Chlamydial Antibodies and Risk of Prostate Cancer

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Tarja Anttila, Leena Tenkanen, Sonja Lumme, et al.
Cancer Epidemiol Biomarkers Prev 2005;14:385-389.
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Cancer Epidemiology, Biomarkers & Prevention
Tarja Anttila, 1 Leena Tenkanen, 2 Sonja Lumme, 2 Maija Leinonen, 1 Randi Elin Gislefoss, 3
Göran Hallmans, 4 Steinar Thoresen, 5 Timo Hakulinen, 6 Tapio Luostarinen, 6 Pär Stattin, 7
Pekka Saikku, 8 Joakim Dillner, 9 Matti Lehtinen,10 and Matti Hakama10
1
2
3
National Public Health Institute, Oulu, Finland; Helsinki Heart Study, Helsinki, Finland; Janus Serum Bank, Oslo, Norway;
Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University Hospital, Umeå, Sweden;
5
6
7
Norwegian Cancer Registry, Oslo, Norway; Finnish Cancer Registry, Helsinki, Finland; Department of Urology, Umeå University Hospital,
8
9
Umeå, Sweden; Department of Medical Microbiology, University of Oulu, Finland; Department of Microbiology, University
10
Hospital of Malmö, Sweden; and University of Tampere School of Public Health, Tampere, Finland
4
Abstract
Objective: We assessed the risk of prostate cancer by
exposure to Chlamydia trachomatis.
Method: Seven hundred thirty eight cases of prostate cancer
and 2,271 matched controls were identified from three serum
sample banks in Finland, Norway, and Sweden by linkage to
the population based cancer registries.
Results: A statistically significant inverse association (odds
ratio, 0.69; 95% confidence interval, 0.51-0.94) was found. It
was consistent by different serotypes and there was a
consistent dose-response relationship.
Conclusion: C. trachomatis infection is not likely to increase
the risk of prostate cancer. Whether the inverse relationship
is true or due to difficulties in measuring the true exposure
in prostatic tissue by serology, confounders or other sources
of error remain open. (Cancer Epidemiol Biomarkers Prev
2005;14(2):385 – 9)
Introduction
The prostate cancer is one of the most common malignant
neoplasms in men all over the world. Annually, more than
10,000 men in the Nordic countries are diagnosed with
prostatic cancer. Despite of its importance, relatively little is
known of its aetiology. Long asymptomatic period and
generally slow growth rate of the tumor have hampered the
studies on the etiologic hypotheses.
Prostate cancer is rare below age 40, and then incidence
rates double for each subsequent decade of life. Family history
and ethnicity/country of residence are the only firmly
established risk factors for prostate cancer (1). Besides
hormones (2-4) and dietary factors (5-8), a role for sexual
behavior and associated infectious agents has been supported
by some previous studies of prostate cancer (1, 3, 9-11).
Chlamydia trachomatis is nowadays considered as the most
common bacterial cause of sexually transmitted diseases (12).
C. trachomatis is an obligate intracellular Gram-negative
bacterium, which, like all chlamydial species, has a tendency
to cause chronic persistent infections. In women, chronic C.
trachomatis infections have been connected to pelvic inflammatory disease, ectopic pregnancies, and infertility (13-15).
Furthermore, our earlier seroepidemiologic studies have
suggested that chronic C. trachomatis infections increase the
risk of cervical cancer (16-18). In sexually active men, C.
trachomatis is the main cause of nongonococcal urethritis.
Nonbacterial prostatitis, an idiopathic disease, is the most
common form of prostate inflammation constituting about 50%
of all cases. There has been much speculation, but only a little
Received 9/16/03; revised 8/31/04; accepted 9/15/04.
Grant support: The Nordic Cancer Union, the Nordic Council of Ministers, the European
Union Biomed 5 Concerted Action on Evaluation of the Role of Infections in Cancer using
Biological Specimen Banks, and the Cancer Society of Finland.
The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
Note: The Janus Serum Bank is owned and financed by the Norwegian Cancer Society.
Nina Opaas serves as Janus coordinator, and Åsa Ågren serves as coordinator for the Northern
Sweden Health and Disease Cohort.
This is publication no. 28 from the Nordic Biological Specimen Biobanks working group on
Cancer, Causes & Control.
