Photochemistry and Photobiology, 2016, 92: 355–359
Research Note
Actinic Prurigo in Singaporean Chinese: A Positive Association with
HLA-DRB1*03:01
Qiping Chen†,1, Meixin Shen†,2, Yee Kiat Heng1, Thiam Seng Colin Theng1, Hong Liang Tey1,
Ee Chee Ren2 and Wei-Sheng Chong*1
1
National Skin Center, Singapore, Singapore
2
Singapore Immunology Network, A*STAR, Singapore, Singapore
Received 14 November 2015, accepted 21 December 2015, DOI: 10.1111/php.12569
ABSTRACT
Studies have reported the association of human leukocyte
antigen (HLA) genes with susceptibility to develop actinic
prurigo (AP) in Caucasians, but there were no studies in
Asian populations, including the Chinese. Our study was per-
formed to determine if AP is associated with susceptibility or
protective HLA alleles or haplotypes in Singaporean Chinese.
All Chinese patients diagnosed with AP at National Skin
Center, Singapore, from January 2002 to April 2015 were
invited to participate in the study. Clinical data and pho-
totesting results were collated, and HLA typing was per-
formed. Among 14 patients included, 11 were male and the
mean age was 49.6 (37.9–61.3) years. All patients did not
have a family history of AP and none had mucosal involve-
ment, as such these clinical features differed from Caucasian
AP patients. The frequency of DRB1*03:01 in AP patients
was significantly higher compared to healthy controls (43%
vs 16%, P = 0.022, odds ratio (OR) 3.89). Concurrently, the
frequency of HLA-B*58:01-DRB1*03:01 haplotype was also
significantly increased (25% vs 7%, P = 0.004, OR 4.23). In
conclusion, HLA-DRB1*03:01 was associated with AP in Sin-
gaporean Chinese patients. This novel allelic association may
possibly be utilized as a biological marker to aid in the diag-
nosis of AP in Chinese patients.
INTRODUCTION
Actinic prurigo (AP) is an uncommon chronic pruritic photoder-
matosis characterized by intensely pruritic and usually excoriated
papules or nodules on the sun-exposed areas, predominantly
forearms, hands, face and neck, induced by ultraviolet (UV) radi-
ation, namely UVA and UVB. The eruption may extend to
involve the sun-covered areas, especially the buttocks, but
lesions in these areas are usually less severe. It is commonly
associated with mucosal involvement such as cheilitis and con-
junctivitis. In the Caucasian population, AP is generally of child-
hood onset, with female predominance (1). This condition is
found more frequently in Native American (Amerindian), the
Mestizo population and some Indian groups from Mexico, Gua-
*Corresponding author email: wschong@singnet.com.sg (Wei-Sheng Chong)
†Joint first authors.
© 2016 The American Society of Photobiology
355
temala, Honduras, Colombia, Bolivia and Peru, as well as in
some populations from Northwestern Europe (England, Ireland
and Scotland) (2–11).
Actinic prurigo is rare in Asians and is reported to have dif-
ferent clinical features from the West, such as late onset of the
disease and the relative lack of mucosal involvement (12,13).
The exact prevalence of AP in Asia remains unknown. It
accounts for only 5% of photodermatoses evaluated in the Photo-
dermatology Clinic at the National Skin Center (NSC), which is
a tertiary referral dermatology center in Singapore (14).
The diagnosis of AP can be difficult and its pathogenesis is
poorly understood. Multiple studies have reported the association
of human leukocyte antigen (HLA) genes with susceptibility to
develop AP and shown ethnic differences. There are known
associations with class II HLA alleles, in particular HLA-
DRB1*04:07 in the British (5,7,8) and Mexicans (11), DR3 in
South American and DRB1*14 in Canadian populations (9).
Associations with class I HLA alleles such as HLA-Cw*04,
A*24, A*28 and B*39 have also been reported (11). Despite
multiple reports of HLA association with AP in various popula-
tions, such an HLA association study has not been performed in
Asians. The objective of our study was to determine if AP was
associated with any susceptibility or protective HLA allele or
haplotype in our Asian population.
MATERIALS AND METHODS
Patient selection. Patients diagnosed with AP who attended the
Photodermatology Clinic at NSC from January 2002 to April 2015 were
considered for inclusion in our study. Patients who agreed to participate
in the study were re-evaluated based on history, physical examination
and clinical photographs by two independent consultant dermatologists
with expertise in photodermatology.
As Singapore comprises a predominant Chinese population, almost all
of our AP patients recruited were Chinese. Patients of other ethnic groups
were excluded as their numbers were too few to be of statistical signifi-
cance. A total of 14 AP patients of Chinese descent were recruited for
this study.
Clinical data. Clinical data and phototesting results were collated and
blood was drawn from patients for HLA typing. Control subjects were
randomly selected from a database of healthy individuals recruited in
Singapore, who consented to the use of their DNA for research. HLA
allele and haplotype frequencies of patients were compared with those of
130 healthy Chinese individuals. Single allele associations for HLA-A, -
356 Qiping Chen et al.

