MAJOR ARTICLE
Risk Association between Human Leukocyte
Antigen–A Allele and High-Risk Human
Papillomavirus Infection for Cervical Neoplasia
in Chinese Women
Denise P. C. Chan,1 Tak-Hong Cheung,2 Ann O. Y. Tam,1 Jo L. K. Cheung,1 So-Fan Yim,2 Keith W. K. Lo,2
Nelson S. S. Siu,2 Daniel X. Zhou,1 and Paul K. S. Chan1,3
Departments of 1Microbiology and 2Obstetrics and Gynaecology, and 3School of Public Health, Faculty of Medicine, The Chinese University
of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China
To examine the association between human leukocyte antigen–A (HLA-A) allele polymorphism, human papillomavirus (HPV) infection, and risk for cervical neoplasia in Chinese women, 263 patients (155 with cervical
intraepithelial neoplasia [CIN] II/III and 108 with invasive cervical cancer [ICC]) were compared with 572
controls. Overall, regardless of HPV status, a decreased risk for ICC was observed for patients with A*0207/
0215N or A*2402, and an increased risk was observed for patients with A*1104. The protective association of
A*0207/0215N was reproduced in HPV-16–positive patients with ICC, but not in subgroups infected with
other HPV types. The risk association between A*1104 and both HPV-16 and HPV-18 was reproduced in the
subgroups with CIN III/ICC. The protective association between A*2402 and HPV-16, HPV-18, HPV-52, and
HPV-58 was consistently observed in all subgroups with CIN III/ICC, suggesting a linkage with a general
antioncogenic genetic factor. The results of the present study indicate that HLA-A polymorphism is one of
the host genetic factors that alter the risk for the development of cervical cancer in Chinese women.
Cervical cancer is the second most common cause of
cancer mortality in women worldwide [1]. Epidemiological studies have demonstrated a strong link between
human papillomavirus (HPV) infection and the development of cervical cancer [2–5]. A few studies have revealed the genotype spectrum of HPV types in women
with cervical intraepithelial neoplasia (CIN) and cervical cancer from Hong Kong [6, 7]. Besides high-risk
HPV-16 and HPV-18, HPV-52 and HPV-58 (which are
Received 28 April 2005; accepted 9 June 2005; electronically published 7
October 2005.
Potential conflicts of interest: none reported.
Financial support: Research Grants Council of the Hong Kong Special Administrative Region (grant CUHK4071/01M).
Presented in part: 22nd International Papillomavirus Conference, Vancouver,
Canada, 30 April–6 May 2005 (abstract P-435).
Reprints or correspondence: Prof. Paul K. S. Chan, Dept. of Microbiology, The
Chinese University of Hong Kong, 1/F, Clinical Science Building, Prince of Wales
Hospital, Shatin, New Territories, Hong Kong Special Administrative Region,
People’s Republic of China ([email protected]).
The Journal of Infectious Diseases 2005; 192:1749–56
2005 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2005/19210-0012$15.00
uncommon worldwide) were found to be prevalent in
our Chinese population [8, 9].
Although HPV infection, particularly that with the
oncogenic HPV-16 and HPV-18, is considered to be
the necessary or major risk factor for cervical cancer,
it is not sufficient for the development of cervical cancer. Other risk factors, such as the host genetic background, and environmental factors may also contribute
to the carcinogenic process. It is clear that most HPV
infections are transient and regress spontaneously. Only
a minority of women infected with HPV develop persistent infection that may evolve into CIN and/or progress to invasive cervical cancer (ICC) [10, 11].
The host immune system is critical in controlling
HPV infection and determining disease outcome. HLA
plays an important role in regulating cell-mediated immunity against pathogens. HLA class I and II molecules
are highly polymorphic. Individuals expressing different
HLA alleles may differ in their ability to handle a given
set of HPV-derived peptides; hence, HLA alleles influence the outcome of infection.
