347
Research article/Raziskovalni prispevek
GENETIC POLYMORPHISM OF CYTOCHROMES P450
2C9 AND 2C19 IN SLOVENIAN POPULATION
GENETSKI POLIMORFIZEM CITOKROMOV P450 2C9 IN 2C19 V SLOVENSKI POPULACIJI
Darja Herman, Vita Dolžan, Katja Breskvar
Institute of Biochemistry, Faculty of Medicine, Vrazov trg 2, 1525 Ljubljana
Arrived 2002-09-02, accepted 2003-04-07; ZDRAV VESTN 2003; 72: 347–51
Ključne besede: farmakogenetika; genotipizacija; CYP2C9;
CYP2C19
Izvleček – Izhodišča. Citokromi P450 2C9 (CYP2C9) in 2C19
(CYP2C19) so vključeni v presnovo različnih zdravil. Kodi-
rata jih polimorfna gena CYP2C9 in CYP2C19, zaradi česar
prihaja do interindividualnih razlik v hitrosti in učinkovito-
sti zdravljenja. Genetski polimorfizem postane klinično po-
memben predvsem pri zdravilih, ki imajo majhno terapevt-
sko širino. Namen raziskave je bil določiti frekvence polimorf-
nih alelov CYP2C9 in CYP2C19 v slovenski populaciji in na
ta način oceniti delež posameznikov s povečanim tveganjem
za nastanek neželenih učinkov zdravila.
Metode. Polimorfizem genov CYP2C9 in CYP2C19 smo anali-
zirali s tehniko genotipizacije. Ta temelji na pomnoževanju
ustreznega dela genomske DNK z verižno reakcijo s polime-
razo in na cepitvi pomnoženega odseka z ustreznim encimom.
Uporabili smo vzorce DNK 129 nesorodnih, zdravih posame-
znikov, ki smo jih dobili na Centru za transfuzijo Republike
Slovenije in na Pediatrični kliniki v Ljubljani.
Rezultati. V analizirani skupini smo zasledili, da je ena tretji-
na posameznikov imela vsaj enega od polimorfnih alelov
CYP2C9, med njimi pa je bilo 3,2% posameznikov z obema
polimorfnima aleloma. Frekvenci alelov CYP2C9*2 in
CYP2C9*3 sta bili 0,122 oz. 0,063. Podobno je skoraj ena tret-
jina posameznikov imela vsaj enega od polimorfnih alelov
CYP2C19. Frekvenci alelov CYP2C19*2 in CYP2C19*3 sta
bili 0,159 oz. 0,004.
Zaključki. Rezultati naše raziskave kažejo, da ima približno
tretjina Slovencev zmanjšano metabolno kapaciteto za zdra-
vila, ki se presnavljajo prek CYP2C9 oz. CYP2C19. Takim ose-
bam bi bilo treba med zdravljenjem z zdravili z majhno tera-
pevtsko širino ustrezno prilagoditi odmerek zdravila oz. na-
tančneje spremljati potek zdravljenja, še posebno v obdobju
uvajanja zdravila. Pri 1–3% takšnih posameznikov pa je večja
verjetnost pojava hujših neželenih učinkov zdravil.
Key words: pharmacogenetic; genotyping; CYP2C9; CYP2C19
Abstract – Background. Cytochrome P450 2C9 (CYP2C9) and
2C19 (CYP2C19) participate in metabolism of many clinically
important drugs. Genetic polymorphisms of the CYP2C9 and
CYP2C19 genes are described which may affect drug treat-
ment. The aim of this study was to determine the frequencies
of polymorphic CYP2C9 and CYP2C19 alleles in Slovenian
population in order to estimate the proportion of the popula-
tion that might experience adverse drug reaction.
Methods. The polymorphism of CYP2C9 and CYP2C19 was
analysed by a genotyping technique, based on polymerase
chain reaction (PCR) followed by restriction enzyme analy-
sis. DNA samples from 129 unrelated healthy subjects were
obtained from the Blood Transfusion Centre of Slovenia and
University Children’s Hospital in Ljubljana.
Results. In the analysed group of samples one-third of indivi-
duals carried at least one of the defective CYP2C9 alleles whi-
le among them 3.2% of individuals had both alleles affected.
