ARTICLE
Auteur(s) :, Claudia Bueno Cardoso1, Ana Maria
Uthida-Tanaka2, Renata Ferreira Magalhães2,
Luiz Alberto Magna3, Maria Helena Stangler
Kraemer1,*
1Department of Clinical Pathology, School of Medical
Sciences, State University of Campinas (UNICAMP), Rua Gustavo
Rodrigues Dória, 255, CEP 13083-060 Campinas – SP BrazilFax:
(+55-19) 3788 9934.
2Department of Dermatology, School of Medical Sciences,
State University of Campinas, Brazil
3Medical Genetics Department, School of Medical
Sciences, State University of Campinas, Brazil
accepté le 3 Janvier 2005
Psoriasis is a common, relapsing skin disorder of unknown cause,
which is considered to be multifactorial and genetically determined
[1]. It is clinically characterized as epidermal
hyperproliferation, abnormal keratinocyte differentiation and
inflammation (dermatosis), resulting from the infiltration of
activated T helper cells and mononuclear cells into the dermis and
epidermis, as well as by release of proinflammatory cytokines
[2-4]. Although the pathogenesis of psoriasis remains elusive, it
has recently been understood as an immunologically T cell-mediated
disease, possibly autoimmune in nature [5]. The clinical phenotype
of psoriasis vulgaris, including chronic plaque lesions, affects
90% of the adult patients. Its prevalence is between 1% and 2% of
the population in Europe and North America but it is relatively
rare among Blacks, Japanese and South Americans, absent in Eskimos
and rare in Native American Indians [6]. Psoriasis affects
approximately 3 million individuals in the Brazilian population,
although the prevalence rate of the disease has not been precisely
determined and is probably between 2% and 3%.The genetic background
of the disease, well defined but complex, has been intensively
investigated in thousands of patients and matched controls,
including hundreds of families of psoriasis patients and hundreds
of twins [4, 7, 8]. It is probably polygenic and despite
considerable research effort the genetics of psoriasis remain
unclear, with the genes involved located on several chromosomes.
Furthermore, its strongest genetic association is with the HLA
class I and class II genes on 6p21, which seem to play a role in
disease susceptibility [9, 10]. The onset of the disease may be
related to activation of TCD4+ cells and their continued activation
through TCD8+ cells, providing a link with the association between
MHC class I and class II [11].The association of PsV with HLA
antigen was first described in 1972 [12]; in 1980 the association
of psoriasis with HLA class I alleles was demonstrated, with
HLA-Cw6 as the most highly associated allele [13]. Further evidence
of linkage of psoriasis to HLA-DRB – DQB alleles was provided by a
variety of results in different populations; the haplotypes
HLA-Cw6, HLA-B13, HLA-B57, DRB1*0701/*02 and -DQB1*0303 [14] have
been described in association with psoriasis in different
populations from Europe, Japan, Israel and Brazil.Our previous
studies were based on serological assignment of HLA class I and
class II antigens, and we investigated the association of HLA class
I and class II alleles with early-onset psoriasis in patients from
Campinas (Brazil), compared with the control population [15].In
this study, we used the polymerase chain reaction (PCR) –
sequence-specific primers (SSP) method. This typing has proved to
be sensitive and specific for medium and high-resolution and we
carried out PCR/SSP typing for class II -HLA-DRB1/B3/B4/B5 and
-DQB1 loci. Therefore, we analysed the polymorphism of the HLA-DRB
and DQB alleles and extended haplotype according to age of disease
onset, in Brazilian patients with psoriasis.
Material and methods
Patients and controls
This study included 60 patients with psoriasis vulgaris, living in
Campinas, state of São Paulo, south-eastern region of Brazil. They
were randomly selected and all of them attended the Dermatology
Ambulatory of the Teaching Hospital, School of Medical Sciences,
State University of Campinas. Thirty-two patients were male (mean
age = 51.5 years) and 28 female (mean age = 52.5 years), age range
from 17 to 84 (mean age = 52 years). Patients were followed during
the period 2002 to 2003.
The diagnosis of psoriasis vulgaris was established according to
the following clinical criteria:
- a) aspect of dermatological lesion (positive spermaceti
sign and positive Auspitz sign after Brocq’s methodical
curettage);
- b) presence of one to hundreds of lesions in the form of
well-defined erythematous-scaly injuries of several sizes;
- c) location of lesions (limbs, particularly knees and
elbows, scalp, sacral region, genital mucous membranes and mucous
membranes of the lips.
