Genetic polymorphisms of cytochrome P450 among patients with Balkan endemic nephropathy (BEN).
OBJECTIVE
The concept of multifactorial etiology of BEN anticipates that a combination of polymorphic gene variants and various environmental factors causes an increased risk for the disease. CYP enzymes play a key role in the metabolic activation of environmental chemicals and toxins. CYP3A enzymes are particularly relevant for xenobiotic metabolism because of their broad substrate specificity and abundant expression in the human liver, intestine, and kidney. Previous phenotyping analysis on CYP2D6 enzyme activity in BEN patients proposed a modifying effect of CYP2D6 gene variants on BEN risk, but it was not approved with molecular-genetic methods. The aim of the current case-control study was to compare the frequency of CYP2D6 and CYP3A5 polymorphisms, as well as one CYP3A4 promoter variant in BEN patients and controls in order to investigate a possible association between individual genetic variations in these genes and susceptibility to BEN.


METHODS
Ninety-six nonrelated Bulgarian BEN patients from endemic villages in the Vratza district and 112 healthy Bulgarians from nonendemic areas (controls) were genotyped. Identification of alleles was done by allele-specific PCR or by rapid-cycle amplification on the LightCycler, followed by sequence-specific detection.


RESULTS
The UM, PM, and EM + IM genotype frequencies of CYP2D6 did not differ significantly between the two groups (P > 0.05). The CYP3A4*1B allele was only found in the heterozygous form, with allelic frequencies of 5.21% in the patients and 2.23% in the healthy individuals (P = 0.11). The CYP3A5*1 allele was more prevalent in BEN patients with a frequency of 9.38% compared to 5.36% in the controls and was associated with a higher risk for BEN (OR 2.41, 95% CI 1.09-5.33) (P = 0.02).


CONCLUSIONS
Our results demonstrate that the CYP3A5*1 allele, previously reported as a marker for CYP3A5 expression in human kidney, is associated with increased risk for BEN, while CYP3A4*1B and CYP2D6 genotypes do not significantly modify the risk for the disease.
Atanasova
Srebrena Y
SY
Department of Clinical Chemistry, Georg-August University, Robert Koch Street 40, 37075 Goettingen, Germany. srebrena_a@yahoo.com
von Ahsen
Nicolas
N
Toncheva
Draga I
DI
Dimitrov
Tzvetan G
TG
Oellerich
Michael
M
Armstrong
Victor W
VW
D000368:Aged; D001449:Balkan Nephropathy / Q000235:genetics*; D016022:Case-Control Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012307:Risk Factors
D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human