The frequencies of CYP2C9*2 and CYP2C9*3 were 0.122 and
0.063, respectively. Almost one-third of Slovenian individu-
als analysed carried at least one of the CYP2C19 polymor-
phic allele. The frequencies of CYP2C19*2 and CYP2C19*3
were 0.159 and 0.004, respectively.
Conclusions. The results of our study indicate that approxi-
mately one-third of the patients from Slovenian population
may require either adjustments of dose or increased monito-
ring when initiating treatment with CYP2C9 and CYP2C19
substrates having a narrow therapeutic index. High risk of
adverse drug reaction may be expected in 1–3% of eventual
patients.
This work was financially supported by Ministry of Education, Science and Sport of Slovenia (Grant No. P0-0503-0381).
Introduction
Cytochromes P450 (CYPs) are a superfamily of heme proteins
which catalyse many types of reactions, predominantly hy-
droxylations. They participate in oxidative metabolism of a
wide variety of structurally diverse compounds, including en-
dogenously synthesised compounds such as steroids and fat-
ty acids, as well as exogenous compounds such as drugs, car-
ZDRAV VESTN 2003; 72: 347–51
348 ZDRAV VESTN 2003; 72
cinogens and environmental agents. Genes for cytochromes
P450 (CYPs) are classified according to their sequence simila-
rities, into distinct gene families (designated by CYP followed
by an Arabic numeral) and subfamilies (designated by a letter
following the Arabic numeral). Individual genes are designa-
ted by the second Arabic numeral following the letter (1).
CYP2C gene subfamily represents a cluster of four genes on
the chromosome 10q24, arranged in the sequential order
CYP2C8-CYP2C9-CYP2C19-CYP2C18 (2). CYP 2C8, 2C9, 2C18
and 2C19 share more than 82% amino acid identity. Despite
the high level of sequence similarity they exhibit relatively
little overlap of substrate specificity (3). All members of this
subfamily are genetically polymorphic. Among them  and
CYP2C19 are clinically the most important. They both partici-
pate in metabolism of many drugs with narrow therapeutic
index and genetic polymorphism may result in increased to-
xicity or in altered efficacy of such drugs in the affected indi-
vidual (4–7). Beside genetic polymorphism, the additional ca-
uses for variations in drug metabolism are: induction or inhi-
bition of cytochromes P450 due to concomitant drug thera-
pies or environmental factors, physiological status and accom-
panying disease (8). In respect to the metabolic capacity for
certain drug, individuals can be phenotypically divided into
two groups: extensive metabolizers (EMs) and poor metabo-
lizers (PMs) (9).
Best known drug substrates for CYP2C9 are weak acids con-
taining carboxylic group in their structure. Oral hypoglyce-
mic agents such as tolbutamide, some antiepileptic drugs such
as phenytoin, oral anticoagulant warfarin, a number of non-
steroidal anti-inflammatory drugs such as ibuprofen, diclofe-
nac, piroxicam and angiotensin II blockers such as losartan
are principally metabolised by CYP2C9 (detailed information
on the substrates, inhibitors and inducers of clinically relevant
cytochromes P450 is available at http://medicine.iupui.edu/
flockhart/). The activity of CYP2C9 is inducible by rifampicin,
barbiturates, carbamazepine and ethanol. The resulting incre-
ase in substrate’s elimination rate mostly attenuates the phar-
macological effect of the drug. On the other hand, many drugs
such as amiodarone, fluconazole, phenylbutazone, sulphin-
pyrazone, sulphaphenazole and certain other sulphonamides
have been reported to inhibit CYP2C9 activity. The resulting
elevation of plasma concentration of parent compound may
lead to serious adverse drug effects and toxicity (10).
Two single nucleotide polymorphisms (SNPs) affecting the
CYP2C9 gene have been unambiguously related to impaired
drug metabolism (10). The substitution of C416T in exon 3 of
CYP2C9*2 allele results in Arg144Cys (11), whereas A1061C in
exon 7 of CYP2C9*3 allele results in Ile359Leu substitution (12).
The functional wild-type allele is classified as CYP2C9*1. Re-
cently, some other polymorphisms of this gene have been de-
tected (see http://www.imm.ki.se/CYPalleles/). To date, seve-
ral in-vitro and in vivo studies have indicated that the CYP2C9*2
and CYP2C9*3 alleles are both associated with decreased me-
tabolic capacity for their substrates (4, 11–16).