HLA, HPV, and Cervical Cancer • JID 2005:192 (15 November) • 1749
Recently, several studies have suggested a possible association
between HLA polymorphism and the development of cervical
cancer [12–14]. However, diverse findings have been reported
from different populations [15–17]. To date, similar investigations have not been conducted on Chinese women. In the present
study, we determined the risk associations between HLA-A allele,
high-risk HPV infection status, and cervical neoplasia.
SUBJECTS AND METHODS
Study population. Chinese women with cervical neoplasia attending the gynecology clinic at the Prince of Wales Hospital
were included in the present study. Blood samples and cervical
scrape or biopsy samples were obtained from participants who
had provided written, informed consent. The present study was
approved by the local institutional ethics committee. The HLAA allele frequencies determined from the Hong Kong Marrow
Match Registry, as reported by Middleton et al. [18], served as
our reference for risk assessment.
HPV typing. HPV detection and typing were performed
using the HPV Consensus PCR/Line Blot Genotyping Kit (Roche
Molecular Systems), which can identify 37 genital HPV types.
Briefly, DNA was extracted from cervical scrape or biopsy samples, using the QIAamp DNA mini kit (Qiagen). The presence
of HPV DNA was subsequently detected using a polymerase
chain reaction (PCR)–based assay with biotinylated PGMY L1
consensus primers. The reaction mixture consisted of 50 mmol/
L KCl; 4 mmol/L MgCl2; 200 mmol/L each dATP, dCTP, and
dGTP; 600 mmol/L dUTP; 1 mmol/L each biotinylated PGMY09/
PGMY11 primer; and 7.5 U of AmpliTaq Gold DNA polymerase.
The amplification steps were as follows: a 9-min enzyme activation at 95C, followed by 40 cycles of 95C for 30 s, 55C for
1 min, and 72C for 1 min, and a final 5-min extension at 72C.
The PCR products were then hybridized using the oligonucleotide probes immobilized on the nylon membrane strip to identify the HPV genotype.
HLA-A typing. The HLA-A allele profiles of recruited patients were determined by use of the sequence-based typing
method, as described at the 13th International Histocompatibility Workshop and Conference [19]. Genomic DNA was first
isolated from blood samples; PCR targeting the HLA-A exon
2 and exon 3 regions, for amplification of a 1-kb fragment,
was then performed. Briefly, the 100-mL reaction mixture consisted of 50 mmol/L KCl, 1.5 mmol/L MgCl2, 200 mmol/L each
dNTP (Amersham Biosciences), 0.4 mmol/L each primer, 2 U
of HotStar Taq DNA polymerase (Qiagen), 20 mL of Q solution,
and 10 mL of the extracted DNA sample. The amplification
profile was as follows: a 15-min enzyme activation at 95C,
followed by 35 cycles of 94C for 1 min, 60C for 1 min, and
72C for 1 min, and a final 8-min extension at 72C. Direct
sequencing reactions using the universal primers M13F (5TGTAAAACGACGGCCAGT-3) and M13R (5-CAGGAAAC1750 • JID 2005:192 (15 November) • Chan et al.
AGCTATGACC-3) were then performed on the purified PCR
products. The HLA-A allele profile of each patient was then
determined by matching the sequence data with the custommade HLA-A allele library. This library was created using the
HLA-A sequencing database at the Anthony Nolan Trust Web
site [20]. For individuals, ambiguous results that suggested heterozygosity were resolved by resequencing the samples with
AINT1F (5-GCGCCG/TGGAGGAGGGT-3) and AINT3R (5TCCTTGTGGGAGGCCAG-3) sequencing primers, which were
designed for heterozygous HLA-A allele determination.
Statistical analysis. HLA-A phenotype frequencies (PFs)
were determined by direct counting. The x2 test or Fisher’s exact
test, as appropriate, was used to determine the risk association
between HLA-A alleles and cervical neoplasia. Subgroup analyses
were performed according to the status of HPV infection. P
values were corrected for multiple comparisons by multiplication
with the number of HLA-A alleles being compared, which is in
accordance with the Bonferroni method [21]. Corrected P (Pc)
! .05 was considered to be statistically significant.
