title: Frequency distribution of cytochrome P450 3A4 gene polymorphism in ethnic populations and in transplant recipients.
abstract: CYP 3A4 plays a vital role in the metabolism of many drugs including immunosuppressants. An association between a transition of A --> G at position -290 of the 5'-regulatory region of the CYP 3A4 gene and an effect on the level of transcription has been reported. The CYP 3A4-G variant frequency varies substantially in different populations. In addition it has been demonstrated in association with several disease conditions, including clinical grades of prostate cancer, breast cancer, secondary leukemia, hypercholesterolemia and diabetes. We sought to determine the frequency distributions, in African American (AFAM) and Caucasian (CAU) populations as well as patients with multiple complex diseases, such as those that had undergone cardiac or renal transplantation. Sequence-specific primers and PCR were used to determine genotype variation in 206 AFAM and 108 CAU individuals. CYP 3A4-G genotype was present with a higher frequency in AFAM individuals as compared with CAU (83% vs. 3%, p < 0.0001, RR = 3.9). The homozygous AA allele was predominantly present in CAU (97%) but only 17% in AFAM (p < 0.0001, RR = 2.5). In contrast, the homozygous GG allele was only detected in AFAM group (14.6%). The frequency distribution of homozygous GG and AA alleles were inversely present in male vs. female patients with CTx or RTx. Pre-transplantation clinical conditions demonstrated that hypertension (HTN), hyperlipidemia and to a lesser extent diabetes (DM) were present in CTx and RTx patients with homozygous GG alleles. In addition, 75% of AFAM patients with homozygous GG genotype experienced multiple rejection episodes with severity grades of 3A after cardiac transplantation, and 31.5% of homozygous GG patients with RTx suffered from rejections (p < 0.05; RR = 2.4). In conclusion, CYP 3A4 genotype demonstrated a remarkable interindividual variation between AFAM and CAU populations, and furthermore CTx patients with homozygous GG genotype were at higher risk of developing rejection as compared with RTx patients. This indicates an underlying heterogeneity with regard to the disease characteristics as well as the therapy regimen.
authors.affiliation: Department of Surgery, The University of Mississippi Medical Center, Jackson, Mississippi 39216-4500, USA.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Zhou
authors.forename: W Henry
authors.initials: WH
authors.lastname: Barber
authors.forename: Charles K
authors.initials: CK
authors.lastname: Moore
authors.forename: Lee Y
authors.initials: LY
authors.lastname: Tee
authors.forename: Giorgio
authors.initials: G
authors.lastname: Aru
authors.forename: Sebron
authors.initials: S
authors.lastname: Harrison
authors.forename: Brenda
authors.initials: B
authors.lastname: Mangilog
authors.forename: D Olga
authors.initials: DO
authors.lastname: McDaniel
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D011110:Polymorphism, Genetic; D012737:Sex Factors; D014184:Transplantation, Homologous; D044465:White People / Q000235:genetics
chemical_list: D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human