B and -DRB1 loci, as well as haplotype associations with different

combinations of these HLA loci were tested.
Phototesting was carried out using Supuvasun Mutzhas 3000
high-pressure metal-halide source (spectral output 350–450 nm, peak
370–385 nm) (Munich, Germany) for UVA, Dermaray M-DMR-100
bank of seven fluorescent bulbs (FL20S E-30/DMR 305 nm, emission
spectrum 290–390 nm, peak 305 nm) (Eisai, Japan) for UVB and Kin-
dermann slide projector equipped with a 150 W light bulb (Ochsenfurt,
Germany) for visible light. The patients’ buttocks were exposed to incre-
mental doses of UV radiation. The minimal erythema dose (MED)
responses for UVA and UVB were read at 24 h and the lowest dose to
achieve “just perceptible erythema” was taken as the MED.
DNA processing and HLA genotyping. DNA was extracted from
blood using the DNeasy Blood and Tissue Kit (Qiagen) according to
manufacturer’s instructions. Sequence-based typing (SBT) was employed
to genotype all cases and population controls at three HLA loci, namely
HLA-A, -B and -DRB1 (15,16). Briefly, HLA loci were amplified using
locus-specific primers on a thermal cycler (Applied Biosystems), and
then electrophoresed on a 2% agarose gel. Amplified products were Figure 1. Multiple prurigo nodules on the nape of neck.
excised and purified using QIAquick Gel Extraction Kit (Qiagen). Cycle
sequencing of amplified HLA loci was performed using the BigDye
Terminator Cycle Sequencing Kit (version 3.1; Applied Biosystems) and
analyzed using capillary electrophoresis (ABI Prism 3130xl Genetic
Analyzer; Applied Biosystems). Electropherograms generated were
analyzed and assigned HLA genotypes with SBTengine (GenDx).
All HLA loci in controls were evaluated for Hardy–Weinberg equilib-
rium (HWE) using the Hardy–Weinberg equilibrium test (HWE.test)
implemented in the Population Genetics package (version 1.3.8) in R
(17). All HLA-A, -B and -DRB1 loci were in HWE (P > 0.05).
Statistical analysis: single locus analyses. All statistical analyses were
conducted in RStudio (version 0.99) running R (version 3.2.0). Single
locus analyses were carried out using the “glm” function in the R base
package. The association between AP and single HLA alleles were tested
using unconditional logistic regression models, where HLA alleles were
recoded as a series of binary variables, and the allelic status at the
analyzed HLA locus was set as independent predictor variables. Odds
ratios were calculated from these regression models for all statistically
significant HLA alleles. The statistical significance of each allelic
association was evaluated by the likelihood ratio test (implemented in the
“lmtest” package, version 0.9), and used to compare the regression
coefficients between the full model containing the HLA allele to the Figure 2. Multiple prurigo nodules on the extensor aspect of bilateral
submodel excluding the same allele (18). forearms and hands.
Statistical analysis: haplotype analysis. Two- and three-locus
haplotype analyses were conducted using the haplo.stats package (version
1.6) in R (19). For all haplotype trend regression analyses, we tested two
regression models (additive or dominant) for all two- and three-haplotype Association between HLA-DRB1*03:01 and AP
combinations using the “haplo.glm” function. These regression models
were subsequently assessed using ANOVA from the R Stats package, Single allele analysis showed that HLA-DRB1*03:01 was the
and the additive model with the better fit was applied to the “haplo.cc” allele most strongly associated with AP among all the three loci,
function. In these analyses, the most frequent haplotype that was not the with its genotype frequency significantly increased in the patient
at-risk haplotype was used at the baseline to calculate the P-values group as compared to healthy controls (43% vs 16% respectively,
associated with specific haplotypes, and the odds ratio was computed
using Fisher’s exact test. A P-value of less than 0.05 indicated statistical P = 0.022) with an odds ratio (OR) of 3.89. The second allele
significance for all estimates. most significantly associated with AP was HLA-B*58:01 (43%
vs 18% respectively, P = 0.034, OR 3.49) (Table 1).
Aside from single allele association, the HLA haplotype anal-
RESULTS ysis showed that HLA haplotypes A*33:03-B*58:01, B*58:01-
DRB1*03:01 and A*33:03-B*58:01-DRB1*03:01 were associ-
Patient demographics and clinical characteristics ated with AP. The association of the B*58:01-DRB1*03:01 hap-
Among the 14 Chinese patients analyzed, all were of Fitzpatrick lotype was the strongest, with its frequency significantly
skin phototype III-IV, and the cohort comprised 11 males and increased in the patient group as compared to healthy controls
three females, with a mean age of 49.6 (37.9–61.3) years. The (25% vs 7% respectively, P = 0.004, OR 4.23). There was also
mean age of onset of AP was 42.9 (32.0–53.8) years. The most another significant association with A*33:03-B*58:01 haplotype
commonly affected areas were the forearms, hands, face, ears (21% vs 9%, P = 0.046, OR 2.81). The extended A*33:03-
and neck (Figs. 1 and 2). None of these patients had a family B*58:01-DRB1*03:01 haplotype was more frequently observed
history of AP or had mucosal involvement, such as cheilitis or in patients than the control group (21% vs 7%, P = 0.015, OR
conjunctivitis. Phototesting revealed reduced MED to UVA and/ 3.67) (Table 2), even though A*33:03, as a single allele, was not
or UVB in eight patients (57.1%) with six patients (42.9%) hav- significantly associated with AP (Table 3). We also investigated
ing normal MED. if any HLA allele was negatively associated with AP, but no
such AP protective allele was identified in our study (Table 3).
 Photochemistry and Photobiology, 2016, 92 357

