 2, Greggory S. LaBerge1, Lucia M. Procopciuc3, Pamela R. Fain1, 4, 5 A, Richard A. Spritz1 5. No Title. Pigment Cell Melanoma Res.
36.
Jang
DI
,
Lee
AH
,
Shin
HY
,
Song
HR
,
Park
JH
,
Kang
TB
, et al
.
The role of tumor necrosis factor alpha (Tnf-α) in autoimmune disease and current tnf-α inhibitors in therapeutics
.
Int J Mol Sci
.
2021
;
22
(
5
):
2719
6
. .
37.
Aydıngöz
İE
,
Bingül
I
,
Doǧru-Abbasoǧlu
S
,
Vural
P
,
Uysal
M
.
Analysis of vitamin D receptor gene polymorphisms in vitiligo
.
Dermatology
.
2012
;
224
(
4
):
361
8
. .
38.
Wei
C
,
Jian
Z
,
Wang
L
,
Qiang
H
,
Shi
Q
,
Guo
S
, et al
.
Genetic variants of the APE1 gene and the risk of vitiligo in a Chinese population: a genotype-phenotype correlation study
.
Free Radic Biol Med
.
2013
;
58
:
64
72
. .
39.
Basher
NS
,
Malik
A
,
Aldakheel
F
,
Chaudhary
AA
,
Rudayni
HA
,
Alkholief
M
, et al
.
Deleterious effect of angiotensin-converting enzyme gene polymorphism in vitiligo patients
.
Saudi J Biol Sci
.
2021
;
28
(
8
):
4478
83
. .
40.
Lyu
C
,
Sun
Y
.
Immunometabolism in the pathogenesis of vitiligo
.
Front Immunol
.
2022
;
13
:
1055958
11
. .
41.
Khashim Alswailmi
F
,
Shah
SIA
,
Nawaz
H
,
Al-Mazaideh
GM
.
Molecular mechanisms of vitamin D-mediated immunomodulation
.
Galen Med J
.
2021
;
10
:
e2097
. .
42.
Yan
Q
,
Zhang
B
,
Ling
X
,
Zhu
B
,
Mei
S
,
Yang
H
, et al
.
CTLA-4 facilitates DNA damage: induced apoptosis by interacting with PP2A
.
Front Cell Dev Biol
.
2022
;
10
:
728771
. .
43.
Tian
J
,
Wang
Y
,
Ding
M
,
Zhang
Y
,
Chi
J
,
Wang
T
, et al
.
The Formation of melanocyte apoptotic bodies in vitiligo and the relocation of vitiligo autoantigens under oxidative stress
.
Oxid Med Cell Longev
.
2021
;
2021
:
7617839
. .
44.
Boniface
K
,
Seneschal
J
.
Vitiligo as a skin memory disease: the need for early intervention with immunomodulating agents and a maintenance therapy to target resident memory T cells
.
Exp Dermatol
.
2019
;
28
(
6
):
656
61
. .
45.
Namazi
MR
,
Rouhani
S
,
Moarref
A
,
Kiani
M
,
Tabei
SS
,
Hadibarhaghtalab
M
.
Vitiligo and rise in blood pressure: a case–control study in a referral dermatology clinic in southern Iran
.
Clin Cosmet Investig Dermatol
.
2020
;
13
:
425
30
. .
46.
Singh
M
,
Mansuri
MS
,
Kadam
A
,
Palit
SP
,
Dwivedi
M
,
Laddha
NC
, et al
.
Tumor Necrosis Factor-alpha affects melanocyte survival and melanin synthesis via multiple pathways in vitiligo
.
Cytokine
.
2021
;
140
:
155432
. .
47.
Connor
TJ
,
Brewer
C
,
Kelly
JP
,
Harkin
A
.
Acute stress suppresses pro-inflammatory cytokines TNF-alpha and IL-1 beta independent of a catecholamine-driven increase in IL-10 production
.
J Neuroimmunol
.
2005
;
159
(
1–2
):
119
28
. .
48.
Webb
KC
,
Tung
R
,
Winterfield
LS
,
Gottlieb
AB
,
Eby
JM
,
Henning
SW
, et al
.
Tumour necrosis factor-α inhibition can stabilize disease in progressive vitiligo
.
Br J Dermatol
.
2015
;
173
(
3
):
641
50
. .
49.
Pierini
A
,
Strober
W
,
Moffett
C
,
Baker
J
,
Nishikii
H
,
Alvarez
M
, et al
.
TNF-α priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment
.
Blood
.
2016
;
128
(
6
):
866
71
. .
50.
Fu
C
,
Chen
J
,
Lu
J
,
Yi
L
,
Tong
X
,
Kang
L
, et al
.
Roles of inflammation factors in melanogenesis (Review)
.
Mol Med Rep
.
2020
;
21
(
3
):
1421
30
. .
51.
Yazici
AC
,
Erdal
ME
,
Kaya
TI
,
Ikizoglu
G
,
Savasoglu
K
,
Camdeviren
H
, et al
.
Lack of association with TNF-alpha-308 promoter polymorphism in patients with vitiligo
.
Arch Dermatol Res
.
2006
;
298
(
1
):
46
9
. .
52.
Rajendiran
KS
,
Rajappa
M
,
Chandrashekar
L
,
Thappa
DM
,
Devaraju
P
.
Association analysis of tumor necrosis factor alpha promoter polymorphisms and vitiligo susceptibility in South Indian Tamils
.