Requests for reprints: Matti Hakama, Tampere School of Public Health, University of
Tampere, FIN-33014, Finland. Phone: 358-3-2156788; Fax: 358-3-2156057.
E-mail: matti.hakama@uta.fi
Copyright D 2005 American Association for Cancer Research.
proof, that chlamydial infection might be responsible for many
cases of apparent nonbacterial prostatitis (19, 20). However, as
early as 1972, Mårdh et al. showed the more frequent presence
of chlamydial antibodies in men with chronic prostatitis
compared with the controls (21) and later studies have also
suggested that antichlamydial immunoglobulin A (IgA) and
immunoglobulin G (IgG) antibodies are present in patients
with chronic prostatitis (22, 23).
The presence of C. trachomatis antibodies against several
immunotypes and possibly also the presence of elevated titers
against the agent may indicate the cumulative exposure to C.
trachomatis infection (24, 25). There are also studies on the
persistence of C. trachomatis antibodies with age and over time
(24, 25). This is important because the risk factors for prostate
carcinoma evidently exist at early phase of the disease
preceding the long latency period in the development of
cancer. Large serum sample banks stored in the Nordic
countries enabled us to estimate the risk of prostate cancer
among men with and without serologically diagnosed C.
trachomatis infection by a longitudinal nested case-control
design. The aim of our study was to evaluate the risk of
prostate cancer due to infection to C. trachomatis.
Materials and Methods
Serum banks in Finland, Norway, and Sweden were used to
study risk of prostate cancer in men with and without
serologic diagnosis of C. trachomatis infection. More than
200,000 men have donated serum samples to the three serum
banks participating in the study.
The Cohorts. The Finnish cohort contained blood samples of
f19,000 men aged 40 to 55 who participated in 1981 to 1982 in
the first health examination for the Helsinki Heart Study, a
primary-prevention trial in middle aged men to reduce
coronary heart disease risk by lowering serum lipid levels with
gemfibrozil (26). The participants were selected by screening
from employees in two governmental agencies and five
industrial companies. The serum samples were stored at 20jC.
In Norway, the Janus project was initiated in 1973 and
contained serum samples from about 160,000 men (27). Most
participants were recruited from several counties in Norway
Cancer Epidemiol Biomarkers Prev 2005;14(2). February 2005
385
386
during routine health examinations or in conjunction with
screening for risk factors of cardiovascular diseases. The
samples were collected also from blood donors from the
Red Cross Blood Donor Center in Oslo and sera were stored
at 25jC.
The men in The Northern Sweden Health and Disease
Cohort were recruited through the Västerbotten intervention
project (VIP), which started in Sweden 1985 and is still
ongoing. Each year, all residents aged 30, 40, 50 and 60 were
invited to participate in a health promoting project, including
the donation of biological samples for future medical research.
The participants were also recruited through the northern
Sweden part of the WHO Multinational Monitoring of Trends
and Determinants in Cardiovascular Disease Study (MONICA;
refs. 28, 29). The MONICA study recruited participants in
1986, 1990, and 1994. These two projects, VIP and MONICA, in
Västerbotten and Norrbotten consisted about 30,000 men as
a representative population sample for the study. Plasma
samples were stored at 80jC. All subjects provided informed
consent before enrollment and the study was approved by
each respective local Research Ethical Committee.
titration series in a blinded fashion. Positive control serum
was included in every test series. All the sera were tested by
one laboratory technician and fluorescence pattern was
interpreted by one experienced reader (T.A.).
Statistical Methods. To describe the data, we presented the
prevalences of the different chlamydial exposures among cases
and controls. However, to maintain the matching of the casecontrol design in the analysis, the estimation of the effect of
exposure was done by calculating the odds ratios (OR) and
their 95% confidence intervals (95% CI) using conditional
logistic regression analysis. First, to give an overall view (the
OR) of the effect of C. trachomatis on prostate cancer risk, the
variable describing the exposure, the IgG antibody titer level,
was dichotomized using the above described limit values for
positive exposure. Next, to explore the pattern of doseresponse, the exposure variable was categorized at three levels
(e.g., for C. trachomatis the titer levels of <16, 16, and z32
represented ‘‘no exposure’’, ‘‘intermediate exposure’’, and
‘‘elevated exposure’’ respectively. Similarly, titer levels for C.
pneumoniae were classified to no exposure (<32), intermediate
exposure (32-64), and elevated exposure (z128). A consistent
trend in the estimated ORs for these exposure levels is
considered to strengthen the inference based on the overall OR.