Table 1. Human leukocyte antigen (HLA) alleles associated with actinic prurigo in the Singaporean Chinese.
Cases (n = 14) Controls (n = 130) Odds ratio
Regression analysis Likelihood ratio test
HLA allele Count Frequency Count Frequency P-value OR 2.5% 95.5% P-value

B*58:01 6 0.43 23 0.18 0.034* 3.49 1.06 11.02 0.040*

DRB1*03:01 6 0.43 21 0.16 0.022* 3.89 1.18 12.39 0.027*
DRB1*15:02 2 0.14 3 0.02 0.043* 7.06 0.87 46.80 0.065NS

*Significant. NS, not significant; OR, odds ratio.

Table 2. Human leukocyte antigen (HLA) haplotypes associated with actinic prurigo in the Singaporean Chinese.
Cases (2n = 28) Controls (2n = 260) Odds ratio†
Regression analysis
HLA haplotype Count Frequency Count Frequency P-value OR 2.5% 95.5%

A*33:03-B*58:01 6 0.21 23 0.09 0.046* 2.81 1.04 7.63

B*58:01-DRB1*03:01 7 0.25 19 0.07 0.004* 4.23 1.60 11.21
A*33:03-B*58:01-DRB1*03:01 6 0.21 18 0.07 0.015* 3.67 1.32 10.19

*Significant. †Odds ratio calculated using Fisher’s exact test. OR, odds ratio.

