Association of gene-modifiers polymorphisms with cancer risk at longterm 'low' dose ionizing irradiation

摘要

A study was carried out aiming to determine the association of 14 biallelic polymorphisms of thegenes encoding for excision repair enzymes (hOGG1 326С>G, XPD1 751A>C, XPG1 1104G>C, XRCC1 194C>T,280A>G, 399G>A), xenobiotic-metabolizing enzymes (GSTT1 (+/-), GSTM1 (+/-), CYP2C19 681G>A), andendothelial nitric oxide synthase (NOS3 691С>T, 774С>T, 894G>T, VNTRint4) with malignant neoplasmdevelopment risk at long-term radiation exposure of low intensity.Objects studied. Group 1 was comprised of 95 workers of basic enterprise of the Siberian Group of ChemicalEnterprises (SGCE), affected by cancer and underwent a professional radiation expose (median of summary dose ofexternal gamma-irradiation was 71.3 mSv). Group 2 was comprised of 135 workers of the auxiliary departments of theSGCE, affected by cancer and underwent no any professional radiation expose. Group 3 was comprised of 148 healthyworkers of basic enterprise of the SGCE, underwent a professional radiation exposure (median of summary dose ofexternal gamma-irradiation was 74.0 mSv). Peripheral blood samples were obtained from the participants, and DNAwas extracted and typed by the polymorphisms of the interest.Results. Malignant neoplasm risk was associated with the XRCC1 399G*, XRCC1 399AA, GSTM1(-),NOS3 774T*, XRCC1 399GG, CYP2C19 681G*, and CYP2C19 681GG. According to the the False Discovery Ratecontrol procedure (FDR), these polymorphisms were satisfied to the condition of p-level experimental < FDR p-level.However, only for the CYP2C19 681G* it was shown that p-level (1group vs 3group) = 0.0026 and p-level (2group vs3group) = 0.2096, and for the CYP2C19 681GG it was shown that p-level (1group vs 3group) = 0.0051 and p-level(2group vs 3group) = 0.1472. Hence, only the CYP2C19 681G* and the CYP2C19 681GG are significantly associatedwith the risk of cancer in persons at long-term radiation expose at “low” doses. A “high-risk” combination of genotypesby five polymorphisms was selected: XRCC1 280GG, hOGG1 326C*, XPD1 751AA, GSTM1-, NOS3 774T*. Aprevalence of this combination in Group 1 was 14/83, in Group 2 it was 1/100, and in Group 3 it was 1/119. Thecarriers of this combination have more than 20-fold risk of cancer at long-term professional radiation exposure at “low”dose levels: OR (1group vs 3group) = 24.14 (95% CI 3.21-502.64), p experimental = 0.0000581.