Single-nucleotide polymorphism in the 5-α-reductase gene ( SRD5A2 ) is associated with increased prevalence of metabolic syndrome in chemotherapy-treated testicular cancer survivors

Boer, Hink; Westerink, Nico-Derk L.; Altena, Renske; Nuver, Janine; Dijck-Brouwer, D.A. Janneke; Faassen, Martijn van; Klont, Frank; Lefrandt, Joop D.; Zwart, Nynke; Boezen, H. Marike; Smit, Andries J.; Meijer, Coby; Gietema, Jourik A.

doi:10.1016/j.ejca.2015.11.009

Cited by 6 publications

(8 citation statements)

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“…15–19 Some investigations have demonstrated MetS risk to be higher among TCS compared to controls, 15–18 but others have not. 19 Boer et al 20 reported MetS to be more prevalent in TCS carrying the minor allele of a single nucleotide polymorphism (SNP), rs523349 (V89L), compared to wild type (33% vs. 19%, P =.032). This SNP is a nonsynonymous coding variant in the gene SRD5A2, encoding steroid 5-α-reductase type II.…”

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors

Zaid

Gathirua-Mwangi

Fung

et al. 2018

J Natl Compr Canc Netw

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Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. TCS were aged<55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-α-reductase gene, ), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ≥3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; <.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; <.001) or abdominal obesity (28.2% vs 40.1%; <.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; =.59), did not differ by treatment (=.20), and was not related to rs523349 (=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; <.001), total cholesterol levels (26.3% vs 11.1%; <.001), and body mass index ≥25 kg/m (75.1% vs 69.1%; =.04). On multivariate analysis, age at evaluation (<.001), testosterone level ≤3.0 ng/mL (odds ratio [OR], 2.06; =.005), and elevated sICAM-1 level (OR, 3.58; =.001) were significantly associated with MetS. Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment-associated MetS requires further characterization.

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Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors

Zaid

Gathirua-Mwangi

Fung

et al. 2018

J Natl Compr Canc Netw

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“…5α-reductase types 1 and 2, which are products of the SRD5A1 and SRD5A2 expression, are associated with the process of reducing testosterone to dihydrotestosterone. Since the prostate is a gland dependent on androgens, these genes may play a part in the etiology and treatment of both BPH and prostate tumors [ 8 ]. The relationship between the incidence of prostate diseases and the SRD5A2 polymorphism has been confirmed by many studies [ 8 , 13 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Since the prostate is a gland dependent on androgens, these genes may play a part in the etiology and treatment of both BPH and prostate tumors [ 8 ]. The relationship between the incidence of prostate diseases and the SRD5A2 polymorphism has been confirmed by many studies [ 8 , 13 , 14 ]. Reports on the association between the SRD5A1 polymorphism and BPH are less numerous [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…Both type 1 and type 2 can be found in prostate epithelial cells, but type 2 is also observed in prostate stromal cells. The available literature provides few publications concerning the influence of genetic variations in the SDR5A1 and SRD5A2 genes on the prostate function and size in the course of BPH [ 8 , 9 , 10 ]. Selected polymorphic variants of the SDR5A1 and SRD5A2 genes can influence the activity of hormones that are essential for BPH etiology, thus contributing to individual responsiveness to treatment [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Analysis of the SRD5A1 and SRD5A2 Genes in Patients with Benign Prostatic Hyperplasia with Regard to Metabolic Parameters and Selected Hormone Levels