Cancer Registries. The Cancer Registry of Norway, the
Finnish Cancer Registry, and the regional cancer registry at the
Umeå Oncological Centre, which covers the four northernmost
counties in Sweden, are population based and country- or
county-wide (30). All the registries receive notifications from
hospitals, hematology and pathology laboratories, and physicians and have almost 100% coverage in reporting. The registry
practices and definitions are comparable due to close and longlasting collaboration between the registries.
Results
Case Ascertainment and Control Selection. Cases with
prostate carcinoma were identified by linking the data files of
the serum banks with the national cancer registries (regional
in Sweden) in 1997 using personal identification numbers.
Prostate cancers diagnosed before time of the blood sampling
were excluded. When more than one pre-diagnostic sample
was available, the earliest (the oldest) was chosen. For each
case, four controls were selected randomly from those that
were alive at the time of diagnosis of the case and without
diagnosis of prostate cancer at end of 1996 and fulfilled the
matching criteria: age at serum sampling (F2 years), time of
serum sampling (F2 months; in part of the Norwegian cohort,
F6 months), same country and region inside the country
(Norway). If four controls per case fulfilling the matching
criteria could not be identified, either matching criteria were
widened or less than four control subjects were accepted. Some
of the stored frozen Finnish samples had been accidentally
thawed and were matched for thawing.
From the time of the serum sampling until end of 1996, 138
cases and 497 controls from Finland, 514 cases and 1,433
controls from Norway, and 86 cases and 341 controls from
Sweden were available for analysis. Thus, the total number of
cases and controls was 738 and 2,271, respectively.
Table 1. Numbers and percentage distribution of cases
with prostate cancer in the Nordic serum sample study by
study characteristics and country
Chlamydial Serology. C. trachomatis- and C. pneumoniaespecific IgG antibodies were measured by the microimmunofluorescence method, which is considered a gold standard of
chlamydial serology (31) with specificity estimated at 83% to
89% and sensitivity at 79% to 88% (32, 33). Elementary bodies
of pooled serovars BED (B-group), CJHI (C-group), and GFK
(intermediate group) of C. trachomatis (Washington Research
Foundation, Seattle, WA) and Kajaani 6 strain of C. pneumoniae
were used as antigens. FITC-conjugated antihuman IgG
(Kallestad, Chaska, MO) was used as conjugate. The serum
samples were analyzed at 2-fold dilutions for C. trachomatis
and at 4-fold dilutions for C. pneumoniae. Titres of z16 were
considered positive for C. trachomatis IgG antibodies and titres
of z32 for IgG were considered positive for C. pneumoniae. The
antibody determinations of each case and the individual
controls were always done simultaneously in the same
Of the 738 cases with prostate carcinoma, 514 were from
Norway, 138 were from Finland, and 86 were from Sweden. At
the time of serum sampling the mean age of the cases was 48.9
years (range 34-73 years) and the mean age at diagnosis was
62.9 years (range 44-79 years). The median time between
withdrawal of serum and cancer diagnosis was 14 years (range
0-25 years; Table 1). In the total cohort, 66% of the serum
samples had been taken before 1980, 19% between 1980 and
1984, and 15% after 1985. Of all cases, 493 (67%) were localized,
178 (24%) were nonlocalized, and in 67 (9%) the stage was
unknown.
