Open AccessGlutathione S‐transferase genes and the risk of type 2 diabetes mellitus: Role of sexual dimorphism, gene–gene and gene–smoking interactions in disease susceptibility
Author(s) -
Azarova Iuliia,
Bushueva Olga,
Konoplya Alexander,
Polonikov Alexey
Publication year - 2018
Publication title -
journal of diabetes
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.949
H-Index - 43
eISSN - 1753-0407
pISSN - 1753-0393
DOI - 10.1111/1753-0407.12623
Subject(s) - gstp1 , genotype , odds ratio , genotyping , glutathione s transferase , medicine , type 2 diabetes mellitus , diabetes mellitus , endocrinology , gene , glutathione , biology , genetics , enzyme , biochemistry
Background Compromised defense against reactive oxygen species (ROS) is considered important in the pathogenesis of type 2 diabetes mellitus (T2DM); therefore, genes encoding antioxidant defense enzymes may contribute to disease susceptibility. This study investigated whether polymorphisms in genes encoding glutathione S‐transferase M1 ( GSTM1 ), T1 ( GSTT1 ), and P1 ( GSTP1 ) jointly contribute to the risk of T2DM. Methods In all, 1120 unrelated Russian subjects (600 T2DM patients, 520 age‐ and sex‐matched healthy subjects), were recruited to the study. Genotyping was performed by multiplex polymerase chain reaction (PCR; del/del polymorphisms of GSTM1 and GSTT1 ) and TaqMan‐based PCR (polymorphisms I105V and A114V of GSTP1 ). Plasma ROS and glutathione levels in study subjects were analyzed by fluorometric and colorimetric assays, respectively. Results Genotype del/del GSTT1 was significantly associated with the risk of T2DM (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.17–2.21, P = 0.003). Gender‐stratified analysis showed that the deletion genotypes of GSTM1 (OR 1.99, 95% CI 1.30–3.05; P = 0.0002, Q = 0.016) and GSTT1 (OR 2.23, 95% CI 1.22–4.09; P = 0.008, Q = 0.0216), as well as genotype 114A/V of GSTP1 (OR 2.85, 95% CI 1.44–5.62; P = 0.005, Q = 0.02) were associated with an increased risk of T2DM exclusively in males. Three genotype combinations (i.e. GSTM1 + × GSTT1 +, GSTM1 + × GSTP1 114A/A and GSTT1 + × GSTP1 114A/A) showed significant associations with a decreased risk of T2DM in males. Conclusions This study demonstrates, for the first time, that genes encoding glutathione S‐transferases jointly contribute to the risk of T2DM, and that their effects on disease susceptibility are gender specific.