Clin. Otolaryngol.

2002, 27, 61–67

HLA associations with nasopharyngeal carcinoma in

Southern Chinese: a meta-analysis
D.B. GOLDSMITH,
T.M. WESTy & R. MORTON

Departments of
Otolaryngology, and yCardiac Research, Green Lane Hospital, Auckland, New Zealand

Accepted for publication 15 October 2001

G O L D S M I T H D . B . , W E S T T . M . & M O RT O N R .
(2002) Clin. Otolaryngol. 27, 61–67
HLA associations with nasopharyngeal carcinoma in Southern Chinese: a meta-analysis
The literature relating to human leucocyte antigens (HLA) and nasopharyngeal carcinoma (NPC) identifies
conflicting ranges of possible allelic associations. We aimed to clarify this by conducting a systematic review to
identify and quantify associations present across all of the available studies. A literature search was performed
and, subsequently, a meta-analysis was performed on 13 published studies using both fixed-effects and
random-effects models when appropriate. Evidence for positive associations between NPC and the HLA
alleles A2, B14 and B46 (P ¼ 1.57  105, 1.13  103 and 6.38  105 respectively) were found, and negative
associations were identified for the alleles A11, B13 and B22 (P ¼ 5.42  103, 0.017 and 0.009). Whereas an
association between HLA-B13 or B22 and NPC has not been noted previously, the results for HLA-A2, A11,
B14 and B46 are in accordance with published studies. There is evidence that specific allele subtypes or
combinations of alleles may carry particular risk for NPC.
Keywords nasopharyngeal carcinoma (NPC) nasopharyngeal neoplasms HLA Chinese meta-analysis

Nasopharyngeal carcinoma (NPC) is a disease with a high
incidence in ethnic Chinese people inhabiting the south-east-
ern provinces of China1 and Hong Kong.1–3 Chinese incidence
rates of 25–50 per 100 000 compare with Caucasian rates of
less than one per 100 000. Migrants from Southern China to
low incidence countries maintain their higher incidence.2
Environmental effects such as diet and Epstein-Barr virus
(EBV) have been implicated in the causation of NPC.1,4–6
Migrants tend to take their ‘microenvironments’ with them by
maintaining traditional foods consumed and activities per-
formed. However, in Singapore, where Chinese, Malays and
Indians live close together and share many of the same eating
and social habits, the incidence of NPC per 105 age-standar-
dized male population per year is 18.5, 3.1 and 0.9, respec-
tively.1 This suggests that genetic factors are likely to be more
important than environmental factors. Other populations that
have an increased risk of NPC include south-east Asian, non-
Chinese Mongoloid groups,3 African groups7–9 and Pacific
Island Polynesian populations.10 The Polynesians are recog-
Correspondence: Randall P. Morton, Department of Otolaryngology,
Green Lane Hospital, Auckland, New Zealand (e-mail: randallm@
adhb.govt.nz).
nized as having genetic links to Southern Chinese.10 Inter-
marriage between Chinese and Thai (low NPC risk)
populations produces an intermediate risk of NPC.3
In the early 1970s, research into possible genetic factors
was begun. Studies looking at red cell markers and serum
protein systems identified links with NPC, the strongest being
with the human leucocyte antigens (HLA).11 In the mid 1970s,
the alleles A2, B13 and B46 were identified as being sig-
nificantly associated with NPC.12,13 There followed many
studies that focused on this issue, with varying results. This
has led to uncertainty in the significance of the associations
between NPC and specific alleles because of the heterogeneity
of the pattern of statistical significance seen in these studies. In
an attempt to apply some order to the numerous and various
papers on HLA and NPC, we performed a systemic review.
Materials and methods
All studies that examined HLA associations in Chinese people
recently diagnosed with NPC were eligible for this analysis.
Chinese people were defined as people living in China,
Malaysia, Singapore, Hong Kong and California, provided
the individuals within the study group identified as being

