Supplemental
Materials and Methods
Patients
Hungary
The Hungary case-control series contains 262 bladder cancer cases and 65 controls
from the Department of Urology, Semmelweis University, Budapest. All cases and
controls
are
Caucasians,
which
were
confirmed
by
questionnaire-based
documentation of nationality. The median age at diagnosis was 70 (range 27-95)
years. 60% of the participants were males. The controls (80% males) were cancer
free. Data were collected from 2004 to 2006. Data on tumour stage and grade were
obtained through the cancer registry. Controls without malignant disease were
frequency-matched for age (time of examination) with the cases. Data collected in
cases and controls, include age, gender, a documentation of occupational activities
and exposures to known or suspected occupational bladder carcinogens and lifetime
smoking habits.
East Germany
The Wittenberg case-control series (Lutherstadt Wittenberg bladder cancer study) as
described (Golka et al. 2009) was used. In brief, 212 patients with a confirmed
bladder cancer from the Department of Urology, Paul Gerhardt Foundation,
Lutherstadt Wittenberg, Germany, were included. Patients were enrolled from
December 1995 to January 1999. The median age at diagnosis was 66 (range 20-91)
years. 86% of the participants were males. Controls (86% males) were from the
2
same department of urology, but were admitted for treatment of benign urological
diseases. Exclusion criteria were a malignant disease in the medical history or a
missing written informed consent. All cases and controls were Caucasians, which
were confirmed by questionnaire-based documentation of nationality. Data were
collected from July 2000 to May 2005. Cases and controls were matched for age.
Data collected for cases and controls include age, gender, a complete documentation
of occupational activities performed at least for 6 months, documentation of work
places with known bladder cancer risk over the entire working life, exposures to
known or suspected occupational bladder carcinogens, lifetime smoking habits,
family history of bladder cancer, numbers of urinary infections treated by drugs
during the previous 10 years, place of birth and places of residency for more than 10
years. In the case of bladder cancer cases, data on tumour staging, grading and
treatment were taken from the records. Bladder cancer was diagnosed from July
1979 to January 1999.
West Germany
West Germany-ongoing case-control series (W. Germany-ongoing)
The West Germany ongoing case-control series contains bladder cancer cases and
controls from the Department of Urology, St.-Josefs-Hospital Dortmund-Hörde, the
Department of Urology, Klinikum Dortmund, the Department of Urology, Lukasklinik
Neuss, the Department of Urology at the Heinrich-Heine University of Düsseldorf and
from the department of Urology at the Johannes Gutenberg University of Mainz,
Germany. All cases and controls are Caucasians, which was confirmed by
questionnaire-based documentation of nationality. Data on tumour stage and grade
3
were obtained through the cancer registry. All study groups are still ongoing.
Exclusion criterion was a missing written informed consent. Controls were frequencymatched for age (time of examination) with the cases. Data collected for cases and
controls include age, gender, a complete documentation of occupational activities
performed at least for 6 months, documentation of work places with known bladder
cancer risk over the entire working life, exposures to known or suspected
occupational bladder carcinogens, lifetime smoking habits, family history of bladder
cancer, numbers of urinary infections treated by drugs during the previous 10 years,
place of birth and places of residency for more than 10 years.
Dortmund bladder cancer study, St.-Josefs-Hospital Dortmund-Hörde, Germany
The case-control series consists of 129 patients with a confirmed bladder cancer
from the Department of Urology, St.-Josefs-Hospital Dortmund-Hörde, located in an
area of former coal, iron and steel industries and 131 controls from the same
Department of Urology, admitted for treatment of benign urological diseases, enrolled
from July 2009 to April 2010. The median age at diagnosis was 71 (range 35-89)
years. 79% of the participants were males. The 131 control individuals (70% males)
were cancer free and frequency-matched for age with the cases.
Dortmund bladder cancer study, Klinikum Dortmund, Germany
Thirty-two bladder cancer cases and two controls from the Department of Urology,
Klinikum Dortmund, Germany, located in an area of former coal, iron and steel
industries, enrolled from July 2007 to April 2010 were included. The median age at
diagnosis was 67 (range 48-83) years. 72% of the participants were males. Data
4
were collected from July 2007 to April 2010. The two controls (one male) were
cancer free.