RESULTS
Three hundred one Hong Kong Chinese women with cervical neoplasia were recruited to the present study. Their ages
ranged from 20 to 80 years (mean SD age, 45.6 13.1
years). Thirty-eight patients were excluded from analysis because we could not determine their HLA-A allele profiles at
high resolution. Of the 263 patients, 155 (58.9%) received, by
histological analysis, a diagnosis of CIN II/III, and 108 (41.1%)
received a diagnosis of ICC, of whom 87 (80.6%) received a
diagnosis of squamous cell carcinoma and 21 (19.4%) received
a diagnosis of adenocarcinoma.
Among the 255 patients from whom cervical scrapes or biopsy samples were available for HPV typing, the overall rate of
positivity for HPV was 91.0% (232/255), and the rates of positivity for CIN II/III and ICC were 86.6% (129/149) and 97.2%
(103/106), respectively. HPV-16 was the most prevalent HPV
type (detected in 42.2% of HPV-positive subjects), followed
by HPV-52 (15.1%), HPV-18 (14.2%), and HPV-58 (10.3%).
Coinfections with ⭓2 HPV types were found in 57 patients.
A total of 40 HLA-A alleles were found from the study subjects. The most frequently detected HLA-A allele was A*110101
(PF, 0.597), followed by A*330301 (PF, 0.103), A*1102 (PF,
0.068), and A*0203 (PF, 0.061) (table 1).
The possible risk associations between HLA-A alleles and
cervical neoplasia were first examined by regarding all patients,
CIN II/III/ICC (N p 263 ), as the disease group. The HLA-A
allele frequencies in 572 Hong Kong Chinese patients enrolled
in the Marrow Match Registry, as reported by Middleton et al.
[18], were used as the reference group for comparison. Although the sequence-specific oligonucleotide probe–based typing method used by Middleton et al. [18] could differentiate
Table 1. HLA-A phenotype frequencies (PFs) and gene frequencies (GFs) in Hong Kong Chinese women with cervical neoplasia.
Invasive
cervical cancer
(n p 108)
CIN II/III/invasive
cervical cancer
(n p 263)
HLA-A allele
No.
PF
GF
No.
PF
GF
A*010101/0104N
A*0203
A*0204
A*0206
A*0207/0215N
A*0211
A*0212
A*0224
A*0249
A*0255
A*0265
A*030101
A*0308
A*0310
A*110101
A*1102
A*1104
A*1105
A*1106
A*1108
A*2303
A*2304
A*2402
A*2406
A*2423
A*2428
A*2429
A*2609
A*2616
A*2901
A*3001
A*3011
A*310102
A*3108
A*3202
A*3204
A*3301
A*330301
A*3601
A*7401/7402
6
16
1
2
11
1
1
1
1
2
2
4
1
1
157
18
14
1
2
1
1
1
2
2
5
1
2
1
1
4
8
1
6
1
1
1
1
27
3
2
0.023
0.061
0.004
0.008
0.042
0.004
0.004
0.004
0.004
0.008
0.008
0.015
0.004
0.004
0.597
0.068
0.053
0.004
0.008
0.004
0.004
0.004
0.008
0.008
0.019
0.004
0.008
0.004
0.004
0.015
0.030
0.004
0.023
0.004
0.004
0.004
0.004
0.103
0.011
0.008
0.011
0.031
0.002
0.004
0.021
0.002
0.002
0.002
0.002
0.004
0.004
0.008
0.002
0.002
0.365
0.035
0.027
0.002
0.004
0.002
0.002
0.002
0.004
0.004
0.010
0.002
0.004
0.002
0.002
0.008
0.015
0.002
0.011
0.002
0.002
0.002
0.002
0.053
0.006
0.004
3
8
0
1
4
0
1
1
0
0
1
2
0
0
65
4
7
0
2
0
0
1
0
1
2
1
0
0
1
2
4
1
3
0
0
0
0
7
1
2
0.028
0.074
0
0.009
0.037
0
0.009
0.009
0
0
0.009
0.019
0
0
0.602
0.037
0.065
0
0.019
0
0
0.009
0
0.009
0.019
0.009
0
0
0.009
0.019
0.037
0.009
0.028
0
0
0
0
0.065
0.009
0.019
0.014
0.038
0
0.005
0.019
0
0.005
0.005
0
0
0.005
0.009
0
0
0.369
0.019
0.033
0
0.009
0
0
0.005
0
0.005
0.009
0.005
0
0
0.005
0.009
0.019
0.005
0.014
0
0
0
0
0.033
0.005
0.009
NOTE.