# 2002 Blackwell Science Ltd 61

62 D.B. Goldsmith et al.

Chinese in origin. Studies that were unclear as to the popula-
tion studied, or that used mixed ethnic populations, were
excluded.
Electronic searches of Medline (1966–2000), Embase
(1988–1999) and Cinahl (1982–1999) were conducted using
a combination of subject headings and text words relating to
the terms ‘NPC’, ‘Nasopharyngeal Neoplasms’, ‘HLA’ and
‘Chinese’ to identify published studies in any language. Then,
we examined the reference lists of any studies and review
articles published in English for additional publications. All
papers were then reviewed for specific population groups
covered within each study, and if Southern Chinese ethnic
groups were not obviously involved, the paper was discarded.
The remaining papers were presented to two independent
observers, who selected appropriate publications based on the
information supplied within each paper, the methods used and
the populations sampled. Disagreements between reviewers
were resolved by consensus.
From the papers that were originally identified, studies were
discarded because of mixing of Chinese and non-Chinese, or
their results being included in more recent papers. The results
concerning HLA-A and -B alleles from one study by Chan
et al.14 were discarded owing to their inclusion in another
study15; however, the results relating to HLA-DR alleles
(being omitted from the 198315 paper) were included. The
meta-analysis was not performed on any allele that was
identified in only one study. When a publication presented
the results of multiple studies separately, each study was
treated independently. Studies using either serological or
polymerase chain reaction (PCR) techniques to identify
HLA type were included.
Statistical heterogeneity in the results of the trials was
assessed both by inspection of graphical presentations and
by calculating a test of homogeneity.16 Those alleles that had a
P-value of less than 0.10 for the Qw statistic (evidence for
homogeneity) were further analyzed using a fixed-effect
method; those with no evidence of homogeneity of allelic
effect (P-value > 0.10) were further studied with a random-
effects model.16
The fixed-effect method17 provides an estimate of an
overall odds ratio and variance for an allele, when variation
of the estimates is assumed to be as a result of random
sampling error. The random-effects model, as described by
DerSimonian and Laird,16 assumes variation across studies as
well as variation of the allelic effect (within-study variation).
In this instance, a difference in proportion is the measure of
allelic effect, with both the mean (m) and population variance
(D2) being restricted to this scale. A test for significance
was performed on the data using the t-distribution, and
confidence intervals for the difference in proportions were
calculated. A ‘file drawer analysis’,18 which calculates
the number of studies with null results that are unpubli-
shed, which are required to invalidate the results, was also
performed.
Results
Out of 27 studies of HLA allelic association with NPC that
were performed from 1974 to 1999, 13 were deemed suitable
for analysis (Table 1). As only one study investigated HLA-C
alleles, these alleles were excluded from further analysis.
Individual alleles were tested for homogeneity of their effect

Table 1. Relevant genetic studies on HLA genes associated with NPC

No of No A-alleles No B-alleles No DR- Significant alleles

Study Year Country No. of cases controls studied studied alleles studied identified

Simons12 1974 Singapore 144 148 6 12 – A2, B13

Simons29 1975 Singapore 31 31 8 14 – None
Simons30 1977 Singapore/ 153 91 7 17 – None
Malaysia
Jing20 1977 USA 37 48 11 15 – A2



Chan14 1981 Singapore 22/21 43/43 – DR4
Cui27 1982 China 33 33 11 17 – B17
Chany15 1983 Singapore 141/ 238/ 9 17 – A11,B13, B17,
172/53 92/38 Bw46
Ou24 1985 China 50 40 2 2 10 B17, A11
Zhang25 1986 China 24 49 13 26 – A1, B63, A11,
A2/B17
Yiy31 1988 China 26/34 68/46 1 3/4 5 Bw6
Yuan23 1988 China 53 212 13 17 6 A11, Bw46
Li32 1995 Hong Kong 57 85 – – 13 None
Ooi33 1997 Singapore 55 59 3z 2z – None


Only data relating to DR alleles extracted from this publication.
yPapers containing the results of multiple individual studies.
zOnly significant allele associations reported.