Interethnic differences in CYP2C9 allele distribution have
been described. Among African-American and Oriental po-
pulations, more than 95% of individuals carry the wild-type
genotype (*1/*1). Among Caucasian populations, approxima-
tely two-thirds of individuals have the wild-type genotype, whi-
le one-third carries either the *1/*2 or *1/*3 genotype. Less
than 2.5% of Caucasian individuals carry the *2/*2, *2/*3 and
*3/*3 genotype which make them poor metabolizers of
CYP2C9 substrates. Gender-specific differences were not ap-
parent in the distribution of polymorphic alleles in these po-
pulations (17).
CYP2C19 is involved in the metabolism of antiepileptics such
as mephenytoin, diazepam and phenobarbitone, proton
pump inhibitors such as omeprazol, certain antidepressants
such as imipramine, barbiturate derivates such as hexobarbi-
tal and the antimalarial drugs progauanil and chloroprogu-
anil (9). Certain drugs, such as ketoconazole, cimetidine, flu-
voxamine, and fluoxetine, have been reported to inhibit
CYP2C19 (18). Increased metabolism of CYP2C19 substrates
has been shown after treatment of patients with carbamaze-
pine, rifampicin and some others drugs.
The predominant genetic polymorphisms in CYP2C19 are two
null alleles, which result in impaired metabolism of CYP2C19
substrates. The substitution of G681A in exon 5 of CYP2C19*2
variant allele creates an aberrant splice site resulting in an
alteration of the reading frame of mRNA and truncated non-
functional protein (19). The substitution of G636A in exon 4
of CYP2C19*3 allele results in a premature stop codon, which
is common in Oriental populations but very rare in Caucasi-
ans (20). Some other rare alleles have been identified (see http:/
/www.imm.ki.se/CYPalleles/). PMs of CYP2C19 represent ap-
proximately 3–5% of Caucasians (21). Higher frequencies of
PMs (13–23%) are found in most Asian populations (20).
The aim of this study was to determine the frequencies of poly-
morphic CYP2C9 and CYP2C19 alleles in Slovenian populati-
on and compare them to that reported for other Caucasians.
This information is important to estimate the proportion of
the Slovenian population that might experience adverse drug
reactions due to genetic polymorphism of CYP2C9 and
CYP2C19.
Subjects and methods
DNA samples from 129 unrelated healthy subjects were obta-
ined from the Blood Transfusion Centre of Slovenia (n = 40)
and University Children’s Hospital in Ljubljana (n = 89). Both
groups were sampled to represent the Slovenian population
and consisted of hospital and university staff and medical stu-
dents. Participants in the study were not selected according
to age, gender or any other criteria since genotype distribu-
tion is not confounded by these factors. The study was appro-
ved by the Slovenian Ethics Committee for Research in Medi-
cine.
Genotyping of CYP2C9*2 and CYP2C9*3 was performed by
polymerase chain reaction (PCR) followed by restriction enzy-
me analysis, as validated by Yasar et al. (1999). CYP2C9*2 was
analysed by amplification of a fragment having an AvaII re-
striction site present in the wild-type allele but absent in the
CYP2C9*2 allele because of the C416 T mutation. For analysis
of the CYP2C9*3 allele, two different forward primers were
used to generate products which both cover polymorphic se-
quence in exon 7. One of the primers would generate a NsiI
site from the wild-type allele, while the other forward primer
would generate a KpnI site from the CYP2C9*3 allele (22).
PCR-based restriction enzyme tests were also used for the
analysis of CYP2C19*2, CYP2C19*3 and CYP2C19*4, as des-
cribed by Goldstein and Blaisdell (1996) (23), and Ferguson et
al. (1998) (24). The CYP2C19*2 allele was analysed by ampli-
fication of exon 5 followed by digestion with SmaI which cle-
aves the wild-type sequence but does not cleave the
CYP2C19*2 allele. Similarly, the PCR fragments from the am-
plification of exon 4 were digested with BamHI which cle-
aves the wild-type sequence but not the CYP2C19*3 allele (23).
The CYP2C19*4 allele was analysed by amplification of exon
1 using primer that introduces a PstI site only in the
CYP2C19*4 allele (24). The examples of restriction analysis of
amplification products are shown in Figure 1.
Results
All of 129 DNA samples were successfully amplified and dige-
sted with appropriate restriction enzymes. Five different
CYP2C9 genotypes were identified in the sample represent-
349
ing Slovenian population (Table 1a). Two-thirds of healthy in-
dividuals (n = 86) were homozygous for the wild-type allele
and one-third (n = 43) carried at least one polymorphic allele.