CIN, cervical intraepithelial neoplasia.
85 different HLA-A alleles, it did not provide fine typing for
all HLA-A alleles. As a result, only 22 of the 40 alleles identified
in the present study were included for disease-association assessment. A significant negative association for HLA-A alleles
A*0203, A*0206, A*0207/0215N, and A*2402 (Pc p .040 for
all) and a significant positive association for A*1104 (Pc p .040)
were observed (table 2). However, when subgroup analyses were
restricted to patients with ICC (n p 108 ) as the disease group,
only A*0207/0215N and A*2402 had a significant negative as-
sociation (Pc p .040 for both); A*1104 had a significant positive
association (Pc p .040).
To assess the effect of HPV infection on the risk association
for HLA-A alleles, subgroup analyses were performed according
to HPV infection status (tables 3 and 4). In HPV-16–positive
patients with CIN II/III/ICC, HLA-A alleles A*0207/0215N and
A*2402 had a negative association (Pc p .029 for both), whereas
A*1104 had a positive association (Pc p .029). The negative
association for alleles A*0207/0215N and A*2402 remained significant when the analyses were restricted to HPV-16–positive
subgroups with CIN III/ICC and ICC (Pc p .029 for both).
However, a positive association for A*1104 was observed in the
subgroup with CIN III/ICC but not in the subgroup with ICC.
Analyses for HPV-18, HPV-52, and HPV-58 were restricted
to patients with CIN III/ICC, since the numbers for other categories were too low. HPV-18–positive patients with CIN III/
ICC had a negative association with A*2402 (Pc p .015 ) and a
positive association with A*1104 (Pc p .015). A negative association with A*2402 was also observed for HPV-52– and
HPV-58–positive patients with CIN III/ICC (Pc p .028 and
Pc p .027, respectively).
DISCUSSION
The association between HLA class I alleles and cervical neoplasia has been investigated less often than has that between
HLA class II alleles and cervical neoplasia [22–24]. The present
study has, to our knowledge, provided the first report on the
association between HLA-A allele, high-risk HPV infection, and
the development of cervical neoplasia in the Chinese population. In contrast to most previous studies, in which HPV infection status was not considered or was limited to only the
most common type (HPV-16), the present study included the
detection of several HPV types, using a broad-catching method.
Therefore, we were able to assess the association between HPV
type and HLA-A allele. In particular, the patients in the present
study had a relatively high prevalence of HPV-52 and HPV-58;
similar analysis of their associations with HLA alleles was not
available.
Recent population-based studies conducted in the United
States and in Costa Rica have revealed that A*3101 was associated with an increased risk for developing low-grade squamous epithelial lesions but not for developing high-grade squamous epithelial lesions or cervical cancer [25]. A*3101 existed
at a low frequency in our study population and was significantly associated with cervical neoplasia. Our initial analyses, regardless of HPV infection status, indicated a protective
effect of A*0207/0215N and A*2402, which was reproduced
when the analysis was restricted to the subgroups with CIN
III/ICC and ICC, respectively. The protective effect of A*2402
seemed to be strong and was not dependent on the type of
HPV infection: significant associations were revealed for the
HLA, HPV, and Cervical Cancer • JID 2005:192 (15 November) • 1751
1752
84
0
53
A*0203
A*0204
A*0206
0
9
A*0224
A*0301
19
21
A*2901
A*3001
A*310102
0
108
0.0
18.9
0.0
0.0
3.7
3.3
2.4
0.0
0.0
28.0
0.0
7.7
48.8
1.6
0.0
0.0
0.0
24.0
9.3
0.0
14.7
2.1
F, %
3
27
1
1
6
8
4
1
2
2
14
18
157
4
1
1
1
11
2
1
16
6
No.