Neuss bladder cancer study, Lukasklinik Neuss, Germany
The ongoing case-control series consists of 97 bladder cancer cases and two
controls from the Department of Urology, Lukasklinik Neuss, Germany. The median
age at diagnosis was 74 (range 26-93) years. 77% of the participants were males.
Data on tumour stage and grade were obtained through the cancer registry. The two
male control individuals were cancer free. Data was collected from June 2009 to April
2010.
Düsseldorf bladder cancer study, Heinrich-Heine University, Germany
The ongoing case-control series consists of 41 bladder cancer cases and 15 controls
from the department of Urology at the Heinrich-Heine University of Düsseldorf,
Germany. The median age at diagnosis was 70 (range 27-95) years. 83% of the
participants were males. The controls (93% males) were cancer free. Data was
collected from November 2009 to April 2010.
Mainz bladder cancer study, Johannes Gutenberg University, Germany
Eighteen bladder cancer cases and nine controls from the department of Urology at
the Johannes Gutenberg University of Mainz, Germany, were included. The median
age at diagnosis was 63 (range 37-81) years. 72% of the participants were males.
Data on tumour stage and grade were obtained through the cancer registry. The nine
control individuals (78% male) were cancer free. Data was collected from January
2010 to April 2010.
5
West Germany–industrial burdened case-control series (W. Germany-industrial)
The West Germany – industrial burdened case-control series (W. Germany industrial) consists of two independent case groups and one control cohort.
Dortmund hospital based case-series (DO-hospital)
Eighty-seven patients with confirmed bladder cancer from the Department of Urology,
Klinikum Dortmund, Germany, located in an area of former coal, iron, and steel
industries, were included. Exclusion criterion was a missing written informed consent.
Data were collected from November 1993 to June 1995. All items of the
questionnaire applied in Dortmund were also included in the extended version of the
questionnaire presented to the cases and controls in the Lutherstadt Wittenberg
group. Bladder cancer was diagnosed from July 1981 to June 1995. The median age
at diagnosis was 67 (range 45-94) years. 84% of the participants were males.
Dortmund occupational case-control series (DO-occupational)
The Occupational case-series (study on patients with suspected occupational
bladder cancer) as described (Golka et al. 2009) was used. Details of the ongoing
study on 329 suspected cases of occupational bladder cancer from Germany, mainly
from the Federal State of North Rhine-Westphalia, reported to the authorities and
surveyed for recognition of an occupational disease (in Germany named
“Berufskrankheit BK 1301”) from February 1996 to April 2010 were reported recently.
The individuals were suspected to be exposed to occupational bladder carcinogens,
mostly carcinogenic aromatic amines, azo dyes based on carcinogenic aromatic
amines or polycyclic aromatic hydrocarbons. According to the situation at work
6
places in former decades, 93% of the patients were males. All patients were
Caucasians. The median age at diagnosis was 60 (range 32-83) years. All surveyed
bladder cancer patients gave informed consent for genotyping of enzymes relevant
for bladder cancer and N-acetyltransferase 2 phenotyping by caffeine metabolites.
Therefore, blood and urine samples were also obtained. Occupational and
concurrent non-occupational risk factors for bladder cancer were explored by three
medical specialists in a personal interview.
Dortmund controls (DO-controls)
The control group consists of persons from the greater Dortmund area, Germany,
who did not present a malignancy in the medical history. Dortmund is a city with
approximately 600,000 inhabitants located in North Rhine-Westphalia, which is the
westernmost and - in terms of population and economic output - the largest Federal
State of Germany. Briefly, 180 patients of the Department of Surgery of the Klinikum
Dortmund without any malignancy in the medical history, 230 patients without
malignancies from the St. Elisabeth Hospital in Iserlohn, Germany, 21 persons with
suspected occupational diseases other than bladder cancer, 95 former hard coal
miners with pneumoconiosis recognized for an occupational disease surveyed for the
course of their disease, 323 persons participating in an ongoing study on the impact
of enzyme polymorphisms on selected brain functions as well as 60 staff of the
Dortmund institute serving as controls in different studies were included. In total, 909
individuals were combined to a control group representing inhabitants of the greater
Dortmund area. The median age at examination was 68 (range 20-91 years) and
51 % of the controls were males.