Two subjects were homozygous for CYP2C9*2 allele and two
subjects were compound heterozygous for CYP2C9*2 and
CYP2C9*3 allele. No subject homozygous for CYP2C9*3 alle-
le was detected. The frequency of polymorphic CYP2C9*2
and CYP2C9*3 alleles were 0.12 and 0.06, respectively (Table
1b). These frequencies were similar to those reported for
other Caucasian populations (Table 2).
When the samples were analysed for CYP2C19 polymorphism,
four different genotypes were detected. Approximately two-
thirds of the individuals (n = 88) were homozygous for the
wild-type allele. Almost one-third was heterozygous for
CYP2C19*2 allele (n = 39) while only
one individual was heterozygous carri-
er of CYP2C19*3 allele. One subject ho-
mozygous for CYP2C19*2 allele and
none for CYP2C19*3 allele were identi-
fied (Table 1a). No subject carrying
CYP2C19*4 allele was detected in Slo-
venian population. The frequencies of
CYP2C19*2 and CYP2C19*3 alleles we-
re determined as 0.159 and 0.004, re-
spectively (Table 1b). These frequen-
cies were similar to those reported for
other Caucasian populations as well
(Table 3).
Applying Hardy-Weinberg equation,
predicted CYP2C9 and CYP2C19 ge-
notype frequencies were calculated
from observed allele frequencies. The
predicted frequencies were not signifi-
cantly different from the observed fre-
quencies. This means that the populati-
on was in Hardy-Weinberg equilibrium.
Discussion
The identification of decreased metabo-
lic activity in polymorphic CYP2C9 and
CYP2C19 stimulated a number of inve-
stigations to find out the distribution of
genetic polymorphisms in different po-
pulations.
Of the 129 individuals from Slovenian
population analysed in our study, one-
third (n = 43) carried at least one of the
defective CYP2C9 alleles, among them
four individuals (3.2% altogether) had
both alleles defective. The frequencies
of CYP2C9*2 and CYP2C9*3 in our po-
pulation were 0.122 and 0.063, respec-
tively, and were similar to those in
other Caucasian populations. Only in
Spanish population the prevalence of
the CYP2C9*2 and CYP2C9*3 alleles ap-
pears to be greater (25). In contrast to
Caucasians, the variant alleles are virtu-
ally non-existent in Orientals (26), Afri-
cans (27) and African-Americans (12).
The most frequent CYP2C19 alleles in
Caucasian individuals are CYP2C19*1
and CYP2C19*2 whereas CYP2C19*3
and CYP2C19*4 are extremely rare or
absent. Higher allelic CYP2C19*3 fre-
quency was observed in the Oriental
populations (20, 28). Almost one-third
of Slovenian individuals analysed (n =
41) carries at least one CYP2C19 polymorphic allele. The fre-
quencies of CYP2C19*2 and CYP2C19*3 alleles in Slovenian
population were 0.159 and 0.004, respectively, which is com-
parable to other Caucasian populations. The fact that we didn’t
detect any CYP2C19*4 allele is not surprising since reported
frequency of this allele in other Caucasians was also very low
(0.006) (24).
The CYP2C9 and CYP2C19 genetic polymorphisms were
shown to be clinically important in patients treated with drugs
having a narrow therapeutic index (4–7). The results of our
study indicate that approximately one-third of individuals from
Slovenian population may require either adjustments of dose
or increased monitoring when initiating treatment with
CYP2C9 and CYP2C19 substrates having a narrow therapeu-
Figure 1. PCR-based restriction enzyme analysis for CYP2C9 and CYP2C19 alleles.
(A) The 691-bp fragment of exon 3 of CYP2C9 gene was amplified by PCR, followed
by AvaII digestion (a). The 141-bp PCR products of exon 7 of CYP2C9 gene were
digested by NsiI (b) and KpnI (c), respectively. (B) The 321-bp PCR product of exon
5 of CYP2C19 gene was digested by SmaI (d). The 271-bp PCR product of exon 4 of
CYP2C19 gene was digested by BamHI (e). Molecular weight markers (M) were:
ϕ X174 DNA digested by HaeIII (A) and pUC18 digested by HpaII (B). All fragments
were separated on 3% agarose gel.