1.1
10.3
0.4
0.4
2.3
3.0
1.5
0.4
0.8
0.8
5.3
6.8
59.7
1.5
0.4
0.4
0.4
4.2
0.8
0.4
6.1
2.3
F, %
…
0.49 (0.31–0.79)
…
…
0.61 (0.22–1.63)
0.91 (0.36–2.24)
0.62 (0.17–2.02)
…
…
0.02 (0.00–0.08)
…
0.88 (0.48–1.61)
1.56 (1.14–2.11)
0.97 (0.25–3.46)
…
…
…
0.14 (0.07–0.27)
0.08 (0.01–0.32)
…
0.38 (0.21–0.67)
1.09 (0.36–3.16)
OR (95% CI)
CIN II/III/invasive cervical cancer
(n p 263)
NS
NS
NS
NS
NS
NS
NS
NS
NS
.040
.040
NS
NS
NS
NS
NS
NS
.040
.040
NS
.040
NS
Pc
3
26
1
1
5
5
4
1
2
2
14
13
133
3
1
1
1
11
2
1
16
6
No.
1.3
11.4
0.4
0.4
2.2
2.2
1.7
0.4
0.9
0.9
6.1
5.7
58.1
1.3
0.4
0.4
0.4
4.8
0.9
0.4
7.0
2.6
F, %
…
0.55 (0.34–0.89)
…
…
0.59 (0.19–1.67)
0.65 (0.21–1.87)
0.71 (0.19–2.33)
…
…
0.02 (0.00–0.09)
…
0.72 (0.36–1.42)
1.45 (1.06–2.01)
0.83 (0.18–3.37)
…
…
…
0.16 (0.08–0.31)
0.09 (0.01–0.36)
…
0.44 (0.24–0.78)
1.26 (0.41–3.65)
OR (95% CI)
CIN III/invasive cervical cancer
(n p 229)
NS
NS
NS
NS
NS
NS
NS
NS
NS
.040
.040
NS
NS
NS
NS
NS
NS
.040
.040
NS
NS
NS
Pc
1
7
0
0
3
4
2
0
1
0
7
4
65
2
1
1
0
4
1
0
8
3
No.
0.9
6.5
0.0
0.0
2.8
3.7
1.9
0.0
0.9
0.0
6.5
3.7
60.2
1.9
0.9
0.9
0.0
3.7
0.9
0.0
7.4
2.8
F, %
…
…
0.30 (0.12–0.69)
NC
NC
0.75 (0.17–2.71)
1.12 (0.32–3.58)
0.75 (0.12–3.53)
NC
…
0.00 (0.00–0.12)
…
0.46 (0.14–1.38)
1.59 (1.02–2.47)
1.18a
…
NC
0.12 (0.04–0.35)
0.09 (0.00–0.62)
NC
0.46 (0.20–1.03)
1.33 (0.29–5.18)
OR (95% CI)
Invasive cervical cancer
(n p 108)
NS
NS
NC
NC
NS
NS
NS
NC
NS
.040
.040
NS
NS
NS
NS
NS
NC
.040
NS
NC
NS
NS
Pc
a
CI undefined.
NOTE. Corrected P (Pc) values were determined by the x2 test or Fisher’s exact test, as appropriate, and were adjusted for multiple comparisons using the Bonferroni correction. Allele variables showing
significant Pc values (!.05) are presented in bold. CI, confidence interval; CIN, cervical intraepithelial neoplasia; F, frequency; NC, not calculated; NS, not significant; OR, odds ratio. Ellipses indicate undefined
ORs.