7
Pakistan
The Pakistan case-control series contains 103 bladder cancer cases, 101 controls
from the Sindh Institute of Urology and Transplantation, Civil Hospital, Karachi and
126 population based controls. All cases and controls are Pakistani, which was
confirmed by questionnaire-based documentation of nationality. The median age at
diagnosis was 61 (range 24-82) years. 87% of the participants were males. The
controls (80% males) were cancer free. Data were collected from April 2003 to
January 2004. Data on tumour stage and grade were obtained through the cancer
registry. Controls without malignant disease were frequency-matched for age (time of
examination) with the cases. Data collected in cases and controls include age,
gender, a documentation of occupational activities and exposures to known or
suspected occupational bladder carcinogens and lifetime smoking habits.
Venezuela
The Venezuelan case-control series contain 112 bladder cancer cases from
Departments of Urology, University Hospital at Central University, Caracas; Domingo
Luciani Hospital from the Venezuelan Institute of Social Security, Caracas; Oncologic
Hospital “Padre Machado”, Caracas, and Policlínica Metropolitana, Caracas. A total
of 190 controls were from the same departments of urology, as well as from the
Medical Faculty at Central University, Caracas, and all were free of any type of
cancer. All cases and controls are Venezuelan; though some of the patients were
residents in Venezuela but were of different origin, mainly Colombian, Ecuadorian,
Peruvian, Italian and Portuguese which was confirmed by questionnaire-based
documentation of nationality. The median age at diagnosis was 59 (range 29-87)
years. 71% of the participants were males. The controls (41% males) were cancer
8
free. Data were collected from December 2006 to November 2009, the study is still
ongoing. Data on tumour stage and grade were obtained by the cancer registry.
Controls without malignant disease were frequency-matched for age (time of
examination) with the cases. Data collected in cases and controls include age,
gender, a complete documentation of occupational activities performed at least for 6
months, documentation of work places with known bladder cancer risk over the entire
working life, exposures to known or suspected occupational bladder carcinogens,
lifetime smoking habits, family history of bladder cancer, numbers of urinary
infections treated by drugs during the previous 10 years, place of birth and places of
residency for more than 10 years. In the case of bladder cancer cases, data on
tumour staging, grading and treatment were taken from the records. The local ethics
committees approved the study plan and design.
Analysis of polymorphisms
For differentiating between the homozygous frequent (A/A), homozygous variant
(G/G) and heterozygous (A/G) form of the sequence of interest approximately 5-8
ml of venous blood was taken into a 9 ml tube (Sarstedt, Nümbrecht,
Germany) from the cubital vein with EDTA as the anticoagulant and was frozen at
-20°C (Saravana et al. 2008). DNA was isolated using a QIAamp DNA blood maxi kit
(Qiagen, Hilden, Germany) according to the manufacturer’s protocol (Arand et al.
1996). DNA concentrations were determined using a NanoDrop ND-1000 UV/Visspectrophotometer
(PEQLAB
Biotechnologie
GMBH,
Erlangen,
Germany).
Genotyping was performed on an ABI7500 Sequence Detection System with the use
of TaqMan® assays (Applied Biosystems, Darmstadt, Germany). A final reaction
volume of 15 μl was used per well of a 96-well plate. The reaction mix for
9
amplification was prepared by mixing 7.5 µl TaqMan ® Universal PCR Master Mix
(Applied Biosystems, Foster City, CA 94404, U.S.A.) and 0.75 µl Working Stock of
SNP Genotyping Assay (Applied Biosystems, Foster City, CA 94404, U.S.A.) per
sample. To this reaction mixture 1 µl DNA solution (with a total of 10 ng DNA) and
5.75 µl distilled water were added to achieve a final volume of 15 µl. Amplification
was performed using a protocol with 40 cycles, 15 s at 92 °C (denature), 1 min at 60
°C (anneal/extend). An initial hold with 10 min at 95 °C was applied. Analysis of data
was performed according to the manufacturer’s instructions (Applied Biosystems
7300/7500/7500, fast real-time PCR System Allelic Discrimination Getting Started
Guide).