# 2002 Blackwell Science Ltd, Clinical Otolaryngology, 27, 61–67

 HLA and NPC: results of a meta-analysis 63

Table 2. Test of homogeneity of allelic effect across the studies (Table 2). Those HLA alleles with P-values
Allele Dfy Qw P-value
less than 0.10 (A1, A2, A11, A24, B14, B17, B18, B46 and
DR1–4) were identified as having a homogeneous effect
A1 8 20.893 0.008 across studies and were further analyzed using the fixed-
A2 11 21.757 0.026
A3 8 9.465 0.305
effects method. The remaining alleles were analyzed with
A9 10 7.440 0.683 the random-effects model.
A10 8 7.492 0.485
A11 11 37.452 1.0  104
A19 6 5.339 0.501 fix ed-effects method
A24 2 6.621 0.037
A28 5 3.836 0.573 A total of 12 alleles with homogeneous effects were analyzed
A29 4 4.079 0.400 with the fixed-effects model (Table 3). Of these, A2 (P ¼
B5 8 5.560 0.696 1.57  105), A11 (P ¼ 5.42  103), B14 (P ¼ 1.13  103)
B7 8 4.668 0.792 and B46 (P ¼ 6.38  105) had strong associations with NPC,
B8 5 6.093 0.297
B12 7 7.098 0.419 conferring risk ratios (RR) of 1.854, 0.608, 7.937 and 1.952
B13 9 10.620 0.303 respectively (Fig. 1).
B14 2 7.932 0.019
B15 9 11.868 0.221
B16 7 7.022 0.427 random-effects m ethod
B17 12 36.981 2.25  104
B18 6 12.061 0.061 A total of 23 alleles shown to have heterogeneous effects
B21 2 2.918 0.233 across the 13 studies were analyzed with the random-effects
B22 8 7.128 0.492
B27 7 10.929 0.142
model (Table 4). B13 and B22 were shown to have negative
Bw35 8 12.105 0.147 associations with NPC, with decreases in proportion of NPC
B37 3 3.928 0.269 to control (mdiff) of 0.052 (P ¼ 0.017, D2w ¼ 0.089%) and
B40 7 4.976 0.663 0.042 (P ¼ 0.009, D2w ¼ 0), respectively (Fig. 2). None of the
B46 7 13.806 0.055
B62 2 1.578 0.454 remaining alleles had significant associations.
DR1 4 21.574 2.0  104
DR2 6 10.793 0.095
DR3 4 11.871 0.018
f i l e d r aw e r a n a ly s i s
DR4 6 25.499 3.0  104 From 9 to 152 unpublished studies, showing no association
DR5 3 2.166 0.539
DR7 4 4.835 0.305 between the significant HLA-alleles mentioned above and
DR8 3 5.395 0.145 NPC, would be required to assume that the associations
identified are as a result of sampling bias. These are as
Marked alleles (in bold) indicate homogeneous effects requiring the
follows: HLA-A2, 50 studies; -A11, 152 studies; -B13, 39
Mantel-Haenszel model; all others require a random-effects model.
yDegrees of freedom. studies; -B14, 9 studies; -B22, 10 studies; and -B46, 32


P-values < 0.10 indicate homogeneity of effect. studies.

Table 3. Fixed-effects (Mantel–Haenszel) method

Allele prevalence (%)
95% Confidence
HLA Cases Controls RR P Interval
A1 3.34 2.49 1.342 0.999 0.700, 2.573
A2 87.62 47.26 1.854 1.57  105 1.538, 2.234
A11 27.88 45.85 0.608 5.42  103 0.503, 0.735
A24 9.58 16.38 0.585 0.346 0.284, 1.203
B14 3.88 0.49 7.937 1.13  103 2.636, 23.898
B17 20.75 14.06 1.476 0.574 1.166, 1.868
B18 2.14 1.35 1.590 0.995 0.521, 4.853
Bw46 39.45 20.00 1.952 6.38  105 1.542, 2.470
DR1 11.25 6.27 1.796 0.478 0.973, 3.315
DR2 23.93 20.40 1.173 0.995 0.806, 1.706
DR3 19.24 14.29 1.347 0.856 0.812, 2.234
DR4 27.44 27.68 0.991 1.000 0.860, 1.143