A*3601
A*330301
0
14
A*2609
A*3301
0
A*2406
0
0
A*2402
A*3202
0
160
A*1104
44
A*1102
279
0
A*0212
A*110101
0
A*0211
137
12
A*010101/0104N
A*0207/0215N
No.
Control
(n p 572)
Risk association of HLA-A alleles in Hong Kong Chinese women with cervical neoplasia.
HLA-A allele
Table 2.
1753
0
53
A*0204
A*0206
0
9
A*0224
A*0301
0
0.0
18.9
0.0
0.0
3.7
3.3
2.4
0.0
0.0
28.0
0.0
7.7
48.8
1.6
0.0
0.0
0.0
24.0
9.3
0.0
14.7
2.1
F, %
3
12
0
1
4
3
2
0
1
1
5
6
52
2
1
1
1
2
2
1
5
4
No.
3.1
12.2
0.0
1.0
4.1
3.1
2.0
0.0
1.0
1.0
5.1
6.1
53.1
2.0
1.0
1.0
1.0
2.0
2.0
1.0
5.1
4.1
F, %
…
0.60 (0.30–1.18)
NC
…
1.12 (0.32–3.54)
0.92 (0.21–3.37)
0.83 (0.13–3.91)
NC
…
0.03 (0.00–0.18)
…
0.78 (0.29–1.98)
1.19 (0.76–1.86)
1.30a
…
…
…
0.07 (0.01–0.28)
0.20 (0.03–0.87)
…
0.31 (0.11–0.83)
1.99 (0.53–6.81)
OR (95% CI)
CIN II/III/invasive cervical cancer
(n p 98)
NS
NS
NC
NS
NS
NS
NS
NC
NS
.029
.029
NS
NS
NS
NS
NS
NS
.029
NS
NS
NS
NS
Pc
3
12
0
1
4
3
2
0
1
1
5
6
48
2
1
1
1
2
2
1
5
4
No.
3.2
12.8
0.0
1.1
4.3
3.2
2.1
0.0
1.1
1.1
5.3
6.4
51.1
2.1
1.1
1.1
1.1
2.1
2.1
1.1
5.3
4.3
F, %
NC
…
0.63 (0.31–1.24)
NC
…
1.17 (0.33–3.70)
0.96 (0.22–3.52)
0.87a
…
0.03 (0.00–0.19)
…
0.82 (0.30–2.08)
1.10 (0.69–1.73)
a
1.36
…
…
…
0.07 (0.01–0.29)
0.21 (0.04–0.91)
…
0.33 (0.11–0.87)
2.07 (0.55–7.13)
OR (95% CI)
CIN III/invasive cervical cancer
(n p 94)
NS
NS
NC
NS
NS
NS
NS
NC
NS
.029
.029
NS
NS
NS
NS
NS
NS
.029
NS
NS
NS
NS
Pc
1
3
0
0
3
2
1
0
1
0
1
1
23
1
1
1
0
0
1
0
1
2
No.
2.4
7.3
0.0
0.0
7.3
4.9
2.4
0.0
2.4
0.0
2.4
2.4
56.1
2.4
2.4
2.4
0.0
0.0
2.4
0.0
2.4
4.9
F, %
NC
…
0.34 (0.08–1.17)
NC
NC
2.07 (0.47–7.78)
1.49 (0.00–7.01)
1a
…
0.00 (0.00 –0.31)
…
0.30 (0.01–2.10)
1.34 (0.68–2.66)
a
1.56
…
…
NC
0.00 (0.00–0.38)
0.24 (0.01–1.71)
NC
0.15 (0.01–1.00)
2.39
a
OR (95% CI)
Invasive cervical cancer
(n p 41)
NS
NS
NC
NC
NS
NS
NS
NC
NS
.029
NS
NS
NS
NS
NS
NS
NC
.029
NS
NC
NS
NS
Pc
a
CI undefined.
