Genetic Polymorphisms of Very Important Pharmacogene Variants in the Blang Population from Yunnan Province in China.

BACKGROUND: We aimed to enrich the pharmacogenomic information of a Blang population (BP) from Yunnan Province in China. METHODS: We genotyped 55 very important pharmacogene (VIP) variants from the PharmGKB database and compared their genotype distribution (GD) in a BP with that of 26 populations by the χ 2 test. The minor allele frequency (MAF) distribution of seven significantly different single-nucleotide polymorphisms (SNPs) was conducted to compare the difference between the BP and 26 other populations. RESULTS: Compared with the GD of 55 loci in the BP, among 26 studied populations, GWD, YRI, GIH, ESN, MSL, TSI, PJL, ACB, FIN and IBS were the top-10 populations, which showed a significantly different GD >35 loci. CHB, JPT, CDX, CHS, and KHV populations had a significantly different GD <20 loci. A GD difference of 27-34 loci was found between the BP and 11 populations (LWK, CEU, ITU, STU, PUR, CLM, GBR, ASW, BEB, MXL and PEL). The GD of five loci (rs750155 (SULT1A1), rs4291 (ACE), rs1051298 (SLC19A1), rs1131596 (SLC19A1) and rs1051296 (SLC19A1)) were the most significantly different in the BP as compared with that of the other 26 populations. The genotype frequency of rs1800764 (ACE) and rs1065852 (CYP2D6) was different in all populations except for PEL and LWK, respectively. MAFs of rs1065852 (CYP2D6) and rs750155 (SULT1A1) showed the largest fluctuation between the BP and SAS, EUR, AFR and AMR populations. CONCLUSION: Our data can provide theoretical guidance for safe and efficacious personalized drug use in the Blang population.

Genetic analysis of pharmacogenomic VIP variants in the Wa population from Yunnan Province of China.

BACKGROUND: The variation of drug responses and target does among individuals is mostly determined by genes. With the development of pharmacogenetics and pharmacogenomics, the differences in drug response between different races seem to be mainly caused by the genetic diversity of pharmacodynamics and pharmacokinetics genes. Very important pharmacogenetic (VIP) variants mean that genes or variants play important and vital roles in drug response, which have been listed in pharmacogenomics databases, such as Pharmacogenomics Knowledge Base (PharmGKB). The information of Chinese ethnic minorities such as the Wa ethnic group is scarce. This study aimed to uncover the significantly different loci in the Wa population in Yunnan Province of China from the perspective of pharmacogenomics, to provide a theoretical basis for the future medication guidance, and to ultimately achieve the best treatment in the future. RESULTS: In this study, we recruited 200 unrelated healthy Wa adults from the Yunnan province of China, selected 52 VIP variants from the PharmGKB for genotyping. We also compared the genotype frequency and allele distribution of VIP variants between Wa population and the other 26 populations from the 1000 Genomes Project ( http://www.1000Genomes.org/ ). Next, χ2 test was used to determine the significant points between these populations. The study results showed that compared with the other 26 population groups, five variants rs776746 (CYP3A5), rs4291 (ACE), rs3093105 (CYP4F2), rs1051298 (SLC19A1), and rs1065852 (CYP2D6) had higher frequencies in the Wa population. The genotype frequencies rs4291-TA, rs3093105-CA, rs1051298-AG and rs1065852-GA were higher than those of the other populations, and the allele distributions of rs4291-T and rs3093105-C were significantly different. Additionally, the difference between the Wa ethnic group and East Asian populations, such as CDX, CHB, and CHS, was the smallest. CONCLUSIONS: Our research results show that there is a significant difference in the distribution of VIP variants between the Wa ethnic group and the other 26 populations. The study results will have an effect on supplementing the pharmacogenomics information for the Wa population and providing a theoretical basis for individualised medication for the Wa population.

Fc receptor-like 1, 3, and 6 variants are associated with rheumatoid arthritis risk in the Chinese Han population.