Rył

Rotter

Grzywacz

et al. 2017

IJERPH

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Introduction: The etiology of benign prostatic hyperplasia (BPH) has not so far been fully explicated. However, it is assumed that changes in the levels of hormones associated with aging can contribute to the development of prostatic hyperplasia. Dihydrotestosterone combines with the androgen receptor (AR) proteins of the prostate gland. Enzyme activity is based on two isoenzymes: type 1 and type 2. 5α-reductase type 1 is encoded by the SRD5A1 gene, and type 2 is encoded by the SRD5A2 gene. The aim of our study was to determine the frequency of the SRD5A1 (rs6884552, rs3797177) and SRD5A2 (rs523349, rs12470143) genes’ polymorphisms, and to assess the relationships between the genotypes of the tested mutations, and the levels of biochemical and hormonal parameters in patients with BPH. Material and Methods: The study involved 299 men with benign prostatic hyperplasia. We determined the serum levels of particular biochemical parameters—fasting plasma glucose (FPG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides (TG)—by the spectrophotometric method, using ready reagent kits. The ELISA method was used to determine the levels of the following hormonal parameters and proteins: total testosterone (TT), free testosterone (FT), insulin (I), luteinizing hormone (LH), and sex hormone binding protein (SHBG). Metabolic syndrome was diagnosed. Genotyping was performed by real-time PCR. Results: We analyzed the relationships between the incidence of particular diseases and the genotypes of the SRD5A1 and SRD5A2 polymorphisms among patients with BPH. The BPH patients with the CC genotype of the SRD5A2 rs523349 and rs12470143 polymorphisms were considerably less frequently diagnosed with metabolic syndrome (MetS) (p = 0.022 and p = 0.023 respectively). Our analysis revealed that homozygotes with the CC of the SDR5A2 rs12470143 polymorphism had visibly higher HDL levels than those with the TT and CT genotypes (p = 0.001). Additionally, we found that the patients with the CC genotype of the SDR5A2 rs12470143 polymorphism had considerably higher FT levels (p = 0.001) than the heterozygotes with the CT and the homozygotes with the TT of the genetic variant analyzed in our study. Furthermore, the patients with at least one G allele of the SRD5A2 rs523349 polymorphism had significantly lower SGBG levels (p = 0.022) compared with the homozygotes with the CC genotype. The presence of at least one A allele (AA + AG genotypes) of the SRD5A1 rs3797177 polymorphism entailed notably lower serum insulin levels than those observed in homozygotes with the GG genotype (p = 0.033). Conclusions: The study described in this article shows that selected SRD5A1 and SRD5A2 polymorphisms can alter the levels of metabolic and hormonal parameters in patients with BPH. Special attention should be paid to the SDR5A2 rs12470143 polymorphism, which is associated with a change in lipid profile, as well as with the inheritance and incidence rate of MetS among these patients. An analysis of the frequency o...

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“…SNPs in the glutathione S-transferase genes GSTP1 and GSTM3 have been associated with neurotoxicity and ototoxicity in platinum-treated TC patients [4][5][6]. SNPs in the 5-αreductase type II (SRD5A2) gene were associated with prevalence of the metabolic syndrome in TC survivors after platinum-based chemotherapy [7]. This finding, however, could not be replicated [8].…”

Section: Introductionmentioning

confidence: 97%

Genome-wide association study of cardiovascular disease in testicular cancer patients treated with platinum-based chemotherapy

et al. 2020

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Genetic variation may mediate the increased risk of cardiovascular disease (CVD) in chemotherapy-treated testicular cancer (TC) patients compared to the general population. Involved single nucleotide polymorphisms (SNPs) might differ from known CVD-associated SNPs in the general population. We performed an explorative genome-wide association study (GWAS) in TC patients. TC patients treated with platinum-based chemotherapy between 1977 and 2011, age ≤55 years at diagnosis, and ≥3 years relapse-free follow-up were genotyped. Association between SNPs and CVD occurrence during treatment or follow-up was analyzed. Data-driven Expression Prioritized Integration for Complex Trait (DEPICT) provided insight into enriched gene sets, i.e., biological themes. During a median follow-up of 11 years (range 3–37), CVD occurred in 53 (14%) of 375 genotyped patients. Based on 179 SNPs associated at p ≤ 0.001, 141 independent genomic loci associated with CVD occurrence. Subsequent, DEPICT found ten biological themes, with the RAC2/RAC3 network (linked to endothelial activation) as the most prominent theme. Biology of this network was illustrated in a TC cohort (n = 60) by increased circulating endothelial cells during chemotherapy. In conclusion, the ten observed biological themes highlight possible pathways involved in CVD in chemotherapy-treated TC patients. Insight in the genetic susceptibility to CVD in TC patients can aid future intervention strategies.

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Single-nucleotide polymorphism in the 5-α-reductase gene ( SRD5A2 ) is associated with increased prevalence of metabolic syndrome in chemotherapy-treated testicular cancer survivors

Cited by 6 publications

References 32 publications

Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors

Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors

Molecular Analysis of the SRD5A1 and SRD5A2 Genes in Patients with Benign Prostatic Hyperplasia with Regard to Metabolic Parameters and Selected Hormone Levels

Genome-wide association study of cardiovascular disease in testicular cancer patients treated with platinum-based chemotherapy

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