Ying Chin Lin

Relation of polymorphism of arsenic metabolism genes to arsenic methylation capacity and developmental delay in preschool children in Taiwan

ABSTRACT Inefficient arsenic methylation capacity has been associated with developmental delay in children. The present study was designed to explore whether polymorphisms and haplotypes of arsenic methyltransferase (AS3MT), glutathione‐S‐transferase omegas (GSTOs), and purine nucleoside phosphorylase (PNP) affect arsenic methylation capacity and developmental delay. A case‐control study was conducted from August 2010 to March 2014. All participants were recruited from the Shin Kong Wu Ho‐Su Memorial Teaching Hospital. In total, 179 children with developmental delay and 88 children without delay were recruited. Urinary arsenic species, including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) were measured using a high‐performance liquid chromatography‐linked hydride generator and atomic absorption spectrometry. The polymorphisms of AS3MT, GSTO, and PNP were performed using the Sequenom MassARRAY platform with iPLEX Gold chemistry. Polymorphisms of AS3MT genes were found to affect susceptibility to developmental delay in children, but GSTO and PNP polymorphisms were not. Participants with AS3MT rs3740392 A/G + G/G genotype, compared with AS3MT rs3740392 A/A genotype, had a significantly lower secondary methylation index. This may result in an increased OR for developmental delay. Participants with the AS3MT high‐risk haplotype had a significantly higher OR than those with AS3MT low‐risk haplotypes [OR and 95% CI, 1.59 (1.08–2.34)]. This is the first study to show a joint dose‐response effect of this AS3MT high‐risk haplotype and inefficient arsenic methylation capacity on developmental delay. Our data provide evidence that AS3MT genes are related to developmental delay and may partially influence arsenic methylation capacity. HIGHLIGHTSAS3MT genotypes were found to affect susceptibility to developmental delay.AS3MT rs3740392 A/G and G/G genotype had a significantly low SMI (DMA/MMA) index.AS3MT high‐risk haplotype was significantly associated with developmental delay.

Combined effects of DNA methyltransferase 1 and 3A polymorphisms and urinary total arsenic levels on the risk for clear cell renal cell carcinoma

Our previous study showed that high urinary total arsenic levels were associated with higher odds ratio (OR) for renal cell carcinoma (RCC). Single nucleotide polymorphisms (SNPs) of DNA methyltransferases (DNMTs) might influence DNMT enzyme activity associated with tumorigenesis. In this study, we investigated the association of five SNPs from DNMT1 (rs8101626 and rs2228611), DNMT3A (rs34048824 and rs1550117), and DNMT3B (rs1569686) with the risk of clear cell renal cell carcinoma (ccRCC). We also examined the combined effects of DNMT genotypes and urinary arsenic levels on ccRCC risk. We conducted a hospital-based case-control study, which included 293 subjects with ccRCC and 293 age- and gender-matched controls. The urinary arsenic species were determined by a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Genotypes were investigated using polymerase chain reaction and restriction fragment length polymorphism analyses. We observed that the DNMT1 rs8101626 G/G genotype was significantly associated with reduced odds ratio (OR) of ccRCC [OR=0.38, 95% confidence interval (CI) 0.14-0.99]. Subjects with concurrent DNMT1 rs8101626 A/A+A/G and DNMT3A rs34048824 T/T+T/C genotypes had significantly higher OR for ccRCC [OR=2.88, 95% CI 1.44-5.77]. Participants with the high-risk genotype of DNMT1 rs8101626 and DNMT3A rs34048824 with concurrently high urinary total arsenic levels had even higher OR of ccRCC in a dose-response manner. This is the first study to evaluate variant DNMT1 rs8101626 and DNMT3A rs34048824 genotypes that modify the arsenic-related ccRCC risk in a geographic area without significant arsenic exposure in Taiwan.

The polymorphism XRCC1 Arg194Trp and 8-hydroxydeoxyguanosine increased susceptibility to arsenic-related renal cell carcinoma