# 2002 Blackwell Science Ltd, Clinical Otolaryngology, 27, 61–67

64 D.B. Goldsmith et al.

Figure 1. Fixed-effects model showing the calculated overall RR

( 95% confidence intervals). Figure 2. Random-effects model, showing the mean differences (m)
between proportions of alleles in NPC and in the normal population
( 95% confidence intervals).
Table 4. Random-effects model
Estimated overall effects Estimated variation in 95% Confidence
and their standard errors
the true effects
Interval
Allele mw S.E. D2w P-value
3 3 3
A3 3.07  10 4.90  10 3.3  10 0.549 0.013, 0.007
A9 0.027 0.021 0 0.221 0.014, 0.068
A10 3.70  104 0.011 0 0.974 0.022, 0.021
A19 5.05  103 0.018 0 0.790 0.041, 0.030
A28 5.2  103 0.005 0 0.372 0.016, 0.005
A29 1.5  103 0.004 1.6  106 0.690 0.008, 0.005
B5 2.76  103 0.016 0 0.860 0.028, 0.034
B7 6.453 0.006 0 0.318 0.018, 0.005
B8 1.39  103 0.005 3.0  105 0.803 0.012, 0.009
B12 2.92  103 0.008 8.0  106 0.736 0.019, 0.013
B13 0.052 0.018 8.9  104 0.017 0.088, 0.017
B15 0.011 0.022 1.1  103 0.641 0.053, 0.032
B16 1.83  103 0.017 8.1  106 0.920 0.032, 0.036
B21 0.030 0.021 5.5  104 0.296 0.012, 0.071
B22 0.042 0.012 0 0.010 0.066, 0.017
B27 0.011 0.013 5.0  104 0.426 0.038, 0.015
B35 4.36  103 0.015 6.1  104 0.776 0.033, 0.025
B37 3.76  103 0.007 5.0  105 0.637 0.018, 0.010
B40 0.050 0.022 0 0.054 0.093, 0.008
B62 1.03  104 0.040 0 0.998 0.078, 0.078
DR5 0.035 0.018 0 0.146 0.071, 1.1  104
DR7 5.16  103 0.030 8.0  104 0.873 0.054, 0.064
DR8 0.084 0.049 0.004 0.185 0.012, 0.179


Calculation yields a weighted least squares difference in proportion between NPC cases and control (mw) as well as its sampling variance
(D2w ).

