L. E. Sal’nikova, T. I. Ivanova, T. V. Kondrashova, E. A. Akaeyva, T. V. Elisova, I. N. Vesnina, N. Sh. Lapteva, A. G. Chumachenko, G. I. Kuznetsova, A. V. Rubanovich
The frequency of homozygotes deletion of GSTM1 gene in most human populations is about 50%. This suggests that the normal functional GSTM1 allele is practically minor, as its frequency does not exceed 30%. The strong predomination of deleted GSTM1 allele is all the more surprising that in most cases homozygotes by deletion show an enhanced sensitivity to chemical toxicants and a tendency to some system diseases. How the deletion polymorphism of GSTM1 is supported on the population level? In this work, we present two groups of the data on the associations of the normal functional GSTM1 genotype: 1) with diseases of female reproduction sphere and 2) with the frequency of spontaneous chromosome aberrations in blood lymphocytes of healthy volunteers younger than 25 years. In both cases we observed the protective character of the action of “null” GSTM1 genotypes. The data were obtained in the course of two independent studies on the assosiation of DNA polymorphism with the system diseases and the level of the induced mutagenesis in somatic cells.
The frequencies of “positive” GSTM1(+) genotypes (i.e., +/+ or +/0) were determined for the following groups: myomas, 183 females; fibrous mastopathy (FM), 70 females; group with both diagnoses, 54 females; breast cancer (BC), 162 females; and control, 90 healthy females. It was found that the frequency of GSTM1(+) genotypes tends to an increase in the series “healthy → myomas → FM → myomas and FM → BC”. These differences were significant in the latter case only: the frequency of positive GSTM1(+) for patients with breast cancer was 75.3 compared to 46.7% in control (OR = 2.5; P = 0.0007). The importance of this result is strengthened by the fact that we deal with the genotype characteristic for either of two females in the most of human populations.
The data on the spontaneous level of chromosome aberrations in lymphocytes of peripheral blood for 47 volunteers younger than 25 years old depending on the genotypes by the GSTM1 locus are presented. The frequency of aberrations was estimated by scanning not less than 1000 metaphases per human. The reliable threefold differences between the null and positive GSTM1 genotypes by the total level of chromosome aberrations were found: 0.0028±0.0005 compared to 0.0009±0.0004 for GSTM1(0/0) (P=0.014). The chromatid aberrations show the opposite insignificant trend, which minimizes the differences between genotypes by the total number of aberrations.
In discussion, the literature data indicating that the negative consequences of homozygosis by functional allele can be related to the disturbance of the normal course of apoptosis at the excess of active GSTM1 are presented. Moreover, many natural antioxidants (for example, isothiocyanates) are the substrates for GSTM1 and are subject to “detoxication” along with other compounds. The results of meta-analysis of 206 associative investigations published in 1986-2008 present an indirect corroboration of the existence of elimination of “positive” GSTM1 genotypes. A weak (but nevertheless, significant) gain in the frequency of GSTM1 deletion homozygotes in control selections for the above period (R=0.23; P=0.0006) was found.
In any case the question in the head of the paper can have rather negative answer. If we have the GSTM1 “null” genotype, we loose in the stability to the action of some toxicants, but benefit considerably in some hypothetical processes, which exist inevitably