ABSTRACT This study was designed to explore the relationship between X‐ray repair cross‐complementing group 1 (XRCC1) gene polymorphisms and renal cell carcinoma (RCC) and to investigate whether individuals with an XRCC1 risk genotype, a high level of 8‐OHdG or a high urinary total arsenic concentration have a modified odds ratio (OR) of RCC. We recruited 180 RCC patients and 360 age‐ and sex‐matched controls from a hospital‐based pool. Image‐guided biopsy or surgical resection of renal tumors was performed on RCC patients for pathological verification. Genomic DNA was used to examine the genotype of XRCC1(Arg399Gln), XRCC1(Arg194Trp), XRCC3(Thr241Met) and XPD(Lys751Gln) by PCR‐RFLP. Liquid chromatography with tandem mass spectrometry was used to determine urinary 8‐OHdG levels. A HPLC‐HG‐AAS was used to determine the concentrations of urinary arsenic species. Participants with the genotype XRCC1(Arg194Trp) Arg/Trp + Trp/Trp had a significantly higher OR of RCC than those with the Arg/Arg genotype; the OR and 95% confidence interval was 0.66 (0.45–0.97) after multivariate adjustment. The OR of RCC for the combined effect of high urinary 8‐OHdG levels and high urinary total arsenic concentration in individuals with a XRCC1(Arg194Trp) Arg/Trp + Trp/Trp genotype was higher than in patients with an Arg/Arg genotype, which was evident in a dose response manner. In conclusion, this is the first study to show that the XRCC1 Arg194 allele is a predicting factor for RCC. The more risk factors (high urinary 8‐OHdG levels, high urinary total arsenic concentrations, and XRCC1 Arg194 allele) that were present, the higher the OR of RCC. HighlightsXRCC1(Arg194Trp) was found to affect the risk RCC.XRCC1(Arg194Trp) modified the joint effect of 8‐OHdG and urinary total arsenic.Carried Arg194 allele, and had higher 8‐OHdG and arsenic, the higher OR of RCC

Polymorphisms of Arsenic (+3 Oxidation State) Methyltransferase and Arsenic Methylation Capacity Affect the Risk of Bladder Cancer

The mechanisms underlying how arsenic methylation capacity affects bladder cancer (BC) are still unclear. The objective of this study was to explore the effects of polymorphisms of arsenic (+3 oxidation state) methyltransferase (AS3MT) on BC risk. We conducted a hospital-based study and enrolled 216 BC and 648 healthy controls from 2007 to 2011. Urinary arsenic profiles were measured using high-performance liquid chromatography-hydride generation-atomic absorption spectrometry. The gene polymorphisms of AS3MT were identified using the Sequenom MassARRAY platform with iPLEX Gold chemistry. Inefficient arsenic methylation capacity (high monomethylarsonic acid percentage [MMA%] and low dimethylarsinic acid percentage [DMA%]) was associated with increased risk of BC in a dose-response relationship. AS3MT rs11191438 (C > G) G/G genotype, AS3MT rs10748835 (A > G) G/G genotype, and AS3MT rs1046778 (C > T) T/T genotype were found to be related to BC risk, where the odds ratio (OR) (95% CI) was 0.50 (0.31-0.82), 0.49 (0.30-0.79), and 0.54 (0.36-0.80), respectively. The combination of AS3MT haplotype 2 (AS3MT rs11191453, rs11191454, rs10748835, and rs1046778)s high-risk haplotype (C-G-A-C, T-A-A-C, and T-G-G-T) was significantly associated with increased risk of BC. Among controls, only 3 of the 9 candidate genotypes evaluated, rs1119438 C/C, rs10748835 A/A and rs1046778 C/C, were associated with significantly higher MMA% compared with the other genotypes. No other genotypes or haplotypes were related to arsenic methylation capacity. High MMA%, low DMA% and AS3MT rs1046778 C/C + C/T genotype predicted a significantly higher risk of BC according to stepwise multiple logistic regression analyses. AS3MT gene polymorphisms and arsenic methylation capacity appeared to affect BC risk independently.

Adiponectin gene polymorphisms and obesity increase the susceptibility to arsenic-related renal cell carcinoma

ABSTRACT Our recent study found that high urinary total arsenic levels were associated with renal cell carcinoma (RCC). Recent studies demonstrated that low circulating adiponectin was related to RCC. The aim of the present study was to explore the relationship between adiponectin gene (ADIPOQ) polymorphisms and RCC and investigate whether individuals with an ADIPOQ risk genotype, obesity, and high urinary total arsenic levels have a modified odds ratio (OR) of RCC. A total of 389 RCC patients and 389 age‐ and sex‐matched controls were recruited between November 2006 and December 2012 in Taiwan. Image‐guided biopsy or surgical resection of renal tumors was performed to pathologically verify RCC. Genomic DNA was used to examine the genotypes of the ADIPOQ rs182052, ADIPOQ rs2241766, ADIPOQ rs1501299, and ADIPOQ rs1063539 SNPs by PCR‐RFLP. HPLC‐HG‐AAS was used to measure the concentrations of urinary arsenic species. Participants with the ADIPOQ rs182052 G/A+A/A genotype had a significantly higher OR of RCC compared with those with the ADIPOQ rs182052 G/G genotype. The OR (95% confidence interval [CI]) was 1.70 (1.23–2.36). The OR of RCC for the combined effect of high urinary total arsenic levels and obesity, which was dose‐dependent, in individuals with the ADIPOQ rs182052 G/A+A/A genotype was 9.33 (3.85–22.62). The present study found significant combined effects of obesity and the ADIPOQ rs182052 G/A+A/A genotype on the arsenic‐related risk of RCC in a population with low arsenic exposure. Arsenic exposure, obesity, and the ADIPOQ rs182052 polymorphism could be predictors of a higher OR of RCC. HighlightsADIPOQ rs182052 G/A + A/A genotype was found to affect the risk RCC.ADIPOQ rs182052 A allele modified the effect of BMI and urinary arsenic on RCC.Carried ADIPOQ rs182052 A allele, obesity, and higher arsenic, the higher OR of RCC.

