Polymorphisms of the GSTM1, GSTT1, and CYP2D6 xenobiotic biotransformation genes, which are possible risk markers of cancer in populations of indigenous ethnic groups and Russians of North Siberia

Abstract

The CYP2D6, GSTM1, and GSTT1 xenobiotic biotransformation genes are involved in processes of carcinogenesis in humans due to the presence of mutant variants that decrease or block the expression of genes. Since the middle of the 20th century, there has been an extensive increase in cancer morbidity in human populations, including indigenous ethnic groups of Siberia. The problem of ethnic differences in sus ceptibility to cancer is still pressing. The study of polymorphisms of the CYP2D6 (CYP2D6*3 and CYP2D6*4 alleles), GSTM1, and GSTT1 (GSTM1 0/0 and GSTT1 0/0 "null" genotypes) genes (which are considered as genetic markers of the risk of cancer) was conducted for the first time in practically healthy representatives of the Samoyedic ethnic groups (Selkups, Forest Nenets, and Nganasans) and Russians from Siberia. A signif icant variability in the CYP2D6*4 and GSTM1 0/0 frequency distribution in northern populations was detected. At the same time, there are no significant differences in frequencies of the CYP2D6*3 and GSTT1 0/0 variants among indigenous populations of the Selkups, Forest Nenets, and Nganasans. In the CYP2D6*4 allele frequencies, indigenous ethnic groups are intermediate between Russians of Siberia and Mongolians of China. However, frequencies of the null GSTM1 0/0 and GSTT1 0/0 genotypes in indigenous ethnic groups are significantly lower than in populations of Russians of Siberia and Mongoloids of China (p < 0.05). Gen erally, according to all four studied polymorphic variants, it is possible to predict a decreased risk of cancer in indigenous Samoyedic ethnic groups, as compared with Russians of Siberia. The Forest Nenets population, with an increased frequency of the GSTM1 0/0 genotypes, is an exception; this can be caused by the original ity of their marriage structure and increased inbreeding coefficient. The results we obtained can also be important in predicting the probability of complications and a positive response to drugs that are metabolized by the GSTM1, GSTT1, and CYP2D6 enzymes.

CYP2D6, CYP3A5, and CYP3A4 gene polymorphisms in Russian, Tatar, and Bashkir populations

“…In populations of European ethnicity, the fre quency of the rs3892097*A allele varied from 11% in Turks to 24% in Bosnians. The rs3892097*A allele fre quencies in Russians of Bashkortostan (17.2%) were close to the values obtained in populations of Russians residing in various regions of Russia (15-18%) [7,8,10]. The frequencies of the minor allele in populations of Tatars (9.5%) and Bashkirs (7.1%) were equal to that in the Turkish population (11%) [31].…”

“…The presence of both intereth nic and interracial differences were suggested [6][7][8][9][10]. In populations of European ethnicity, the fre quency of the rs3892097*A allele varied from 11% in Turks to 24% in Bosnians.…”

“…The frequencies of the minor allele in populations of Tatars (9.5%) and Bashkirs (7.1%) were equal to that in the Turkish population (11%) [31]. In Samodians (Selkups, Wood Nentsi, Nganasans), which belong to the Ural race, the frequency of rs3892097*A allele is lower than in Europeans (4.0, 3.3, and 7.3%, respec tively) [8]. In other world populations, the rs3892097*A allele was also observed with a signifi cantly lower frequency, particularly in eastern Asian populations (0.45%; in particular Japanese, 0.2%, Khantsi, 0.14%) and Oceania (1.1%; in particular Taitsi, 0.9%) [34-37, 41].…”

“…Obviously, such studies are important in the Russian Federation, which is populated with subjects of differ ent ethnicities and races, and they have a high social impact. However, the data on the frequencies of allelic variants of "pharmacologic response" genes among residents of Russian population are limited [6][7][8][9][10][11].…”

Distribution of polymorphic variants of genes for xenobiotic biotransformation GSTM1, GSTT1 and GSTP1 in populations of native inhabitants and Russians of Eastern Siberia

“…Образцы ДНК были выделены из лейкоцитарных фракций венозной крови с использованием наборов «Биосилика» (Россия). Выявление делеций в генах GSTM1 и GSTT1 проводилось методом полимеразной цепной реакции в режиме реального времени (Realtime PCR) с интеркалирующим флюоресцентным красителем SYBR GreenI [3]. Генотипирование однонуклеотидных замен в гене GSTP1 проводили в режиме трофильными центрами разнообразных субстратов эндогенного и экзогенного происхождения, что повышает их растворимость в воде и облегчает выведение из клетки.…”