Characteristic
All cohorts, Norway, Finland,
n = 738
n = 514 n = 138
Sweden,
n = 86
Age at serum sampling
<45
45-50
51-60
>60
Age at diagnosis
<45
45-50
51-60
>60
Lag between serum
sampling and
diagnosis (years)
<1
1-4
5-9
10-14
z15
Time of serum sampling
Before 1980
1980-1984
1985-1989
After 1989
Tumor stage
Localized
Nonlocalized
Not determined
n (%)
159 (21.5)
366 (49.6)
200 (27.1)
13 (1.8)
n (%)
146 (28.4)
319 (62.1)
44 (8.6)
5 (1.0)
n (%)
12 (8.7)
38 (27.5)
88 (63.8)
0 (0.0)
1
9
68
8
n (%)
(1.2)
(10.5)
(79.1)
(9.3)
1
20
189
528
(0.1)
(2.7)
(25.6)
(71.5)
1
16
124
373
(0.2)
(3.1)
(24.1)
(72.6)
0
2
47
89
(0.0)
(1.4)
(34.1)
(64.5)
0
2
18
66
(0.0)
(2.3)
(20.9)
(76.7)
13
79
102
181
363
(1.8)
(10.7)
(13.8)
(24.5)
(49.2)
1
16
49
85
363
(0.2)
(3.1)
(9.5)
(16.5)
(70.6)
1
11
30
96
0
(0.7)
(8.0)
(21.7)
(69.6)
(0.0)
11
52
23
0
0
(12.8)
(60.5)
(26.7)
(0.0)
(0.0)
487
141
33
77
(66.0)
(19.1)
(4.5)
(10.4)
487
3
24
0
(94.7)
0 (0.0)
0
(0.6) 138 (100.0) 0
(4.7)
0 (0.0)
9
(0.0)
0 (0.0)
77
(0.0)
(0.0)
(10.5)
(89.5)
493 (66.8)
178 (24.1)
67 (9.1)
365 (71.0)
127 (24.7)
22 (4.3)
66 (47.8)
36 (26.1)
36 (26.1)
62 (72.1)
15 (17.4)
9 (10.5)
Table 2. Prevalence (%) of elevated levels of IgG antibodies
to C. trachomatis* and C. pneumoniaec among cases of
prostate cancer and controls in the Nordic serum sample
study by serotype
Table 4. ORs for prostate cancer by increasing levels of IgG
antibody titers to C. trachomatis and C. pneumoniae
Serotype
Titer
level
OR
(95% CI)
P for
trend
Titer
level
OR
(95% CI)
P for
trend
<16
16
z32
1
0.75 (0.53-1.06)
0.57 (0.34-0.96)
0.009
<32
32-64
z128
1
0.92 (0.75-1.13)
0.78 (0.63-0.97)
0.028
C. trachomatis
b
Pools combined
Serotype pool
BED
CJHI
GFK
C. pneumoniae
Cases
Controls
n (%)
n (%)
55 (7.5)
51
35
16
355
(6.9)
(4.7)
(2.2)
(48.1)
238 (10.5)
216
155
75
1,179
(9.5)
(6.8)
(3.3)
(51.9)
*Titers z16 were considered positive.
cTiters z32 were considered positive.
bAny of serotype pool considered positive.
The presence of serum antibodies against all serotype pools
of C. trachomatis and against C. pneumoniae was higher among
controls than among cases (Table 2). In BED—the commonest
pool—the prevalence of C. trachomatis antibodies was 7% in
cases and 10% in controls, and in pools combined the figures
were 8% and 11%, respectively. C. pneumoniae antibodies were
found in 48% of cases and in 52% of controls (Table 2). No
differences were found in prevalences by age, lag time, or
stage of the disease (data not shown).
The prevalences were further transformed into ORs. Serum
antibodies to C. trachomatis were inversely associated with
prostate cancer risk showing no major differences in the point
estimates of ORs with regard to different C. trachomatis
serotype groups (Table 3). In total cohort (Norway, Finland,
and Sweden) the risk for prostate cancer was significantly
less among those with seropositivity for C. trachomatis (OR,
0.69; 95% CI, 0.51-0.94) than among the seronegatives. The
ORs were similar in Finland (OR, 0.71; 95% CI, 0.40-1.29) and
Norway (OR, 0.70; 95% CI, 0.48-1.03) and somewhat, but not
significantly, lower in Sweden (OR, 0.52; 95% CI, 0.15-1.79).
The corresponding point estimate for C. pneumoniae was
closer to unity and not statistically significant (OR, 0.85; 95%
CI, 0.72-1.01) in the total cohort, and the OR was somewhat
lower in Norway (OR, 0.83; 95% CI, 0.67-1.02) than in Finland
(OR, 0.91; 95% CI, 0.61-1.35) or Sweden (OR, 0.92; 95% CI,
0.57-1.51; Table 3).