Author Correction: The Methylation Capacity of Arsenic and Insulin Resistance are Associated with Psychological Characteristics in Children and Adolescents

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Polymorphisms of TNF-α -308 G/A and IL-8 -251 T/A Genes Associated with Urothelial Carcinoma: A Case-Control Study

Cigarette smoking and exposure to environmental tobacco smoke are well-known risk factors for urothelial carcinoma (UC). We conducted a hospital-based case-control study involving 287 UC cases and 574 cancer-free controls to investigate the joint effects of cigarette smoking and polymorphisms of inflammatory genes on UC risk. Tumor necrosis factor alpha (TNF-α) -308 G/A and interleukin-8 (IL-8) -251 T/A polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism method. People who had ever smoked and those who were exposed to environmental tobacco smoke had significantly increased UC odds ratios (ORs) of 1.65 and 1.68, respectively. Participants who had smoked more than 18 pack-years had a significantly increased UC OR of 2.64. People who had ever smoked and who carried the A/A genotype of the TNF-α -308 G/A polymorphism had a significantly higher UC OR (10.25) compared to people who had never smoked and who carried the G/G or G/A genotype. In addition, people who had ever smoked and who carried the IL-8 -251 T/T genotype had a significantly increased UC OR (3.08) compared to people who had never smoked and who carried the T/A or A/A genotype. In a combined analysis of three major risk factors (cumulative cigarette smoking, the TNF-α -308 A/A genotype, and the IL-8 -251 T/T genotype), subjects with any one, any two, and all three risk factors experienced significantly increased UC ORs of 1.55, 2.89, and 3.77, respectively, compared to individuals with none of the risk factors. Conclusions. Our results indicate that the combined effects of cumulative cigarette exposure and the TNF-α -308 A/A genotype and/or the IL-8 -251 T/T genotype on UC OR showed a significant dose-response relationship.

The Methylation Capacity of Arsenic and Insulin Resistance are Associated with Psychological Characteristics in Children and Adolescents

The goal of the present study was to compare the influence of the methylation capacity of arsenic, as well as insulin resistance on psychological characteristics of school students from elementary and junior high school. 296 elementary and 318 junior high school students participated in health examinations, completed questionnaires and determined their concentrations of urinary arsenic species and psychological characteristics. Insulin resistance was determined by means of the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). We found that HOMA-IR values were significantly related to increased score of the depression and anger after adjusted for age, gender, schools, father’s educational levels, mother’s educational levels, BMI, body fat, and urinary creatinine in all students. Anxiety scores and depression scores of junior high school children were significantly higher compared to elementary school children, but lower in disruptive behavior scores. HOMA-IR levels were significantly inversely related to self-concept scores in junior high school students. A greater urinary inorganic arsenic percentage (iAs%) was marginally significantly related to a higher depression score in junior high school students. This is the first study to show a relationship between HOMA-IR levels or urinary arsenic profiles and psychological distress in school students from elementary and junior high school.

The proper use of coronary calcium score and coronary computed tomography angiography for screening asymptomatic patients with cardiovascular risk factors

Early detection and treatment of coronary artery disease (CAD) can reduce incidences of acute myocardial infarction. In this study, we determined the proper use of contributing risk factors and coronary artery calcium score (CACS) when screening asymptomatic patients with coronary arterial stenoses using coronary computed tomography angiography (CCTA). We reviewed 934 consecutive patients who received CACS and CCTA between December 2013 and November 2016. At least one cardiovascular disease risk factor was present in each of the 509 asymptomatic participants. Patients were grouped based on CACS into “zero,” “minimal” (0 < CACS ≤ 10), “mild” (10 < CACS ≤ 100), “moderate” (100 < CACS ≤ 400), and “excessive” (CACS > 400). Males over 45 years old with diabetes mellitus and hypertension had a higher risk of significant coronary stenosis. In multivariate analysis, age, sex, hypertension, and diabetes mellitus remained significant predictors of stenosis. A CACS of zero occurred in 227 patients (44.6%). There were no significant differences between the “zero” and “minimal” groups (p = 0.421), but the “mild,” “moderate,” and “excessive” groups showed correlations with significant coronary stenosis. Age, sex, diabetes mellitus, and hypertension were associated with higher risk of significant coronary stenosis. Asymptomatic patients with CACSs of zero do not require CCTA, and thereby avoid unnecessary radiation exposure.