BACKGROUND: Rheumatoid arthritis (RA) is the most common autoimmune system diseases in our world. More studies in recent years have shown that FCRL gene polymorphisms is closely related to autoimmune diseases. It is suggested that genetic factors play a crucial role in the pathogenesis of this disease. In this study, we aimed to investigate the relationship between FCRL1 rs2050568, FCRL3 rs2317230 and FCRL6 rs58240276 polymorphisms and RA risk in the Chinese Han population. 506 with RA patients and 509 healthy controls were recruited in this study, and the single nucleotide polymorphisms (SNPs) was successfully genotyped using the Agena MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (95% CIs) after adjusting for age and gender were conducted to assess these SNPs polymorphisms and RA risk. The multifactor dimensionality reduction (MDR) method was conducted to analyze SNP-SNP interaction. RESULTS: Our results revealed that there no significant association was observed between the allele and genotype frequencies among these SNPs and RA risk (all p > 0.05). Straified analysis by age and gender, the results confirmed that FCRL1 rs2050568 T/T genotype enhanced the risk of RA in females (p = 0.014). The G/T - T/T genotype of FCRL3 rs2317230 was correlated with a decreased RA risk in males (p = 0.021). We also observed that the C/T-T/T genotype of FCRL6 rs58240276 was increased the risk of RA in the group at age >  54 years (p = 0.016). In addition, FCRL1 rs2050568-TT, FCRL6 rs58240276-TT and FCRL1 rs2050568-TT, FCRL3 rs2317230-TT, FCRL6 rs58240276-TT are the best models for multi-site MDR analysis (p < 0.05), and the two best models mentioned above and classes RA have the most significant correlation. CONCLUSIONS: Our study demonstrated that FCRL1 rs2050568, FCRL3 rs2317230, and FCRL6 rs58240276 polymorphisms were correlated with RA susceptibility in the Chinese Han population.

Impacts of LOC105371267 Variants on Breast Cancer Susceptibility in Northern Chinese Han Females: A Population-Based Case-Control Study.

BACKGROUND: LOC105371267, also known as PR-lncRNA1, was reported to be a p53-regulated long noncoding RNA (lncRNA), which played an essential role in the pathogenesis of breast cancer (BC). We aimed to observe the potential association between LOC105371267 polymorphisms and BC risk in Northern Chinese Han females. METHODS: Totally, 555 healthy individuals and 561 patients with BC were recruited. Five candidate SNPs (rs6499221, rs3931698, rs8044565, rs3852740, and rs111577197) of LOC105371267 were genotyped with the Agena MassARRAY system. Odds ratio (OR) and 95% confidence intervals (CIs) were applied to evaluate the relationship of LOC105371267 genetic polymorphisms with BC susceptibility. Additionally, stratification analysis based on clinical features and haplotype analysis were also conducted. Finally, multifactor dimensionality reduction (MDR) analysis was performed to assess the SNP-SNP interaction among LOC105371267 variants, and false-positive report probability (FPRP) analysis was used to validate the result of this study. RESULTS: In this study, rs3931698 was a protective factor of BC in total (GG homozygote: OR = 0.30, 95% CI: 0.11-0.82, p=0.018; recessive model: OR = 0.30, 95% CI: 0.11-0.84, p=0.021). In stratification analysis based on the average age of 52 years and clinical characteristics (PR status, III-IV TNM stage), rs3931698 was also demonstrated to be associated with BC susceptibility. In addition, rs6499221 and rs3852740 were also associated with BC susceptibility among patients at age <52 years and patients with BC in a positive status. Thus, the haplotype analysis had a negative result for the incidence of BC (p > 0.05), and haplotype consisting of rs8044565 and rs111577197 was nonsignificantly associated with the BC risk. Finally, MDR and FPRP analyses also validated the result of this study. CONCLUSION: Polymorphisms rs3931698, rs6499221, and rs3852740 of LOC105371267 were found to be associated with the risk of BC in total, and stratification analysis in the Northern Chinese Han females suggested that LOC105371267 variants might be helpful to predict BC progression.