The control group consisted of 100 unrelated healthy adults from
the region of Campinas. Blood samples were collected from blood
donors and volunteers from the blood bank of the Haematology and
Haemotherapy Centre of the State University of Campinas
(Hemocentro). The sample consisted of 65 male (mean age = 36.8
years) and 35 female individuals (mean age = 37.4 years), age range
from 19 to 63 (mean age = 37 years). The control panel is
representative of the population of Campinas and corresponds fairly
to the regional distribution of the patient panel.
The study was carried out and samples were obtained with the
informed consent of patients after approval by the Research Ethics
Committee.
Typing of HLA alleles was performed at the Transplantation
Immunogenetics Laboratory – Teaching Hospital, Division of Clinical
Pathology, School of Medical Sciences, UNICAMP, which is accredited
to perform clinical HLA typing by the Brazilian organizations
Integrated Health Service (Serviço Único de Saúde – SUS) and
Brazilian Association of Histocompatibility (ABH).
HLA-DR-DQ allele typing – Confirmation by PCR-SSP
DNA preparation
Genomic DNA was extracted from peripheral blood leukocytes (PBL)
using a salting-out method [16].
DNA typing of class II
Class II alleles were amplified by PCR using sequence specific
primers and then typed. The second exons of MHC, DRB1 and DQB1
genes were amplified by polymerase chain reaction (PCR) as
described by Zetterquist and Ollerup [17], with sequence specific
primers (PCR/SSP) supplied by One-Lambda, Inc.-CA, USA. The DNA
amplification consisted of 30 three temperature cycles that
included denaturation at 94 °C for annealing and 20 cycles each for
10s at 94 °C, 50s at 59 °C and 30s at 72 °C for extension. The
PCR-SSP kits used were -DR an -DQ medium and high resolution. At
specific level I, medium-resolution typing, HLA-DRB1 alleles were
determined by 13 primer mixes, -DRB3 by 3 primer mixes, -DRB4 by 1
primer mix, -DRB5 by 2 primer mixes and -DQB1 by 5 primer mixes. At
specific level II, high-resolution typing, HLA-DRB1 alleles were
determined by 224 primer mixes, -DRB3 by 16 primer mixes, -DRB4 by
1 primer mix and -DRB5 by 7 primer mixes. The PCR product was
visualized using ethidium bromide-stained 2% agarose gel. Presence
of specific PCR products was visualized by UV transilluminator and
photographically registered [17].
Statistical analysis
Allele and genotype frequencies were obtained by direct counting
and calculated according to the Lamm and Degos method [18],
assuming homozygosity in case of one detectable allele.
Associations between each allele and each genotype found in
patients and controls were compared by means of Chi-square or
two-tailed Fisher’s exact test. The level of significance was set
to p value < 0.05; corrected p-values were obtained by
multiplying the number of alleles tested for each locus. The
strength of the observed associations was estimated by calculating
the relative risk (RR) using the Woolf method, with Haldanes’
continuity correction. Haplotype frequencies and linkage
disequilibrium for two-loci haplotypes were calculated by applying
the formula for estimation of population data.
Results
HLA-DRB3, -B4, -B5 and HLA-DQB1 alleles were determined for both
psoriasis vulgaris patients and healthy controls by the
medium-resolution PCR/SSP method or generic typing, whereas
HLA-DRB1 alleles were determined by high-resolution or specific
typing. Frequencies observed in typed alleles allowed us to
conclude that the population examined is in Hardy-Weinberg
equilibrium.
Allelic and genetic frequencies detected by PCR/SSP in both
psoriasis vulgaris patients and healthy controls
Allelic and genetic frequencies were detected in both groups
examined, by the medium and high-resolution PCR/SSP methods. 114
DRB1 alleles, 51 DRB3 alleles, 23 DRB4 alleles, 18 DRB5 alleles,
and 114 DQB1 were found. In the healthy control group, 190 DRB1
alleles, 72 DRB3 alleles, 53 DRB4 alleles, 26 DRB5 alleles, and 190
DQB1 alleles were detected.