Statistical analysis
Cigarette smoking was defined as non-smokers, former smokers, i.e. smokers that
quitted smoking at least one year before diagnosis (cases) or examination (controls),
and current smokers. Former and current smokers were pooled together as “ever
smokers”. Age was defined as “age at diagnosis” for the cases and “age at
examination” for the control persons. Genetic models are defined according to (Lewis
2002). Deviations from Hardy-Weinberg equilibrium were checked in each study
group and separately for cases and controls using exact chi-square tests. Cochran's
Q test was applied to test for heterogeneity of the odds ratios of the multiplicative
model in the combined Caucasian study groups and in all study groups combined.
Associations of the rs710521 genotype with urinary bladder cancer were evaluated
applying exact chi-square tests in case of the global, recessive, dominant (not
shown) and multiplicative (allelic) model, Armitage trend tests were used for the
additive model. For the combined Caucasian study groups and for all study groups
10
combined the method of Mantel-Haenszel was used to adjust for the different study
groups (combined Caucasian groups: regions are shown, all combined: ethnicities
are shown). Adjusted odds ratios and confidence intervals as well as Wald chisquare tests adjusted for age, cigarette smoking (non smoker, former, current),
gender, and origin in case of combined study groups were calculated using logistic
regression. Effects of smoking on urinary bladder cancer as well as associations
between rs710521, smoking habits and urinary bladder cancer carcinogens were
investigated using exact chi-square tests. The power analysis (Clayton and Hills
1993) was performed for a chi-square test at  = 0.05, risk allele frequency of 0.5 and
0.73 and odds ratios of 1.15, 1.2, 1.25, 1.3, and 1.4, respectively, in the different and
combined study groups (Supplemental Table S4) using the PS Power and Sample
Size Program version 3.0.12 (Dupont and Plummer 1998; Dupont and Plummer
1990). The linkage disequilibrium plot of r² for a region around rs710521
(chromosome 3, 191.078.000 -191.178.000) was obtained using the Haploview V4.2
program (Barrett et al. 2005). The plot is based on HapMap Data PhaseIII/Rel#3,
locations are from NCBI Genome Build 36. A meta-analysis for the multiplicative
model was conducted on the basis of the test and validation set from China as
described by Wang et al. (2009), the two discovery (GWA) and seven follow-up study
groups from Iceland, the Netherland, U.K., Torino (Italy), Brescia (Italy), Belgium,
Eastern Europe, Sweden and Spain presented by Kiemeney et al. (2008) and the
present study groups (Hungary, East Germany, W. Germany-ongoing, W. Germanyindustrial, Pakistan and Venezuela). A further study of Wu et al. (2009) comprising
rs710521 genotypes of totally 1,713 cases and 4,828 controls of four new study
groups was not included into the meta-analysis due to insufficient data on allele
frequencies. Small deviations in the 95% CI for the Kiemeney et al. (2008) study
11
groups result from the necessity to derive the numbers of rs710521[A] alleles in
cases and controls from the given frequencies. The Funnel plot (Light and Pillemer
1984) and Egger's test (Egger et al. 1997) were used to check for a substantial bias
in the study results. Heterogeneity of the allelic ORs was tested using Cochran's Q
test. Combined ORs, 95% CIs and p values were calculated using the method of
Mantel-Haenszel. The level of significance was  = 0.05 for all tests and confidence
intervals. The meta-analysis, funnel plots, Egger's test, forest plots and Cochran's Q
test were performed using the software R, version 2.10.1 (R Development Core
Team 2008). All further calculations were performed using the software package
SAS/STAT®, version 9.2 (SAS/STAT® software, version 9.2. Copyright © 2002-2008),
if not indicated otherwise.
12
Supplemental Tables
Table S1. Distribution of gender in the study groups.
Study groups
Frequency males Frequency males
cases
controls
n
n
%
%
Caucasians combined
963
0.80
795
Hungary
156
0.60
52
Germany combined
807
0.85
743
East Germany
184
0.86
163
West Germany combined 623
0.85
580
W. Germany - ongoing
247
0.78
117
W. Germany - industrial 376
0.91
463
1
DO - hospital
73
0.84
DO - occupational1
303
0.93
2
DO - controls
463
Non Caucasian study groups:
Pakistan
90
0.87
99
Venezuela
79
0.71
78
All combined
1,132
0.80
972
1 Only cases
2 Only controls
For 107 persons gender was not documented.
