BMD Values and <b><i>GSTM3</i></b> Gene Polymorphisms in Combination with <b><i>GSTT1/GSTM1</i></b> Genes: A Genetic Association Study in Slovenian Elderly

Abstract

Background: Much research suggests that oxidative stress is associated with osteoporosis development. Glutathione S-transferases mu3 (GSTM3) are an important group of detoxifying enzymes that eliminate oxidative stress-related products. Objectives: To examine the associations of functional GSTM3 gene polymorphisms (Val224Ile and insdelAGG), their haplotypes and, in combination with GSTT1-null and GSTM1-null polymorphisms, with bone mineral density (BMD) measured at femoral neck (_fn), lumbar spine (_ls) and total hip (_th) and biochemical bone turnover markers in 593 Slovenian elderly women and 119 Slovenian elderly men. Methods:GSTM3, GSTT1-null and GSTM1-null gene polymorphisms using sizing denaturing high-performance liquid chromatography, triplex PCR method or real-time PCR; BMD_fn, BMD_ls, BMD_th values using dual energy X-ray absorptiometry, and plasma osteocalcin, serum bone alkaline phosphatase and free soluble tumor necrosis factor (ligand) superfamily, member 11 (sRANKL) concentrations using a solid-phase, two-site chemiluminescent enzyme-labeled immunometric assay, radioimmunoassay or enzyme immunoassay were determined. Statistical analysis was performed using one-way and two-way ANCOVA with adjustment for potential confounders (age, height and weight). Results: The (borderline) significant differences in BMD_th and BMD_fn values between genotype subgroups of Val224Ile polymorphism of GSTM3 gene (p = 0.057 and 0.053, respectively) with the lowest BMD values among heterozygotes and between 224Ile-insAGG haplotype subgroups (p = 0.048 and 0.019, respectively) were found. Significant differences of BMD_fn between the 224Ile-delAGG haplotype subgroups were observed (p = 0.012). Association of 224Val-insAGG with BMD_fn was of borderline significance (p = 0.062). Conclusion: The results of our study demonstrate the genetic association between detoxifying enzyme GSTM3 and BMD variation, suggesting that the Val224Ile polymorphism and 224Ile-insAGG haplotype could be used for further evaluation of the impact of GSTs gene polymorphisms on osteoporosis, using larger cohorts in searching for osteoporosis risk markers.

Oxidative-Stress-Related Genes in Osteoporosis: A Systematic Review

“…The identified papers were published from 2003 to date. Five studies were conducted in the Slovenia population [ 18 , 19 , 20 , 21 , 22 ], two studies in China [ 23 , 24 ], and one in India, Iran, Spain, Japan, Korea, Egypt, and the United Kingdom each [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Sample size widely varied, ranging from 142 to 426,824 individuals.…”

“…Thirty percent of the studies were conducted in pre or postmenopausal women [ 18 , 21 , 24 , 29 ], and the rest involved both men and women adults [ 19 , 20 , 22 , 23 , 25 , 26 , 27 , 28 , 30 , 31 ]. A total of 72% percent of all the studies were of a cross-sectional design, 21% were case-control studies, and 7% were cohort studies, mostly diagnosed according to the following criteria: osteoporosis T-score ≥ 2.5 SD below peak bone mass by DXA, except one study performed in Spain, which used peripheral instantaneous X-ray imaging [ 27 ].…”

“…GST gene family. Polymorphism in the GST gene family has been reported in three independent studies [ 19 , 20 , 21 ]. Mlakar, in 2011, reported a borderline significant association between rs74837985-C (Lys173Asp) in the GSTM1 gene with BMD lumbar spine values ( p = 0.100).…”

“…Carriers with at least one Ile allele compared to Val/Val homozygotes of GSTM3 were significantly related to the variation in BMD total hip (0.831 ± 0.148/0.859 ± 0.125 vs. 0.858 ± 0.139, p = 0.012). No significant differences in BMD values between genotype subgroups of insAGG polymorphisms were found [ 19 ]. Later, in 2012, Mlakar et al analyzed rs1138272 (Ala114Val) and rs1695 (Ile105Val) polymorphism in the GSTP1 gene in 523 Slovenian pre- and post-menopausal women.…”