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Mendelian Randomization In Environmental
Epidemiology Vladimír Bencko Ladislav
Novotný Charles University in Prague 1st
Faculty of Medicine General University
Hospital Institute of Hygiene and Epidemiology
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ASSOCIATION vs. CONFOUNDING
 cruciferous vegetables rich in
isothiocyanates (ITC)   chemopreventive
properties against malignancies at different
cancer sites including lungs - animals
- humans ? because of potential
confounding dietary and life-style factors
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BIOTRANSFORMATION cruciferous glucosinolate
storage to ITC
animals humans vegetable consumption
myrosinase
glucosinolate

ITC
independent roles of genes to other
dietary, lifestyle factors, reducing
the possibility of confounding
eliminated by glutathione-S-transferases
GSTM1 GSTT1.5 GSTT1.6
/ .. GST genes - / -
ITC tissue ? concentration ?
DNA responsive elements - antioxidant -
electrophile
metabolism phase II proteins ? production
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STUDY DESIGN - Lung Ca vs. dietary cruciferous
vegetables
Our institute participated in a case-control
study of 2141 cases and 2168 controls in six
countries of central and eastern Europe, a
region that has traditionally high rates of
cruciferous vegetable consumption lung cancer
cases and age-sex matched hospital or population
controls recruited from 15 centres in Poland,
Slovakia, Czech Republic, Romania, Russia, and
Hungary by use of an identical protocol and
questionnaire
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STUDY DESIGN vegetable consumption asessment
all participants completed a detailed
standardised lifestyle and food frequency
questionnaire that had been piloted in all
centres before use the dietary component of the
questionnaire listed 23 foods, of which three
were cruciferous vegetables cabbage and a
combination of brussels sprouts with
broccoli the questionnaire was repeated for two
different periods 1. the year before
interview 2. before political and market changes
in 1989 (1991 in Russia) a weighted
age-specific average of the two was calculated
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STUDY DESIGN GST genotyping, ethics
for all individuals PCR-based genotyping for
GSTM1 and GSTT1 neither GSTM1 nor GSTT1 were
related to potential confounding factors in the
controls country, age, smoking status,
education, and dietary variables incl.
cruciferous vegetables Mendelian randomization
in action written informed consent was provided
by all participants before their involvement in
the study ethical approval for recruitment of
participants and genotyping was obtained from
institutional review boards in all the study
centres, and from the IARC ethics committee
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RESULTS

• weekly consumption of cruciferous vegetables
• protected against lung cancer (OR, 95 CI) in
  homozygotes
• - GSTM1 null 067, 049091
• - GSTT1 null 063, 037107
• - M1 / T1 null/null 028, 011067
• similar protective results were noted for
  consumption of
• - cabbage and
• - combination of broccoli and brussels sprouts
• no protective effect was seen in people who were
• - both GSTM1 and GSTT1 positive (088,
  065121)

these data provide strong evidence for a
substantial protective effect of cruciferous
vegetable consumption on lung cancer incidence
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CONCLUSIONS
an overall protective effect was seen for
consumption of cruciferous vegetables at least
once a week compared with less than monthly
adjusted OR 078, 95 CI 064096, which was
much the same for both cabbage consumption and
for broccoli and brussels sprout consumption
the results also accord with those of several
smaller studies of lung cancer, breast cancer,
and colorectal adenomas, which showed a
protective effect in GSTM1 and GSTT1 null carriers
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Acknowledgement

• PROJECT
• supported by EC INCO-COPERNICUS grant
  IC15-CT96-0313,
• NCI grant CA 092039-01A2
• Effect of cruciferous vegetables on lung cancer
  in patients stratified by genetic status a
  mendelian randomisation approach.
• Lancet 2005 366 1558-1560
• Paul Brennan, Charles C Hsu, Norman Moullana,
  Neonilia Szeszenia-Dabrowska, Jolanta Lissowska,
  David Zaridze, Peter Rudnai, Eleonora Fabianova,
  Dana Mates, Vladimir Bencko, Lenka Foretova,
  Vladimir Janout, Federica Gemignani, Amelie
  Chabriera, Janet Hall, Rayjean J Hung, Paolo
  Boffetta and Federico Canzian

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Acknowledgement
INSTITUTIONS
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T h a n k s f o r y o u
r a t t e n t I o n
  Address for correspondence Prof Vladimir
Bencko, MD, PhD Charles University in Prague 1st
Faculty of Medicine General University
Hospital Institute of Hygiene and
Epidemiology vladimir.bencko_at_lf1.cuni.cz