NOTE. Corrected P (Pc) values were determined by the x2 test or Fisher’s exact test, as appropriate, and were adjusted for multiple comparisons using the Bonferroni correction. Allele variables showing
significant Pc values (!.05) are presented in bold. CI, confidence interval; CIN, cervical intraepithelial neoplasia; F, frequency; NC, not calculated; NS, not significant; OR, odds ratio. Ellipses indicate undefined ORs.
A*3601
108
0
A*330301
0
21
A*310102
A*3301
19
A*3001
A*3202
0
0
A*2406
14
160
A*2402
A*2901
0
A*1104
A*2609
44
A*1102
279
0
A*0212
A*110101
0
A*0211
137
84
A*0203
A*0207/0215N
12
A*010101/0104N
No.
Control
(n p 572)
HPV-16 positive
Risk association of HLA-A alleles in human papillomavirus type 16 (HPV-16)–positive Hong Kong Chinese women with cervical neoplasia.
HLA-A allele
Table 3.
84
0
53
A*0203
A*0204
A*0206
0
9
A*0224
A*0301
19
21
A*2901
A*3001
A*310102
0
108
0.0
18.9
0.0
0.0
3.7
3.3
2.4
0.0
0.0
28.0
0.0
7.7
48.8
1.6
0.0
0.0
0.0
24.0
9.3
0.0
14.7
2.1
F, %
0
6
1
0
0
1
1
0
0
0
3
2
17
0
0
0
0
1
0
0
0
1
No.
0.0
18.8
3.1
0.0
0.0
3.1
3.1
0.0
0.0
0.0
9.4
6.3
53.1
0.0
0.0
0.0
0.0
3.1
0.0
0.0
0.0
3.1
F, %
NC
0.99 (0.36–2.61)
…
NC
0.00 (0.00–4.29)
0.94
a
1.29
a
NC
NC
0.00 (0.00–0.40)
…
0.80 (0.13–3.60)
1.19 (0.55–2.57)
0.00 (0.00–10.94)
NC
NC
NC
0.10 (0.01–0.71)
0.00 (0.00–1.55)
NC
0.00 (0.00–0.91)
1.51
a
OR (95% CI)
HPV-18 positive
(n p 32)
NC
NS
NS
NC
NS
NS
NS
NC
NC
.015
.015
NS
NS
NS
NC
NC
NC
NS
NS
NC
NS
NS
Pc
1
3
0
0
2
0
0
0
0
1
1
2
14
0
0
0
1
5
0
0
4
1
No.
3.2
9.7
0.0
0.0
6.5
0.0
0.0
0.0
0.0
3.2
3.2
6.5
45.2
0.0
0.0
0.0
3.2
16.1
0.0
0.0
12.9
3.2
F, %
…
0.46 (0.11–1.62)
NC
NC
1.81 (0.00–8.58)
0.00 (0.00–4.94)
0.00 (0.00–6.91)
NC
NC
0.09 (0.00–0.59)
NS
NS
NC
NC
NS
NS
NS
NC
NC
.028
NS
NS
0.83a
…
NS
NS
NC
NC
NS
NS
NS
NC
NS
NS
Pc
0.86 (0.39–1.89)
0.00 (0.00–11.31)
NC
NC
…
0.61 (0.20–1.71)
0.00 (0.00 –1.60)
NC
0.86 (0.25 –2.67)
1.56
a
OR (95% CI)
HPV-52 positive
(n p 31)
0
2
0
0
0
0
0
0
0
0
1
0
12
0
0
0
0
1
0
0
4
0
No.
0.0
8.7
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
4.3
0.0
52.2
0.0
0.0
0.0
0.0
4.3
0.0
0.0
17.4
0.0
F, %
NC
0.41 (0.07–1.84)
NC
NC
0.00 (0.00–6.06)
0.00 (0.00–6.76)
0.00 (0.00–9.46)
NC
NC
0.00 (0.00–0.56)
…
0.00 (0.00–2.69)
1.15 (0.46–2.84)
0.00 (0.00–15.51)
NC
NC
NC
0.14 (0.01–1.02)
0.00 (0.00–2.18)
NC
1.22 (0.34–3.94)
0.00 (0.00–11.22)
OR (95% CI)
HPV-58 positive
(n p 23)
NC
NS
NC
NC
NS
NS
NS
NC
NC
.027
NS
NS
NS
NS
NC
NC
NC
NS
NS
NC
NS
NS
Pc
a
CI undefined.