# 2002 Blackwell Science Ltd, Clinical Otolaryngology, 27, 61–67


Discussion
To our knowledge this is the first systematic review of
HLA associations with NPC in literature. Our study shows
that 6 out of the 35 alleles in the HLA-A, -B and -DR region
are associated with NPC. Three (A2, B14 and B46) have a
positive correlation with the presence of NPC, and three (A11,
B13 and B22) are associated with the disease-free state.
The results of this paper are only applicable to Southern
Chinese-originating people. Some studies have been carried out
on other populations (Taiwanese,19 Tunisians,8 Caucasians,20
African,9 Malaysians21 and Grecians,22 to name a few), but
their results suggest that alleles other than those shown in
this review may be associated with NPC. It is possible that
the non-Chinese populations have a higher proportion of
‘protective’ alleles that may reduce their incidence of NPC.
One practical concern identified during the meta-analysis
relates to possible differences between the earlier studies that
used serotyping to identify HLA-alleles, and the more recent
studies using PCR. Serotyping requires that a particular HLA
gene product be expressed upon the surface of a cell, as
opposed to PCR, which requires the presence of the particular
HLA sequence on the chromosome. Whereas both identify
the HLA types, the inherent differences between the methods
may account for differences between the results of the papers
used for this analysis. It must be noted that the earlier
serotyping is likely to be less sensitive than the more recent
techniques.
Whereas all Chinese papers identified were used in this
meta-analysis, it is possible that a number were not identi-
fied. The impact of absent papers on this meta-analysis is
unlikely to invalidate these results given the file drawer cal-
culations that indicated that at least nine unpublished papers
showing non-significance are needed before these associa-
tions begin to lose significance. Many of the articles in
this review show null results, indicating that null results are
not, in themselves, cause for not publishing. Apart from HLA-
B14 and -B22, the alleles identified here would require an
unreasonable level of publishing bias to invalidate their
effects.
Most of the significant alleles emerging from this meta-
analysis have been noted by others. HLA-A2 was found to be
significant in two studies;12,20 A11 in four studies;15,23–25 B13
in two studies;12,15 and B46 in two studies.15,23 The signifi-
cance of associations varied considerably between studies,
and HLA-B14 and B22, identified by meta-analysis, have not
previously been significantly associated with NPC in any
study. Allele B40, with a P-value of 0.054, has also not been
identified previously, but it may prove to be relevant with
further investigation.
The relative risks identified here are not particularly large.
For HLA-A2, this is due, in some degree, to its high
prevalence (about 47%) in the normal Chinese population.
# 2002 Blackwell Science Ltd, Clinical Otolaryngology, 27, 61–67
HLA and NPC: results of a meta-analysis 65
Given this prevalence, it is not possible to have an odds
ratio greater than two. Furthermore, it has been shown that
the HLA-A2 alleles can have associations that are opposite
to what one would expect. Using high-resolution oligotyp-
ing, Ren et al.26 identified A2 allelic microvariants in these
groups. Two of these microvariants were each relatively
common in the study populations, but had completely oppo-
site associations. A
0207 associated with the control popula-
tion (Pcorrected ¼ 0.035), conferring a RR of 0.3 (95%
CI ¼ 0.12–0.75). Alternatively, A
0201 positively associated
with NPC (Pcorrected ¼ 0.05), conferring a RR of 3.5 (95%
CI ¼ 1.30–9.50). In addition, when they looked at the nine
cases of NPC carrying A
0207, all were associated with B46,
whereas the control group had A
0207 associating with the
complete range of B alleles (including B46). This suggests
that the risk may be associated with B46, which is in linkage
disequilibrium with A
0207. Further study of microvariants
of alleles may expose a closer association between these
alleles and NPC. Most of the serotyping and PCR employed
in the studies reviewed here were insensitive to the subtle
changes produced by the microvariances in the A2 region.
The overall effect of this on the meta-analysis is to reduce
the power of the results for A2, though to what degree is
unknown.
None of the studies used in this meta-analysis identifies
whether individuals were hetero- or homozygous for a partic-
ular allele. The specific haplotype of an individual could
impact on disease presence or development, with a homo-
zygous condition conferring a more extreme RR dependent on
the properties of that allele and the heterozygous state redu-
cing or abating any effect of a particular allele. Only three
studies have looked at allelic combinations in NPC. The work
of Ren and colleagues (Ren et al.26) is discussed above. Cui
and Lin27 identified an increased proportion of joint occur-
rence of A2/B7 (P < 0.025), A2/B17 (P < 0.01) and B17/B27
(P < 0.025) in NPC patients. Significance with the joint
occurrence of A2/B17 (P ¼ 0.035) was also noted by Zhang.25
While these studies all have small sample sizes, they en-
courage further research into the effects of the HLA alleles
and their combinations.
HLA alleles are not known oncogenes, thus, the involve-
ment of HLA alleles in NPC development is likely to be
indirect. It is well-known that EBV is closely associated with
NPC in Southern Chinese people.4 EBV is known to carry
viral oncogenes, for example, BHRF-1 (an antiapoptotic, bcl-
2 homologueue28), thus, EBV infection of cells of the naso-
pharynx could lead to development of NPC. The host immune
mechanisms usually identify with virally infected cells
through the presentation of viral peptides on HLA antigens
on the surface of the cell. It is possible that some of these
antigens have higher efficiency in triggering an immune
response, thus, are restrictive for EBV infection, whereas
others have reduced efficiency in activating a host response
66 D.B. Goldsmith et al.
and are classed as permissive for EBV infection. It is our
hypothesis that the HLA alleles A11, B13 and B22 fall into the
former category, whereas HLA-A2, B14 and B46 fall into the
latter.
In summary, from the current literature, six alleles demon-
strate statistically significant positive or negative associations
with NPC. The literature is not clear as to the effect of hetero-
or homozygosity of these alleles, nor is it clear as to the effects
of combinations or subtypes of these alleles. It is essential that
these areas be investigated further so that a better, broader
understanding of the genetic associations with NPC can be
gained. Only then can this research be applied to determining
a solution to this disease.
Acknowledgements
R.P. Morton provided the motivation and direction of the
project as well as assisting in writing and revising the manu-
script; T.M. West provided statistical advice and revised the
statistical calculations; D.B. Goldsmith co-ordinated and
performed the literature review, the first draft of the meta-
analysis, and wrote all manuscript drafts. R.P. Morton, T.M.
West, and S.-K. Ong provided the independent reviews of the
papers included in this study. This study was supported by
financial assistance from the Green Lane Research and Edu-
cation Trust, as well as the Head and Neck Trust. We thank
Auckland Healthcare for the provision of resources. Special
thanks also to Dr Derek Bennett for his advice on meta-
analyses.
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