0.60
0.80
0.59
0.86
0.54
0.73
0.51
0.51
0.80
0.41
0.59
13
Table S2. Distribution of age at diagnosis (cases) and at examination
(controls), respectively, in the study groups.
n
Min
Max
Cases
Controls
Hungary
Cases
Controls
Germany combined:
Cases
Controls
East Germany
Cases
Controls
West Germany combined Cases
Controls
W. Germany - ongoing
Cases
Controls
W. Germany - industrial Cases
Controls
DO - hospital
Cases
1,173
1,320
257
65
916
1,255
215
189
701
1,066
302
159
399
907
87
20.1
20.1
27.2
33.6
20.1
20.1
20.1
29.4
26.1
20.1
26.1
21.7
32.1
20.1
44.8
95.2
94.6
95.1
84.2
95.2
94.6
91.3
91.2
95.2
94.6
95.2
94.6
83.9
90.9
83.9
DO - occupational
Cases
312
32.1
DO - controls
Controls 907
Study groups
Status
Caucasians combined
Non Caucasian study groups:
Pakistan
Cases
Controls
Venezuela
Cases
Controls
All combined
Cases
103
124
106
187
1,382
65.9
64.7
68.9
63.5
65.0
64.8
65.0
67.2
65.0
64.4
69.7
63.5
61.4
64.5
66.9
Standard
deviation
11.5
13.5
11.5
12.0
11.4
13.5
11.3
10.3
11.5
14.0
11.1
15.0
10.5
13.8
9.4
83.3 60.0
59.9
10.2
20.1
90.9 67.6
64.5
13.8
24.0
26.0
29.3
20.0
20.1
82.0
77.0
87.1
90.5
95.2
61.0
56.0
58.9
30.2
65.6
59.3
54.3
59.9
35.9
64.9
13.2
13.9
11.9
15.6
11.9
94.6 65.0
60.6
16.6
Controls 1,631 20.0
Media
n
66.4
67.3
70.4
63.5
65.5
67.4
65.7
67.1
65.4
67.5
71.3
66.5
61.2
67.6
67.4
Mean
14
Table S3. Frequencies of cases and controls in the study groups.
n
1,210 (1,115)
1,323 (1,312)
262 (231)
65 (62)
948 (884)
1,258 (1,250)
215 (214)
189 (187)
733 (670)
1,069 (1,063)
317 (299)
160 (159)
416 (371)
909 (904)
87 (87)
329 (284)
909 (904)
HWE p value
0.7069
0.8383
0.9961
0.3348
0.7075
0.9412
0.2673
0.9198
0.2052
0.9796
0.0741
0.983
0.9471
0.9495
0.925
0.9863
0.9495
Cases
103 (103)
Controls
227 (60)
Venezuela
Cases
112 (105)
Controls
190 (187)
All combined
Cases
1,425 (1,323)
Controls
1,740 (1,559)
In parenthesis: number of cases/controls with completely documented
gender, and smoking habits.
P values are given for the test of Hardy-Weinberg equilibrium (HWE).
0.7365
0.0202
0.7135
0.3832
0.6354
0.9889
data for age,
Study groups
Caucasians combined
Hungary
Germany combined
East Germany
West Germany combined
W. Germany - ongoing
W. Germany - industrial
DO - hospital
DO - occupational
DO - controls
Non Caucasian study groups:
Pakistan
Status
Cases
Controls
Cases
Controls
Cases
Controls
Cases
Controls
Cases
Controls
Cases
Controls
Cases
Controls
Cases
Cases
Controls
15
Table S4. Power analysis for the case-control series of the present study and
for Wang et al. (2009) to detect ORs of 1.15 to 1.4.
A. Case-control series of the present study
Germans
Caucasians
All combined
Cases/Controls Freq [A] 1.15
948/1,258
0.5
0.631
1.2
0.849
1.25
0.956
1.3
0.990
1.4
1.0
1,210/1,323
0.73
0.5
0.516
0.699
0.738
0.899
0.886
0.996
0.960
0.996
0.997
1.0
1,425/1,740
0.73
0.5
0.582
0.789
0.803
0.950
0.929
0.993
0.980
0.999
0.999
1.0
0.73
0.674
0.879 0.968 0.994 1.0
The power was calculated assuming a multiplicative model and a frequency of the
risk allele [A] in controls of 0.5 and 0.73, respectively (according to Kiemeney et al.
