Polymorphisms in Turkish population

Department of Medical Biology, Faculty of Medicine, Ankara University, Ankara, Turkey guvemg@yahoo.com.

Human P-glycoprotein (P-gp) is encoded by the MDR1 gene, which is located on chromosomal region 7q21 and consists of 28 exons. To date, over 50 single nucleotide polymorphisms (SNPs) have been reported for the MDR1 gene. The effect of these polymorphisms on P-gp function or their clinical impact is in most cases unknown, but some of the SNPs are known to be of functional relevance and can also alter the pharmacokinetics of substrate drugs. The aim of the current study was to analyze for the first time an existing silent MDR1 C1236T (Gly412Gly) polymorphism in a Turkish population. The genotype frequencies of C1236T SNP in a Turkish population were also compared with those in other populations. One hundred unrelated healthy subjects (48 females, 52 males) were included in this study and all them were of Turkish ethnicity. The genotyping of the C1236T SNP was performed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. The frequencies of the wild-type C and mutant T alleles were 45.5 and 54.5%, respectively. The distribution of C1236T genotype frequencies in our study group was found to be similar to that in Czech, Polish, Portuguese, Russian, Malay, and Japanese populations and different from that in French, German, Chinese, and Indian populations. The distributions of CC, CT, and TT genotypes were 20.0, 51.0, and 29.0%, respectively. Our study provides a framework for future studies concerning the role of polymorphic variants of MDR1 gene in the genesis of various diseases or in designing future pharmacogenetic and pharmacokinetic studies conducted with P-gp substrates in the Turkish population.

Comment in:

Anadolu Kardiyol Derg. 2005 Sep;5(3):187-8.

Department of Genetics, Institute for Experimental Medical Research, Istanbul Medical School, Istanbul University, Istanbul, Turkey.

OBJECTIVE: The glycoprotein Ia/IIa complex is a major platelet collagen receptor. Its surface expression is influenced by two linked single nucleotide polymorphisms (C807T and G873A) in the glycoprotein Ia (GPIa) gene. In this study we aimed to determine the frequency of GPIa C807T/G873A genotype in patients with myocardial infarction (MI) and healthy controls in Turkish population and association between these dimorphisms and risk factors of MI. METHODS: We examined GPIa (C807T/G873A) genotypes in 158 patients with MI and 145 healthy controls. Distributions of the C807T and G873A dimorphisms were investigated by genotyping DNA using multiplexed allele-specific PCR. RESULTS: There was no association between GPIa genotypes and MI. We further analysed each group for all known risk factors such as plasma lipid levels, cigarette smoking, diabetes, hypertension, gender, age, MI history and body mass index. When compared with other two genotypes for glycoprotein Ia (GT/GA and CC/GG), TT/AA showed an association with higher high-density lipoprotein (HDL) -cholesterol levels in the healthy control group, but none in the group with MI. CONCLUSION: The 807TT/873AA genotype of the GPIa gene alone or in combination with risk factors had no major effect on MI, however, it appears to be associated with higher HDL-cholesterol levels in healthy subjects.

Department of Biology, Middle East Technical University, Ankara, Turkey.

Multidrug-resistance (MDR) phenotype is a serious limitation to the effective chemotherapeutic treatment of many cancer types, including leukemia. One of the most important proteins, the over-expression of which is responsible for the multidrug-resistance phenotype in many cancer types, is P-glycoprotein. This protein is the product of the MDR1 gene. In previous studies, single-nucleotide polymorphisms (SNPs) C3435T, G2677T, and T-129C in the MDR1 gene were shown to be correlated with lower P-glycoprotein expression in normal tissues. It was suggested that this might have an advantage in cancer chemotherapy by resulting in a low drug-resistance phenotype. The frequencies of these SNPs were studied in 45 acute leukemia patients (25 of which were primary refractory and 20 of which were drug-sensitive) and 17 healthy individuals, forming a Turkish population of 62 individuals. In the first part of the study, these polymorphisms were compared with other populations. Marked differences were apparent between African and Turkish populations for the C3435T polymorphism. On the other hand, similarities were found between other Caucasian/Asian and Turkish populations (P < 0.001). However, for the G2677T polymorphism, the Turkish population is different than Japanese and German populations (P < 0.001). For the T-129C polymorphism, all individuals in the studied population were homozygous for the T/T genotype. In the second part of this study, drug-resistant and drug-sensitive acute leukemia patients were compared for these SNPs. These polymorphisms did not seem to have a significant effect on P-glycoprotein-mediated drug resistance in the patients studied.