Association with HLA-DRB and DQB1 alleles
HLA-DRB3*02 and HLA-DRB1*0102 alleles showed increased frequency in
patients when compared to healthy controls: HLA DRB3*02 (p = 46.7%,
c = 29%, χ2 = 5.10, p < 0.05, RR = 2.14); HLA-DRB1*
0102 (p = 10%, c = 2%, p < 0.05, RR = 5.44), respectively (table
1)( Table 1 ). We further observed a
decrease in the following allele frequencies in patients when
compared to healthy controls: HLA-DRB1*04 (p = 15%, c = 35%,
χ2 = 7.52, p < 0.05, RR = 0.33); HLA-DRB1*1302 (p =
3.3%, c = 13%, p < 0.05, RR = 0.23) (table 1). In contrast, the
HLA-DQB1 alleles did not show any significant association with
psoriasis (table 2)( Table 2 ).
Table 1 Distribution - HLA-DRB1 e DQB1, RR,
χ2 , p value
|
Controls
|
Psoriasis vulgaris patients
|
|
Gene
|
Allele
|
n(%)
|
frequency
|
n(%)
|
frequency
|
RR
|
χ2
|
p-value
|
|
DRB1
|
*0101
|
17(17)
|
0.0890
|
5(8.3)
|
0.0423
|
0.44
|
2.38
|
0.1570
|
|
*0102
|
2(2.0)
|
0.0100
|
6(10.0)
|
0.0513
|
5.44
|
-
|
0.0533
|
|
*0103
|
2(2.0)
|
0.0100
|
1(1.7)
|
0.0080
|
0.83
|
-
|
1.0000
|
|
*1501
|
9(9.0)
|
0.0460
|
8(13.3)
|
0.0688
|
1.56
|
0.74
|
0.3892
|
|
*1502
|
2(2.0)
|
0.0100
|
1(1.7)
|
0.0080
|
0.83
|
-
|
1.0000
|
|
*1503
|
3(3.0)
|
0.0151
|
3(5.0)
|
0.0253
|
1.70
|
-
|
0.6725
|
|
*1504
|
1(1.0)
|
0.0050
|
0(0.0)
|
0.0000
|
0.00
|
-
|
1.0000
|
|
*1601
|
7(7.0)
|
0.0356
|
3(5.0)
|
0.0253
|
0.70
|
-
|
0.7444
|
|
*1602
|
4(4.0)
|
0.0202
|
3(5.0)
|
0.0253
|
1.26
|
-
|
1.0000
|
|
*0301
|
12(12)
|
0.0619
|
11(18.3)
|
0.0962
|
1.65
|
1.22
|
0.2694
|
|
*0302
|
1(1.0)
|
0.0050
|
1(1.7)
|
0.0083
|
1.68
|
-
|
1.0000
|
|
*0401
|
8(8.0)
|
0.0408
|
2(3.3)
|
0.0167
|
0.40
|
-
|
0.3227
|
|
*0402
|
3(3.0)
|
0.0151
|
1(1.7)
|
0.0080
|
0.55
|
-
|
1.0000
|
|
*0403
|
4(4.0)
|
0.0202
|
1(1.7)
|
0.0083
|
0.41
|
-
|
0.6511
|
|
*0404
|
7(7.0)
|
0.0356
|
2(3.3)
|
0.0167
|
0.46
|
-
|
0.4854
|
|
*0405
|
8(8.0)
|
0.0408
|
1(1.7)
|
0.0083
|
0.19
|
-
|
1.0000
|
|
*0407
|
1(1.0)
|
0.0050
|
0(0.0)
|
0.0000
|
0.00
|
-
|
1.0000
|
|
*0408
|
2(2.0)
|
0.0100
|
0(0.0)
|
0.0000
|
0.00
|
-
|
0.5283
|
|
*0410
|
1(1.0)
|
0.0050
|
0(0.0)
|
0.0000
|
0.0
|
-
|
1.0000
|
|
*0411
|
1(1.0)
|
0.0050
|
2(3.3)
|
0.0167
|
3.41
|
-
|
0.5567
|
|
*0432
|
0(0.0)
|
0.0000
|
1(1.6)
|
0.0080
|
0.00
|
-
|
0.3750
|
|
*1101
|
18(18)
|
0.0945
|
10(16.7)
|
0.0870
|
0.91
|
0.05
|
0.8299
|
|
*1102
|
2(2.0)
|
0.0100
|
3(5.0)
|
0.0253
|
2.58
|
-
|
0.3643
|
|
*1103
|
2(2.0)
|