Table 3. Human leukocyte antigen (HLA) alleles not associated with betes mellitus (T1D) and systemic lupus erythematosus (SLE)
actinic prurigo in the Singaporean Chinese. (20–22). Notably, HLA-DRB1*03:01 is a risk allele for T1D and
Genotype frequency SLE (21,22). In addition, DRB1*03:01 was the strongest genetic
modifier influencing disease severity in type 1 autoimmune hep-
HLA allele Cases (n = 14) Controls (n = 130) P-value atitis among the Dutch population (23).
Human leukocyte antigen associations with AP in various
A*02:01 7.1 18.5 0.31
A*02:07 21.4 20.8 0.95 populations have been reported within the MHC class II region.
A*11:01 71.4 43.1 0.05 DR3 and DRB1*14 were described as susceptibility alleles in
A*24:02 28.6 23.1 0.65 South American and Canadian populations, respectively (9).
A*24:07 7.1 1.5 0.21 Studies on AP in British, Mexican and Colombian populations,
A*31:01 7.1 5.4 0.79
A*33:03 42.9 26.2 0.19 found DRB1*04:07 at high frequencies in their patient cohorts,
B*13:01 14.3 14.6 0.97 in contrast to our current study where the strongest association
B*15:01 21.4 6.2 0.06 was with DRB1*03:01 (5,10,11). Although the strongest HLA
B*15:02 14.3 10.8 0.69 association described in previous studies was with HLA-
B*35:05 7.1 0.8 0.11
DRB1*04:07, we did not observe any patients or controls with
B*39:01 7.1 5.4 0.79
B*40:01 21.4 31.5 0.44 this allele in our study. This might be attributed to the extremely
B*40:06 7.1 4.6 0.68 low allele frequency of HLA-DRB1*04:07 in Chinese popula-
B*46:01 28.6 25.4 0.80 tions (0–0.01%) (24). Nevertheless, our data were in general
B*51:01 14.3 7.7 0.41 agreement with the current literature and understanding that the
B*51:02 7.1 1.5 0.21
B*54:01 7.1 3.1 0.44 HLA-DRB1 region was associated with AP risk. However, this
DRB1*04:05 7.1 12.3 0.58 is the first time that an Asian population comprising Chinese has
DRB1*04:06 7.1 4.6 0.68 been studied, with a novel finding of a different allele,
DRB1*08:02 7.1 2.3 0.32 DRB1*03:01, that is significantly associated with AP in this pop-
DRB1*08:03 21.4 16.9 0.67
ulation.
DRB1*09:01 21.4 26.9 0.66
DRB1*11:01 7.1 11.5 0.62 In addition, the association with MHC class I HLA alleles such
DRB1*12:02 21.4 21.5 0.99 as HLA-Cw*04 has also been reported in Colombian Amerindian
DRB1*14:01 7.1 6.2 0.89 group; A*28 and B*39 alleles were reported to be associated with
DRB1*15:01 7.1 16.2 0.39 AP in Mexican patients (10). However, there have been no
DRB1*16:02 14.3 13.1 0.90
reports of any association of B*58:01 with AP to date. The most
significant role of B*58:01 in skin disorders is its strong associa-
tion with allopurinol-induced severe cutaneous adverse reactions
in Han Chinese patients (25). Our study is the first report of
B*58:01 association with AP, albeit not as strongly as
DISCUSSION
DRB1*03:01. The existence of a B*58:01-DRB1*03:01 haplo-
HLA-DRB1 is a member of the major histocompatibility com- type association in our Chinese cohort suggests a broader suscep-
plex (MHC) class II gene family, whose traditional role in the tibility region within chromosome 6p21.3 where both HLA-
immune system involves presenting exogenous antigens as part DRB1 and HLA-B reside. Similarly, the existence of a B*39-
of immunosurveillance. It is a susceptibility locus for several DRB1*04:07 haplotype association in AP has been found in
autoimmune diseases such as rheumatoid arthritis, type 1 dia- Mexican Mestizo patients (11). This might imply a pathogenic
358 Qiping Chen et al.
role of both MHC classes I and II HLA alleles in the develop-
ment of AP, and possibly other genes located between these two
genes, such as tumor necrosis factor and heat-shock proteins, that
could contribute to the pathogenesis of AP (10). Such HLA types
in AP might determine the actual response to a peptide antigen,
conceivably one induced by UV radiation, to initiate the charac-
teristic AP cutaneous response (5). We also postulate that the
association of HLA-B*58:01 with AP in our study could also be
due to its strong linkage with DRB1*03:01 in the Chinese popu-
lation. Interestingly, the linkage of B*58:01 and DRB1*03:01,
and A*33:03-B*58:01-DRB1*03:01 are well preserved in the
Chinese population (24,26).
The cases of AP in our Chinese cohort were adult-onset, with
male predominance and a lack of family history. Mucosal
involvement was not a feature. These clinical characteristics con-
trast with those of Caucasian populations, and have been dis-
cussed in a previous study from Singapore (12). This is the first
report of the association of HLA-DRB1*03:01 with AP in Chi-
nese patients. HLA-DRB1*03:01 could be a marker of the dis-
ease in this group of patients and could also potentially serve as
a useful diagnostic tool especially in cases of AP presenting with
atypical clinical features. On the other hand, the question of
whether HLA-DRB1*03:01 or the B*58:01-DRB1*03:01 haplo-
type is directly linked pathogenically to the unique clinical pre-
sentation of AP in our cohort remains, although either or both
might have an important role in determining expression of this
disease. Further studies involving a larger number of Chinese
patients are needed to validate such an association and to deter-
mine if such HLA typing can be used eventually as a diagnostic
aid for AP in Chinese.
CONCLUSION
Our study showed an association between AP and HLA-
DRB1*03:01 allele. It might indicate a role of HLA-
DRB1*03:01 in the pathogenesis of AP in the Singaporean
Chinese. The novel HLA-DRB1*03:01 allelic association could
explain a distinct immuno-pathogenic pathway in such patients,
and the possibility that such an association plays a role in
determining a distinctly different phenotype of AP cannot be
entirely excluded. As such, HLA-DRB1*03:01 could be used
potentially as a biological tool to aid in the diagnosis of AP
in Chinese. In addition, there was also a significant association
of AP with HLA-B*58:01-DRB1*03:01 haplotype, which was
well preserved in the Chinese, suggesting a more comprehen-
sive susceptibility region within the MHC regions on chromo-
some 6.
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