NOTE. Corrected P (Pc) values were determined by the x2 test or Fisher’s exact test, as appropriate, and were adjusted for multiple comparisons using the Bonferroni correction. Allele variables showing
significant Pc values (!.05) are presented in bold. CI, confidence interval; CIN, cervical intraepithelial neoplasia; F, frequency; NC, not calculated; NS, not significant; OR, odds ratio. Ellipses indicate undefined ORs.
A*3601
A*330301
0
14
A*2609
A*3301
0
A*2406
0
0
A*2402
A*3202
0
160
A*1104
44
A*1102
279
0
A*0212
A*110101
0
A*0211
137
12
A*010101/0104N
A*0207/0215N
No.
HLA-A allele
Control
(n p 572)
CIN III/invasive cervical cancer
Table 4. Risk association of HLA-A alleles in Hong Kong Chinese women with cervical neoplasia, according to human papillomavirus type 18 (HPV-18), HPV-52, and HPV-58
infection status.
subgroups infected with HPV-16, HPV-18, HPV-52, and HPV58. On the other hand, the protective effect of A*0207/0215N
was HPV-16 specific. An epidemiological protective association
between a particular HLA allele and the development of cervical
neoplasia could reflect the ability of its encoded HLA molecules
to present peptides derived from oncogenic HPVs to the immune system, or it could mean that a protective genetic characteristic is being cosegregated with the allele. It would be interesting to investigate further which protective mechanism is
conferred by A*0207/0215N and A*2402.
NK cells are important in the innate immune response for
clearance of virus-infected or tumor cells. Killer immunoglobulin–like receptors (KIRs) expressed on NK cells bind with the
respective HLA class I molecules expressed on target cells. This
KIR/HLA ligand complex triggers either inhibitory or activating signals to NK cells and CD8+ T cells. Matching of these 2
polymorphic loci would, therefore, potentially affect the outcome of an infection. A recent study has shown that, in individuals, the specific inhibitory KIR/HLA allele pairs were associated with a decreased risk for the development of cervical
neoplasia, whereas the presence of the activating KIR alleles
resulted in an increased risk, especially when the inhibitory
combinations were missing [26]. It would be interesting to
further examine whether the protective effect of HLA-A alleles
observed in the present study is related to the presence of their
inhibitory KIR alleles. Furthermore, protective effects may be
due to their linkage with other HLA alleles, HLA-B or -C, which
were not examined in the present study.
It has been shown that HLA alleles associated with an increased risk for cervical cancer are less discernible in epidemiological studies and that the results are often less reproducible [27]. In the present study, we identified 1 allele, A*1104,
that could possibly be associated with a higher risk. The association was observed for the whole group, regardless of
HPV-infection status, and was reproduced in the subgroups
infected with HPV-16 and HPV-18. That the frequency of
A*1104 was very low in our general population is in line with
data reported on other Chinese populations, including those
from Taiwan and Singapore (allele frequency, ! 0.001) [28].
With such a low frequency in the control group, a false-positive observation is a real concern. It would be important to see
whether the risk association can be reproduced in other Chinese populations. Worldwide, the A*1104 allele is also very rare
but appears with a slightly higher allele frequency (0.017) in
Argentine Toba Rosario [28]. It would be worthwhile to examine the association between A*1104 and cervical neoplasia
in the Argentine Toba Rosario population.
In conclusion, the results of the present study indicate that
HLA-A polymorphism is one of the host genetic factors that
alter the risk for the development of cervical cancer in Chinese
women. These specific alleles and their interactions with high-
risk HPV types should be considered in the development of
therapeutic vaccines.
Acknowledgment
We thank Dr. John S. Sullivan for his critical review on the manuscript.
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