0.0100
|
2(3.3)
|
0.0167
|
1.69
|
-
|
0.6310
|
|
*1104
|
4(4.0)
|
0.0202
|
4(6.7)
|
0.0338
|
1.71
|
-
|
0.4745
|
|
*1110
|
1(1.0)
|
0.0050
|
0(0.0)
|
0.0000
|
0.00
|
-
|
1.0000
|
|
*1118
|
0(0.0)
|
0.0000
|
1(1.7)
|
0.0080
|
0.00
|
-
|
0.3750
|
|
*1201
|
1(1.0)
|
0.0050
|
2(3.3)
|
0.0167
|
3.41
|
-
|
0.5567
|
|
*1301
|
8(8.0)
|
0.0408
|
6(10.0)
|
0.0513
|
1.28
|
0.19
|
0.6647
|
|
*1302
|
13(13.0)
|
0.0673
|
2(3.3)
|
0.0167
|
0.23
|
-
|
0.0508
|
|
*1303
|
2(2.0)
|
0.0100
|
3(5.0)
|
0.0253
|
2.58
|
-
|
0.3643
|
|
*1305
|
1(1.0)
|
0.0050
|
1(1.7)
|
0.0083
|
1.68
|
-
|
1.0000
|
|
*1309
|
1(1.0)
|
0.0050
|
0(0.0)
|
0.0000
|
0.00
|
-
|
1.0000
|
|
*1315
|
0(0.0)
|
0.0000
|
1(1.7)
|
0.0083
|
0.00
|
-
|
0.3750
|
|
*1320
|
0(0.0)
|
0.0000
|
1(1.7)
|
0.0083
|
0.00
|
-
|
0.3750
|
|
*1327
|
1(1.0)
|
0.0050
|
0(0.0)
|
0.0000
|
0.00
|
-
|
1.0000
|
|
*1401
|
5(5.0)
|
0.0253
|
3(5.0)
|
0.0253
|
1.00
|
-
|
1.0000
|
|
*1402
|
2(2.0)
|
0.0100
|
0(0.0)
|
0.0000
|
0.00
|
-
|
0.5283
|
|
*0701
|
20(20.0)
|
0.1055
|
11(18.3)
|
0.0962
|
0.90
|
0.07
|
0.7962
|
|
*0801
|
8(8.0)
|
0.0408
|
3(5.0)
|
0.0253
|
0.61
|
-
|
0.5383
|
|
*0804
|
1(1.0)
|
0.0050
|
1(1.7)
|
0.0083
|
1.68
|
-
|
1.0000
|
|
*0809
|
1(1.0)
|
0.0050
|
0(0.0)
|
0.0000
|
0.00
|
-
|
1.0000
|
|
*0816
|
0(0.0)
|
0.0000
|
2(3.3)
|
0.0167
|
0.00
|
-
|
0.1392
|
|
*0901
|
2(2.0)
|
0.0100
|
2(3.3)
|
0.0167
|
1.69
|
-
|
0.6310
|
|
*1001
|
2(2.0)
|
0.0100
|
4(6.7)
|
0.0338
|
3.50
|
-
|
0.1983
|
Table 2 Positive associations found for HLA-DRB, -DQB1
alleles and haplotypes, detected by SSP in Psoriasis vulgaris
patients
|
Positive associations with HLA-DRB1*0102 and DRB3*02
alleles
|
|
HLA alleles
|
χ2
|
p-value
|
Relative risk
|
|
DRB1*0102
|
|
0.0533
|
5.44
|
|
DRB3*02
|
5.10
|
0.0239 pc = ns
|
2.14
|
|
Positive associations with haplotypes:
|
|
HLA-DRB1*0102/DQB1*05
|
|
Haplotype
|
|
p-value
|
Relative risk
|
|
DRB1*0102/DQB1*05
|
|
0.0533
|
5.44
|
|
HLA-DRB1*0701/DQB1*03
|
|
Haplotype
|
|
p-value
|
Relative risk
|
|
DRB1*0701/DQB1*03
|
|
0.0281
|
9.00
|
Association with HLA-DRB1 and DQB1 haplotypes
We detected two haplotypes positively associated with psoriasis:
DRB1*0102 DQB1*05 (p = 10.0%, c = 2.0%, p < 0.05, RR = 5.44) and
DRB1*0701 DQB1*03 (p = 8.3%, c = 1.0%, p < 0.02, RR = 9.00), as
well as one haplotype negatively associated with the disease,
DRB1*0405 DQB1*03 (p = 0.0%, c = 7.0%, p < 0.04 and RR = 0.10)
(table 3)( Table 3 ).