2008).
B. Case-control series published by Wang et al. (2009) with 415 cases and 465
controls
Cases/Controls Freq [A] 1.15
1.2
1.25
1.3
1.4
Wang et al. 415/465
0.5
0.309
0.478 0.644 0.782 0.939
(2009)
0.73
0.247
0.380 0.522 0.654 0.850
The power was calculated assuming a multiplicative model and a frequency of the
risk allele [A] in controls of 0.5 and 0.73, respectively (according to Kiemeney et al.
2008).
16
Table S5.a. Unadjusted p values for further genetic models (supplemental
information to Table 1).
Study groups
n
cases/
controls
Caucasians
combined
Hungary
Germany
combined
East Germany
West Germany
combined
W. Germany ongoing
W. Germany industrial
DO - hospitala
1,210/1,323 0.76/0.73
Freq
rs710521 [A]
cases/controls
Genotype
model
p value
Additive
model
p value
Multiplicative
model
p value
0.0915
(0.0221)
1.0000
0.0846
0.0910
(0.0219)
1.0000
0.0836
262/65
948/1,258
0.79/0.78
0.75/0.73
0.1005
(0.0424)
0.3607
0.1551
215/189
733/1,069
0.76/0.72
0.75/0.73
0.2235
0.1523
0.1575
0.2223
0.1720
0.2171
317/160
0.74/0.71
0.2966
0.3364
0.3152
416/909
0.76/0.73
0.4693
0.2514
0.2518
87/909
0.75/0.73
0.8086
0.6522
0.5899
DO 329/909
0.76/0.73
a
occupational
Non Caucasian study groups:
Pakistan
103/227
0.86/0.88
0.5196
0.2751
0.4684
0.6251
0.6411
0.6169
Venezuela
All combined
0.2796
0.0378
(0.2436)
0.1246
0.0156
(0.1248)
0.1423
0.0153
(0.1222)
aControls
112/190
0.83/0.78
1,425/1,740 0.77/0.76
are the Dortmund control group
Frequencies (Freq) of the rs710521[A] allele, p values of the exact chi-square test of
independence for the genotype model (global p value) and for the allelic
(multiplicative) model as well as the exact p value of the two-sided CochranArmitage trend test (trend test) for the additive model are given.
The combined Caucasian study groups have been adjusted for different regions
(Hungary, East Germany, West Germany) using the method of Mantel-Haenzsel. All
study groups combined have been adjusted for different ethnicities. The respective
unadjusted p values are given in parenthesis. Risk factor is the A/A genotype and
the [A] allele.
17
Table S5.b. Unadjusted ORs and 95% CIs for different genetic models
(corresponding data to table S5.a).
Study groups
Caucasians combined
Hungary
Germany combined
East Germany
West Germany combined
W. Germany - ongoing
W. Germany - industrial
DO - hospitala
DO - occupationala
Non Caucasian study groups:
Pakistan
Venezuela
All combined
Genotype model
A/A vs
A/A vs
A/G
G/G
OR
OR
(95% CI) (95% CI)
1.20
1.09
1.02-1.43 0.78(1.23)
1.52
(1.04(1.21)
1.45)
(0.881.68)
1.28
0.36
0.73-2.25 0.052.83
1.19
1.16
0.99-1.42 0.831.63
1.14
2.19
0.76-1.70 0.885.44
1.22
1.02
0.9960.711.48
1.48
1.38
1.09
0.92-2.07 0.542.16
1.19
1.17
0.91-1.48 0.721.89
1.18
1.06
0.74-1.89 0.442.56
1.15
1.20
0.88-1.51 0.702.04
Additive
model
Multiplicative model
[A] vs [G]
OR
(95% CI)
1.12
0.98-1.28
(1.16)
(1.021.32)
OR
(95% CI)
1.12
0.98-1.28
(1.16)
(1.02-1.32)
0.75
1.15
0.42-1.33 0.304.44
1.44
2.03
0.87-2.37 0.4010.31
1.20
1.23
1.04-1.40 0.90(1.13)
1.67
0.88
0.87
0.56-1.37 0.53-1.47
1.02
1.02
0.64-1.65 0.61-1.66
1.13
1.13
0.98-1.29 0.98-1.30
1.28
1.25
0.92-1.77 0.90-1.74
1.10
1.10
0.95-1.28 0.94-1.29
1.16
1.17
0.87-1.55 0.86-1.60
1.12
1.12
0.93-1.35 0.92-1.36
1.10
1.11
0.77-1.58 0.77-1.63
1.12
1.09
0.91-1.38 0.87-1.37
1.43
1.39
0.92-2.24 0.89-2.19
1.16
1.16
1.03-1.30 1.03-1.30
(1.10)
(1.10)
18
(0.971.31)
aControls
(1.13)
(0.831.53)
(0.981.23)
(0.98-1.24)
are the Dortmund control group
OR = odds ratio; 95% CI = 95% confidence intervals
Unadjusted ORs and 95% CIs for the genotype model, for the additive model and for
the multiplicative model are given. The combined Caucasian study groups have
been adjusted for different regions (Hungary, East Germany, West Germany). All
study groups combined have been adjusted for different ethnicities. The respective
uncorrected ORs and 95% CIs are given in parenthesis. Risk factor is the A/A
genotype and the [A] allele.