Sl. 1. Restrikcijska analiza pomnoženih fragmentov CYP2C9 in CYP2C19. (A) Ek-
son 3 gena CYP2C9 smo pomnožili z reakcijo PCR in nato 691 bp dolg produkt
cepili z encimom AvaII (a). Pomnoženi fragment eksona 7 gena CYP2C9 (141 bp)
smo cepili z encimom NsiI (b) oz. KpnI (c). (B) Pomnoženi fragment eksona 5 oz.
eksona 4 gena CYP2C19 (321 bp oz. 271 bp) smo cepili z encimom SmaI (d) oz.
BamHI (e). Uporabili smo dolžinske standarde: ϕ X174 DNK, razcepljena s HaeIII
(A) in pUC18, razcepljen z HpaII (B). Vse fragmente smo ločili na 3% agaroznem
gelu.
HERMAN D, DOLŽAN V, BRESKVAR K. GENETIC POLYMORPHISM OF CYTOCHROMES P450 2C9 AND 2C19 IN SLOVENIAN POPULATION
350 ZDRAV VESTN 2003; 72
tic index. High risk of adverse drug reaction may be expected
in 1–3% of eventual patients. It is of potential clinical impor-
tance to be able to identify individuals who have decreased
metabolism for CYP2C9 and CYP2C19 substrates when aim-
ing for rational and individualised pharmacotherapy.
Acknowledgements
The authors wish to thank Blanka Vidan-Jeras from the Blood transfu-
sion Centre of Slovenia and Tadej Battelino and Mirjam Stopar-Obreza
from the University Children’s Hospital for providing DNA samples.
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Table 1. CYP2C9 and CYP2C19 genotypes (a) and allele fre-
quencies (b) in the healthy Slovenian population.
Razpr. 1. Genotip (a) in frekvence alelov (b) CYP2C9 in
CYP2C19 pri zdravi slovenski populaciji.
a)
CYP2C9
Observed
CYP2C19
Observed
genotype
Number (predicted)*
genotype
Number (predicted)*
frequency (%) frequency (%)
Genotip
Ugotovljena
Genotip
Ugotovljena
CYP2C9
Število (pričakovana)*
CYP2C19
Število (pričakovana)*
frekvenca (%) frekvenca (%)
*1/*1 86 66.6 (66.9) *1/*1 88 68.2 (70.0)
*1/*2 25 19.4 (19.6) *1/*2 39 30.2 (26.6)
*1/*3 14 10.8 (10.1) *1/*3 1 0.8 (0.7)
*2/*2 2 1.6 (1.4) *2/*2 1 0.8 (2.5)
*2/*3 2 1.6 (1.5) *2/*3 0 0.0 (0.1)
*3/*3 0 0.0 (0.4) *3/*3 0 0.0 (0.002)
Total
129 100
Total
129 100Skupaj Skupaj
b)
CYP2C9 CYP2C19
alleles
Number Frequency
alleles
Number Frequency
Aleli Aleli
CYP2C9
Število Frekvenca
CYP2C19
Število Frekvenca
*1 207 0.815 *1 216 0.837
*2 31 0.122 *2 41 0.159
*3 16 0.063 *3 1 0.004
Total
254 1.000
Total
254 1.000Skupaj Skupaj
* Predicted frequencies calculated according to the Hardy-Weinberg equa-
tion.
* Pričakovane vrednosti so bile izračunane po Hardy-Weinbergovi enačbi.
Table 2. The distribution of the CYP2C9 allele frequencies in
European Caucasian populations.
Razpr. 2. Porazdelitev frekvenc alelov CYP2C9 v evropskih po-
pulacijah.
Number of subjects CYP2C9 allele frequencies Reference
Število preiskovancev Frekvence alelov CYP2C9 Literatura
*1 *2 *3
British / Britanci
561 0.841 0.106 0.052 Taube et al. (6)
German / Nemci
367 0.815 0.107 0.078 Ackermann et al. (29)
Italian / Italijani
157 0.796 0.112 0.092 Scordo et al. (27)
180 0.739 0.178 0.083 Margaglione et al. (7)
Spanish / Španci
157 0.694 0.143 0.162 Garcia-Martin et al. (25)
Swedish / Švedi
430 0.819 0.107 0.074 Yasar et al. (22)
Turkish / Turki
499 0.794 0.106 0.100 Aynacioglu et al. (30)
Slovenian / Slovenci
127 0.815 0.122 0.063 present study /
pričujoča študija
Table 3. The distribution of CYP2C19 allele frequencies in
European Caucasian populations.