Table 3 Negative associations found for HLA-DRB1 and
-DQB1 alleles and haplotypes, detected by SSP in psoriasis vulgaris
patients
|
Negative associations with HLA-DRB1*1302 and DRB1*04
alleles
|
|
Haplotype
|
|
p-value
|
Relative risk
|
|
DRB1*1302
|
|
0.0508
|
0.23
|
|
DRB1*04
|
7.52
|
0.0061 pc = ns
|
0.33
|
|
Negative associations with haplotype:
|
|
HLA- DRB1*0405/DQB1*03
|
|
Haplotype
|
|
p value
|
Relative risk
|
|
DRB1*0405/DQB1*03
|
|
0.0459
|
0.00
|
Discussion
The presence of disease genes in the HLA region has long been
suspected on the basis of HLA-association studies [19];
nevertheless, the precise genetic basis of HLA association in
psoriasis vulgaris has remained elusive. Since then numerous
association studies performed typically used HLA phenotypes or
genotypes as markers [20]. However, the identification of the
genetic course of these associations can cause extreme difficulties
[21]. Regarding HLA gene associations, many studies have described
increased frequencies of class I HLA alleles, and there is
substantial evidence suggesting that psoriasis is strongly
associated with HLA-CW6 in many populations [22, 23]. Because not
all patients with psoriasis carry HLA-CW6, it has been proposed
that class II HLA alleles are also involved in psoriasis
susceptibility. Choonhakarn, [24] describes the association of Type
I psoriasis with the HLA-DRB1*07-DQB1*03; another research group
[25] demonstrated that HLA-DRB1*0701 and HLA- DRB1*1401 were
significantly increased in a Taiwanese population.
We demonstrated in a previous report on Brazilian psoriasis
patients that human leukocyte antigen HLA-A1,-A2, -CW6,-CW7,
eHLA-DR7,-DQ5, showed significantly higher frequencies in psoriasis
patients than in healthy controls. The present study investigated
the molecular genetic basis of psoriasis on human chromosome 6, a
class II region. Our results revealed two positively associated
alleles in analyzed patients: DRB1*0102 (p < 0.05, RR = 5.44)
and -DRB3*02 (p < 0.02, χ2 = 4.36, RR = 2.14).
Particular attention was given to the analyzed two-loci haplotypes
in the group of psoriasis patients and we found that the
HLA-DRB1*0102/DQB1*05 haplotype (p < 0.05 and RR = 5.44) and the
HLA-DRB1*0701/DQB1*03 haplotype (p < 0.02 and RR = 9.00) were
equally and significantly associated with psoriasis vulgaris, with
a significant difference to those of the controls. The strong
association found in the HLA-DRB1*0701/DQB1*03 haplotype was also
found in psoriasis vulgaris patients in Germany [26].
We have seen protective MHC alleles and haplotypes in this
study: HLA-DRB1*1302 allele (p < 0.05, RR = 0.23) and
HLA-DRB1*04 allele (χ2 = 6.55, p < 0.01 and RR =
0.33), as well as the HLA-DRB1*0405/DQB1*03 haplotype (p < 0.04
and RR = 0.00) were shown to have a protective effect against the
development of psoriasis vulgaris in the patients examined. The
DRB1*0701/DQB1*03 haplotype and the HLA-DRB1*0102/DQB1*05 haplotype
were found in 100% of the patients with an early onset of the
disease (< 40 years old). These data are important due to the
fact that haplotypes containing the DR7 gene play an important role
in psoriasis inheritance and were identified as high-risk
haplotypes in patient groups with early-onset disease [24]. It
seems that the proper interpretation of association studies
strongly depends upon knowledge of the population structure
including the possibility that the disease allele might have arisen
independently on multiple occasions [27].
In conclusion, the present study allows us to determine
significant association between HLA-DRB1*0102/DQB1*O5 and
HLA-DRB1*O701/DQB1*03 haplotypes and a group of psoriasis vulgaris
patients with early onset of the disease. Regarding further allelic
and haplotype associations observed, our data suggests
susceptibility genes as possible triggering factors for the
disease.
Acknowledgements
We thank the patients and the healthy individuals who participated
in this study, as well as Dr. Maria Beatriz Puzzi, from the
Dermatology Department, Dr Arthur Makoto Sakamoto, Dr. Vera Cecilia
Oliveira and Dr. Ana Maria Biral, from the Clinical Pathology
Department, for their cooperation. We also wish to acknowledge the
assistance of Biometrix and the Teaching Hospital of the School of
Medical Sciences – Unicamp – State University of Campinas. This
work was supported by award from FAPESP – São Paulo State Research
Foundation and grant from FAEP – Research and Teaching Support
Fund.
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