Dermatology
.
2020
;
236
(
6
):
554
64
. .
53.
Namian
AM
,
Shahbaz
S
,
Salmanpoor
R
,
Namazi
MR
,
Dehghani
F
,
Kamali-Sarvestani
E
.
Association of interferon-gamma and tumor necrosis factor alpha polymorphisms with susceptibility to vitiligo in Iranian patients
.
Arch Dermatol Res
.
2009
;
301
(
1
):
21
5
. .
54.
Al-Harthi
F
,
Zouman
A
,
Arfin
M
,
Tariq
M
,
Al-Asmari
A
.
Tumor necrosis factor-α and -β genetic polymorphisms as a risk factor in Saudi patients with vitiligo
.
Genet Mol Res
.
2013
;
12
(
3
):
2196
204
. .
55.
Salinas-Santander
M
,
Díaz-García
D
,
Rojas-Martínez
A
,
Cantú-Salinas
C
,
Sánchez-Domínguez
C
,
Reyes-López
M
, et al
.
Tumor necrosis factor-α -308G/A polymorphism is associated with active vitiligo vulgaris in a northeastern Mexican population
.
Exp Ther Med
.
2012
;
3
(
5
):
893
7
. .
56.
El-Raheem
TA
,
Mahmoud
RH
,
Hefzy
EM
,
Masoud
M
,
Ismail
R
,
Aboraia
NMM
.
Tumor Necrosis Factor (TNF)-α- 308 G/A gene polymorphism (rs1800629) in Egyptian patients with alopecia areata and vitiligo, a laboratory and in silico analysis
.
PLoS One
.
2020
;
15
(
12
):
e0240221
. .
57.
Aydingöz
IE
,
Kanmaz-Özer
M
,
Gedikbaşi
A
,
Vural
P
,
Doğru-Abbasoğlu
S
,
Uysal
M
.
The combination of tumour necrosis factor-α -308A and interleukin-10 -1082G gene polymorphisms and increased serum levels of related cytokines: susceptibility to vitiligo
.
Clin Exp Dermatol
.
2015
;
40
(
1
):
71
7
. .
58.
Wu
D
,
Shi
D
,
Zhu
X
.
The association between tumor necrosis factor-α-308 G/A polymorphism and risk for vitiligo: a meta-analysis
.
Int J Dermatol
.
2015
;
54
(
9
):
1045
53
. .
59.
Nie
G
,
Qi
JH
,
Huang
CW
,
Yang
T
,
Shi
N
,
Chen
YJ
.
Meta-analysis of the TNF-α-308G/A polymorphism and vitiligo risk
.
Genet Mol Res
.
2015
;
14
(
4
):
17296
304
. .
60.
Odeh
AMA
,
Bulatova
NR
,
Yousef
AF
.
Genetic association of TNF- alpha polymorphisms with generalized vitiligo in Jordanian population
.
J Genet Disord Genet Med
.
2019
;
3
(
1
):
1
4
.
61.
Singh
S
,
Singh
U
,
Pandey
SS
.
Serum concentration of IL-6, IL-2, TNF-α, and IFNγ in Vitiligo patients
.
Indian J Dermatol
.
2012
;
57
(
1
):
12
4
. .
62.
Liu
X
,
Zhang
Y
,
Wang
Z
,
Liu
L
,
Zhang
G
,
Li
J
, et al
.
PRRC2A promotes hepatocellular carcinoma progression and associates with immune infiltration
.
J Hepatocell Carcinoma
.
2021
;
8
:
1495
511
. .
63.
Wang
M
,
Liao
J
,
Wang
J
,
Qi
M
,
Wang
K
,
Wu
W
.
TAF1A and ZBTB41 serve as novel key genes in cervical cancer identified by integrated approaches
.
Cancer Gene Ther
.
2021
;
28
(
12
):
1298
311
. .
64.
Konsta
OD
,
Le Dantec
C
,
Charras
A
,
Brooks
WH
,
Arleevskaya
MI
,
Bordron
A
, et al
.
An in silico approach reveals associations between genetic and epigenetic factors within regulatory elements in B cells from primary Sjögren’s syndrome patients
.
Front Immunol
.
2015
;
6
(
AUG
):
1
9
. .
65.
Lin
X
,
Deng
FY
,
Lu
X
,
Lei
SF
.
Susceptibility genes for multiple sclerosis identified in a gene-based genome-wide association study
.
J Clin Neurol
.
2015
;
11
(
4
):
311
8
. .
66.
Verhagen
F
,
Kuiper
J
,
Nierkens
S
,
Imhof
SM
,
Radstake
T
,
de Boer
J
.
Systemic inflammatory immune signatures in a patient with CRB1 linked retinal dystrophy
.
Expert Rev Clin Immunol
.
2016
;
12
(
12
):
1359
62
. .
67.
Wang
SH
,
Yang
GH
,
Nie
JW
,
Wang
J
,
Wang
YX
,
Du
MZ
, et al
.
Immunization with recombinant Erns-LTB fusion protein elicits protective immune responses against bovine viral diarrhea virus
.
Vet Microbiol
.
2021
;
259
:
109084
. .
68.
Giri
PS
,
Begum
R
,
Dwivedi
M
.
Meta-analysis for association of TNFA-308(G > A) SNP with vitiligo susceptibility
.
Gene
.
2022
;
809
:
146027
. .
You do not currently have access to this content.