There was a clear inverse dose-response relationship
between the level of serum antibodies to C. trachomatis and
risk of prostate cancer: the higher the titer level the smaller the
risk. When all cohorts were combined the ORs for the
intermediate and elevated titer levels were 0.75 (95% CI,
0.53-1.06) and 0.57 (95% CI, 0.34-0.96) compared with the
lowest level (Table 4). A similar statistically significant but
weaker trend was seen in the case of C. pneumoniae (Table 4).
C. trachomatis
C. pneumoniae
When stratified ORs were estimated by age at serum
sampling or by lag time between sampling and diagnosis or
by stage of the disease at diagnosis, the inverse association
between C. trachomatis and prostate cancer risk remained
persistently at the same level with OR of about 0.7. For those
V50 years of age the OR was 0.71 (95% CI, 0.49-1.02) and for
those >50 years of age the OR was 0.67 (95% CI, 0.37-1.22).
Similarly for those with lag time V15 years the OR was 0.65
(95% CI, 0.42-1.00) and for those with lag time >15 years the
OR was 0.72 (95% CI, 0.46-1.14); and for those with localized
cancer the OR was 0.67 (95% CI, 0.45-1.00) and for those with
nonlocalized cancer the OR was 0.69 (95% CI, 0.37-1.29).
Discussion
In the present prospective case-control study, we show that C.
trachomatis antibodies were not positively associated to the
risk of prostate cancer, but their presence seemed to protect
against cancer. The finding was the same in all three
countries, Finland, Sweden and Norway, and the effect was
even stronger for the higher titres of C. trachomatis antibodies.
The same inverse relationship, although not so strong, was
also seen between antibodies to C. pneumoniae and prostate
cancer.
In the present study, we used the same microimmunofluorescence method, which we have successfully used in our
earlier seroepidemiologic studies for the measurement of
antibodies to C. trachomatis and C. pneumoniae (17, 18, 34).
Antibodies are reasonably stable for several years in serum at
25jC (27). It has been shown that chlamydial IgG antibodies
do not deteriorate even with very long storage time (35).
Matching of cases and controls by storage time was likely to
reduce the effect of potential deterioration. It is unlikely that
methodologic defects are responsible for the overall inverse
association. Furthermore, to minimize the variability, antibodies of each case and its individual controls were always
tested simultaneously in the same titration series in a blinded
fashion by the same observer.
The overall seropositivity for C. trachomatis, 7.5% to 10.5%, is
in accord with national lifetime prevalences among males in
Table 3. ORs with 95% CI of prostate cancer in those with serum positivity to IgG antibodies to C. trachomatis* and
C. pneumoniaec in the Nordic serum sample study by serotype and country
Serotype
C. trachomatis
b
Pools combined
Serotype pool
BED
CJHI
GFK
C. pneumoniae
Total cohort
Finland
Sweden
Norway
OR (95% CI)
OR (95% CI)
OR (95% CI)
OR (95% CI)
0.69 (0.51-0.94)
0.71 (0.40-1.29)
0.52 (0.15-1.79)
0.70 (0.48-1.03)
0.70
0.66
0.65
0.85
0.77
0.69
0.85
0.91
0.52
0.59
0.48
0.92
0.69
0.68
0.66
0.83
(0.51-0.97)
(0.45-0.98)
(0.37-1.14)
(0.72-1.01)
(0.42-1.40)
(0.33-1.45)
(0.34-2.13)
(0.61-1.35)
(0.15-1.79)
(0.17-1.99)
(0.11-2.12)
(0.57-1.51)
*Titers z16 were considered positive and those with IgG titers <16 formed the reference group.
cTiters z32 were considered positive and those with IgG titers <32 formed the reference group.
bAny of serotype pools considered positive.
(0.45-1.03)
(0.42-1.09)
(0.32-1.34)
(0.67-1.02)
387
388
the Nordic countries (10, 36-39). C. trachomatis titer 1:16 was
used in this study. We repeated the analysis with 1:8 as a
cutoff. As expected, this resulted in estimates of higher
prevalence and smaller protective effect probably because of
the unspecific background noise.