19
Table S6. Age, gender and smoking habits adjusted p values, ORs and 95% CIs
for further genetic models (supplemental information to Table 2).
Study groups
Genotype model
A/A vs A/A vs
A/G
G/G
Additive model
Multiplicative
model
p
value
p
value
p
value
OR
OR
95% CI 95% CI
OR
95% CI
OR
95% CI
Caucasians
combined
0.0988 1.22
1.021.47
1.10
0.771.57
0.0893 1.13
0.981.30
0.0894 1.13
0.981.30
Hungary
0.6963 1.15
0.862.15
0.48
0.054.20
0.9916 1.00
0.581.73
0.9920 1.00
0.601.68
Germany combined 0.0519 1.27
1.041.54
East Germany
0.4456 1.15
0.751.76
West Germany
0.0268 1.35
combined
1.081.69
W. Germany 0.4406 1.33
ongoing
0.862.05
W. Germany 0.0601 1.41
industrial
1.061.87
0.3847 1.36
DO - hospitala
0.822.24
0.0723 1.43
DO - occupationala
1.041.95
Non Caucasian study groups:
Pakistan
0.4710 0.85
0.241.44
Venezuela
0.1314 2.09
0.984.44
1.18
0.821.70
1.81
0.694.72
1.03
0.691.55
1.13
0.552.31
1.22
0.692.14
0.81
0.312.08
1.40
0.742.63
0.0391 1.17
1.011.36
0.2437 1.23
0.871.74
0.0905 1.16
0.981.37
0.3606 1.15
0.851.56
0.0509 1.25
0.9991.56
0.6063 1.11
0.751.66
0.0368 1.30
1.021.67
0.0384 1.17
1.011.36
0.2615 1.21
0.871.68
0.0876 1.16
0.981.37
0.3377 1.17
0.851.61
0.0552 1.24
0.9951.54
0.6198 1.10
0.751.62
0.0414 1.29
1.011.64
0.56
0.056.85
0.60
0.065.56
0.2388 0.63
0.291.36
0.1408 1.68
0.843.36
0.2216 0.61
0.281.34
0.1735 1.54
0.832.88
20
All combined
aControls
0.0372 1.14
1.041.45
1.22
0.871.71
0.0185 1.68
1.031.33
0.0186 1.17
1.031.33
are the Dortmund control group
OR = odds ratio; 95% CI = 95% confidence intervals
P values, ORs and 95% CIs adjusted for age, gender and smoking habits for the
genotype model, for the additive model and for the multiplicative model are given.
The combined Caucasian study groups have been adjusted for different regions
(Hungary, East Germany, West Germany). All study groups combined have been
adjusted for different ethnicities. Risk factor is the A/A genotype and the [A] allele.
0.10
0.15
0.25
0.20
Standard error
0.05
0.00
21
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Odds Ratio
Figure S1. The funnel plot of 17 study group results (Kiemeney et al. 2008; Wang et
al. 2009; present study) used for the meta-analysis indicates no substantial bias. This
is confirmed by the Egger's test (p = 0.2981). Thus, the present study groups seem
to provide a solid basis for a meta-analysis of the association of rs710521[A] and
urinary bladder cancer.
22
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