Frequency of Five ImportantCYP2D6Alleles Within an Iranian Population (Eastern Azerbaijan)

Abstract

Polymorphisms in cytochrome P450 genes encoding enzymes of critical importance for drug metabolism have the highest genetic influence on interindividual variations in drug bioavailability. Human CYP2D6 enzyme is claimed to be polymorphically expressed among different ethnic groups. It has been suggested to account for a large part of the interindividual differences in drug metabolism and pharmacokinetics. In the current investigation, 100 healthy unrelated subjects living in Tabriz, Iran, were randomly selected. Genotyping was designed to determine the frequencies of five major and important alleles: CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, and CYP2D6*17. After collecting venous blood samples, polymerase chain reaction-restriction fragment length polymorphism methodology was performed for detection of the alleles (except CYP2D6*5, which has been detected using an allele-specific polymerase chain reaction procedure). Finally, the obtained data were used to determine the allele frequencies. The frequencies for CYP2D6 alleles *2, *4, *5, and *10 were 32%, 12.5%, 3%, and 9%, respectively. CYP2D6*17 was completely absent in this study group. Poor metabolizer phenotype can be related to *4/*4 and *4/*5 genotypes with a total frequency of 4%. This is the first study of the CYP2D6 genetic polymorphism in an Iranian population. The frequencies of the studied alleles resulted in degrees of differences between this population and Orientals, Saudi Arabians, and Caucasians, while similarities to the reported results obtained from the studies among Mediterraneans and South Indians are noticeable.

Frequencies of ThreeCYP2D6Nonfunctional Alleles (CYP2D6*3,*4, and*6) Within an Iranian Population (Mazandaran)

“…The frequency of CYP2D6*4 null allele identified in our sample (9%) was comparable with those found in the Spanish (13.8%) (Menoyo et al, 2006), South Indians (9.2%) (Naveen et al, 2006), Syrians (9.80%) (Fuselli et al, 2004), Central Italians (Fuselli et al, 2004), and the Azeri ethnic group among Iranian population (12.5%) (Kouhi et al, 2009), but was lower than those reported for Caucasians (20.7%) (Sachse et al, 1997) and Southern Spaniards (17.65%) (Fuselli et al, 2004). The other nonfunctional alleles such as CYP2D6*5 has been found at frequencies between 2% and 4% in Caucasians (Sachse et al, 1997), which resembles the previous finding in the Azeri ethnic group among the Iranian population (3.33%) (Kouhi et al, 2009). The frequency of CYP2D6-deficient alleles in different populations is shown in Table 2.…”

“…In Oriental populations, the frequency of the CYP2D6*4 allele is only around 1% or less ( Johansson et al, 1991( Johansson et al, , 1994Wang et al, 1993;Dahl et al, 1995;Jaanson et al, 2002), whereas it occurs with around 6%-7% frequency in Africans and African-Americans (Leathart et al, 1998;Griese et al, 1999). The frequency of CYP2D6*4 null allele identified in our sample (9%) was comparable with those found in the Spanish (13.8%) (Menoyo et al, 2006), South Indians (9.2%) (Naveen et al, 2006), Syrians (9.80%) (Fuselli et al, 2004), Central Italians (Fuselli et al, 2004), and the Azeri ethnic group among Iranian population (12.5%) (Kouhi et al, 2009), but was lower than those reported for Caucasians (20.7%) (Sachse et al, 1997) and Southern Spaniards (17.65%) (Fuselli et al, 2004). The other nonfunctional alleles such as CYP2D6*5 has been found at frequencies between 2% and 4% in Caucasians (Sachse et al, 1997), which resembles the previous finding in the Azeri ethnic group among the Iranian population (3.33%) (Kouhi et al, 2009).…”

“…The most frequent null allele in Caucasians is CYP2D6*4, which occurs with an allele frequency of about 20%-25% and Iranian (Mazandaran) (present study) 100 0.5 9 0.5 Iranian (Eastern Azerbaijan) (Kouhi et al, 2009) 100 nd 12.5 nd Japanes (Chida et al, 1999) 256 0 0.77 nd Chinese (Han) (Zhou et al, 2009) 100 nd 1 0.5 Chinese (mainland) ( Ji et al, 2002) 223 0 0.2 0 Germans (Sachse et al, 1997) 589 2 21 0.9 Polish (Gawronska-Szklarz et al, 1999) 145 2.1 23.1 nd South-Spanish (Agundez et al, 1995) 217 nd 12 nd Spanish (Menoyo et al, 2006) 105 0.95 13.8 0.95 North-Spanish (Bernal et al, 1999) 147 nd 20 nd Turkish (Aydin et al, 2005) 140 2.5 13.9 nd West-African (Griese et al, 1999) 326 0 6.3 0 Saudi-Arabbian (McLellan et al, 1997) 101 nd 3.5 nd Black-Tanzanians (Wennerholm et al, 1999) 106 0 1 0 South-Indian (Naveen et al, 2006) 447 0 7.3 nd Mexican Mestizo (Lopez et al, 2005) 243 1.44 11.21 nd nd, not detected.…”

“…The CYP2D6 polymorphism is due to multiple mutations of the gene, which result in absent, functionally deficient, underexpressed, or overexpressed protein (Marez et al, 1997). Several alleles and allelic variants of the CYP2D6 locus have been identified and frequencies of the alleles widely vary in different populations (Marez et al, 1997;Sachse et al, 1997;Kubota et al, 2000;Lopez et al, 2005;Menoyo et al, 2006;Kouhi et al, 2009). The phenotypic consequences of this variation depend on the combinations of CYP2D6 alleles.…”

“…The incidence of PMs in Black African populations has been estimated from 0% to 19% (Bradford et al, 1998). The incidence of CYP2D6 PMs in healthy Iranian populations has been estimated from 2.5% to 4% (Afshar et al, 2005;Kouhi et al, 2009).…”