Our study population was well defined. The controls were
matched for obvious confounders, which makes selection
bias unlikely. Evidence based on longitudinal studies is
stronger than that based on cross-sectional case-control
studies. Serum banks and cancer registries are ideal for
systematic evaluation of exposure to chlamydial infections
and for identification of individuals who reach the end
point. The sample size of the present study was large and
thus the random fluctuation remains small. Furthermore, the
higher antibody prevalence in controls compared with cases
was found consistently in different countries and there was
a dose-response gradient.
In an earlier Finnish study with another serum bank (10) no
association (RR = 1.0) was found between C. trachomatis
antibodies and risk of prostate cancer. The numbers were few,
however, and based on the confidence interval (0.5-2.0) the
result was also consistent with the 30% protective effect. We
have indicated earlier that women with C. trachomatis antibodies were at increased risk of cervical squamous cell
carcinoma but an inverse association was seen between C.
trachomatis antibodies and cervical adenocarcinoma (17).
Difference by histologic type of tumor was shown also
between lung cancer and C. pneumoniae antibodies: the
presence of antibodies was linked to the squamous cell
carcinoma but not to adenocarcinoma (34). Prostate cancers
are almost uniformly adenocarcinomas. Therefore, the present
study is consistent with some of the previous ones, which,
however, do not explain the finding.
A possibility is that the presence of C. trachomatis in adenoid
cells of prostatic tissue does not induce the formation of serum
antibodies. Recently, it has been suggested that lack of IgA
antibodies to the Hsp60s of C. trachomatis predisposes to male
infertility (40). However, the role of serology in the search of
correlation between C. trachomatis infection and male infertility has been questioned (41-43). Prostate tissue secretes
immunosuppressive proteosomes (44) and seminal fluid
contains high levels of immunosuppressive prostaglandins
(45), which may hamper the development of humoral
antibody response even in cases in which C. trachomatis is
present in the tissue. This could be studied by direct
demonstration of the agent in prostatic tissue (46, 47) which
was not available in the present study. Immunologic mechanisms might explain the lack of positive association but are not
credible explanations of the inverse relationship observed.
The results of the present study further suggest similar
association of both C. trachomatis and C. pneumoniae antibodies
with the risk of prostatic cancer. Misclassification (e.g., due to
cross reactivity) can account for such a relationship. However,
more complex, and differential, misclassification is to be
assumed to explain the inverse relationship between one or
both of the infectious agents and risk of prostate cancer. It is also
possible that if a person has a chlamydial infection in other
parts of the body, the provoked inflammatory response of the
host against these infections may indirectly help the host to fight
against other microbial agents possibly inhibiting the prostatic
cancerous process and by that way protect from prostatic
cancer. Mycobacterial vaccines have been suggested to be useful
in immunotherapy of prostate cancer (48, 49). Chlamydiae
have been shown to inhibit apoptosis of the cells in which
they are hiding, but induce the apoptosis of the other cells (e.g.,
T cells present in the neighborhood (50), and by this way
may destroy important target cells for other microbial agents.
It is also possible that chlamydial antibodies are an indirect
indicator of factors preventing exposure to risk factors of
prostate cancer or reducing the risk of prostate cancer.
Treatment of chlamydia or any disease sufficiently correlated
with chlamydia infection is the most immediate option. There
are examples on such a preventive action (51). We observed a
similar inverse relationship between C. pneumoniae and risk of
prostate cancer, which in principle can be further evidence for
such a mechanism. C. trachomatis is often symptomless in males
and C. pneumoniae has a variety of symptoms, which makes it
unlikely that men positive for these two infections were
subjected to substantially higher doses of, say, antibiotics than
the controls. The hypothesis of the treatment effect is likely to
assume high correlation with a third condition (e.g., gonorrhoea) systematically treated with relatively specific substances
and high doses. Such a third exposure may also belong to
sexual habits, such as ejaculation frequency (52), hormonal
balance (53), or even more remote environmental factors (54).
We showed in the present study that chlamydial antibodies
are more common in controls than in cases of prostate cancer.
We conclude that it is unlikely that C. trachomatis is increasing
the risk of prostate cancer. Whether C. trachomatis infection
prevents prostate cancer remains open. Competing explanations are related to an unidentified confounder, such as to the
effects of treatment of chlamydia or to a related disease or to
the immunologic response to a true etiologic agent or to the
incapability of measuring the true exposure in prostatic tissue
by serology.
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