Razpr. 3. Porazdelitev frekvenc alelov CYP2C19 v evropskih
populacijah.
Number of subjects CYP2C19 allele frequencies Reference
Število preiskovancev Frekvence alelov CYP2C19 Literatura
*1 *2 *3
Danish / Danci
239 0.839 0.161 0.000 Bathum et al. (31)
64 0.820 0.180 0.000 Bathum et al. (31)
German / Nemci
140 0.850 0.150 NT Brockmoller et al. (32)
Portugese / Portugalci
153 0.869 0.131 NT Ruas and Lechner (33)
Swedish / Švedi
160 0.834 0.166 NT Chang et al. (34)
83 0.849 0.145 0.006 Yamada et al. (35)
162 0.852 0.148 0.000 Yamada et al. (35)
Slovenian / Slovenci
127 0.837 0.159 0.004 present study /
pričujoča študija
NT – not tested / ni testirano
351
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V tej številki so sodelovali:
Marija Bocak-Kalan, dr. med., specialistka pediatrinja, Ljubljana
prof. dr. Katja Breskvar, univ. dipl. ing. kem., Inštitut za biokemijo, MF
Ljubljana
prim. dr. Silva Burja, dr. med., specialistka pediatrinja, Služba za gineko-
logijo in perinatologijo, SB Maribor
doc. dr. Vita Dolžan, dr. med., Inštitut za biokemijo, MF Ljubljana
Alenka Erjavec-Škerget, univ. dipl. biol., Laboratorij za medicinsko ge-
netiko, SB Maribor
prof. dr. Alojz Gregorič, dr. med., specialist pediater, Klinični oddelek
za pediatrijo, SB Maribor
Darja Herman, univ. dipl. mikrobiol., Inštitut za biokemijo, MF Ljublja-
na
Rade Iljaž, dr. med., specialist splošne medicine, Zdravstveni dom
Brežice
prim. Igor Japelj, dr. med., specialist ginekolog in porodničar, Služba
za ginekologijo in perinatologijo, SB Maribor
prof. dr. Andreja Kocijančič, dr. med., specialistka internistka, Klinični
oddelek za endokrinologijo, diabetes in presnovne bolezni, KC
Ljubljana
asist. dr. Tomaž Kocjan, dr. med., specialist internist, Klinični oddelek
za endokrinologijo, diabetes in presnovne bolezni, KC Ljubljana
doc. dr. Nadja Kokalj-Vokač, univ. dipl. biol., Laboratorij za medicinsko
genetiko, SB Maribor
prof. dr. Janko Kostnapfel, dr. med., specialist psihiater, Ljubljana
prof. dr. Mirta Koželj, dr. med., specialistka internistka, Klinični odde-
lek za kardiologijo, KC Ljubljana
prim. Bogdan Leskovic, dr. med., specialist internist, Ljubljana
prof. dr. Aleš Mrhar, univ. dipl. farm., Fakulteta za farmacijo Ljubljana
prim. Lucija Oberauner, dr. med., specialistka anesteziologinja, Klinič-
ni oddelek za anesteziologijo in intenzivno terapijo, KC Ljubljana
prim. mag. Ksenija Ogrizek-Pelkič, dr. med., specialistka ginekologinja
in porodničarka, Služba za ginekologijo in perinatologijo, SB Mari-
bor
Iztok Potočnik, dr. med., specialist anesteziolog, Klinični oddelek za
anesteziologijo in intenzivno terapijo, KC Ljubljana
doc. dr. Sonja Praprotnik, dr. med., specialistka internistka, Klinični
oddelek za revmatologijo, Bolnišnica dr. Petra Držaja, KC Ljubljana
Stanko Pšeničnik, Oddelek za biomedicinsko tehniko, SB Maribor
dr. Barbara Salobir, dr. med., specialistka internistka, Center za pljučne
bolezni in alergijo, KC Ljubljana
doc. dr. Mišo Šabovič, dr. med., specialist internist, Klinični oddelek za
žilne bolezni, KC Ljubljana
prof. dr. Stanislav Šuškovič, dr. med., specialist internist, Klinični odde-
lek za pljučne bolezni in alergijo, Bolnišnica Golnik
mag. Boris Zagradišnik, dr. med., Laboratorij za medicinsko genetiko,
SB Maribor