Population Genetic Difference of Pharmacogenomic VIP Variants in the Tibetan Population.

BACKGROUND: Genetic variation influences drug reaction or adverse prognosis. The purpose of this research was to genotype very important pharmacogenetic (VIP) variants in the Tibetan population. METHODS AND MATERIALS: Blood samples from 200 Tibetans were randomly collected and 59 VIP variants were genotyped, and then compared our data to 26 other populations in the 1000 project to further analyze and identify significant difference. RESULTS: The results showed that on comparing with most of the 26 populations from the 1000 project, rs4291 (ACE), rs1051296 (SLC19A1) and rs1065852 (CYP2D6) significantly differed in the Tibetan population. Furthermore, three significant loci were related to drug response. In addition, the allele frequency of Tibetans least differed from that of East Asian populations, and most differed from that of Americans. CONCLUSION: Three significant loci of variation ACE rs4291, SLC19A1 rs1051296 and CYP2D6 rs1065852 were associated with drug response. This result will contribute to improving the information of the Tibetan in the pharmacogenomics database, and providing a theoretical basis for clinical individualised drug use in Tibetans.

The Impacts of IL1R1 and IL1R2 Genetic Variants on Rheumatoid Arthritis Risk in the Chinese Han Population: A Case-Control Study.

BACKGROUND: Rheumatoid arthritis (RA), an autoimmune systemic inflammatory disease, largely resulted from genetic factor. Our purpose was to explore the association for IL1R1 and IL1R2 genetic variants with RA susceptibility in the Chinese Han population. PATIENTS AND METHODS: A total of 508 RA patients and 494 controls were involved in this case-control study; single-nucleotide polymorphisms (SNPs) genotyping was identified by the Agena MassARRAY platform. The relationship between polymorphisms and RA susceptibility was calculated using the Pearson's Chi-square test with odds ratios and 95% confidence intervals (CIs) in multiple genetic models. The Pearson's Chi-square test and Student's t-test were used for sample basic characteristic analysis. And linkage disequilibrium (LD) analysis and haplotype analysis were performed by logistic regression analysis. RESULTS: The result from this study showed that rs2072472 (IL1R2) was an increased risk factor of RA (adjusted OR = 1.41, p = 0.011). Stratified analysis indicated SNPs rs10490571, rs956730, rs3917318 of IL1R1, and SNPs rs4851527, rs719250, rs3218896, rs3218977, rs2072472 of IL1R2 had impacts on RA risk after stratification based on gender and average age (54 years). Finally, haplotype analysis revealed that Ars3218977Ars2072472 haplotype in IL1R2 was related to a decreased RA risk (adjusted OR = 0.79; 95% CI = 0.65-0.94; p = 0.010). Yet, rs3917225(IL1R1) and rs11674595(IL1R2) were not significant in RA association analysis. CONCLUSION: We determined SNPs (rs3917318, rs956730, rs1049057) of IL1R1 and SNPs (rs3218977, rs719250, rs4851527, rs3218896, rs2072472) of IL1R2 were correlated with the RA susceptibility in the Chinese Han population.

Impact of ESR1 Polymorphisms on Risk of Breast Cancer in the Chinese Han Population.

BACKGROUND: The estrogen receptor-1 (ESR1) gene encodes estrogen receptor-α, which is a major biomarker in the development of breast cancer. This study aimed to investigate the effect of ESR1 polymorphisms on breast cancer in Chinese Han women. MATERIALS AND METHODS: We genotyped 4 candidate single nucleotide polymorphisms (SNPs) in ESR1 among 503 patients with breast cancer and 503 healthy people using the Agena MassARRAY platform. The association between ESR1 polymorphisms and breast cancer risk was evaluated using odds ratios (ORs) and 95% confidence intervals (95% CIs) under 4 genetic models. The HaploReg v4.1 and GEPIA database were used for SNP functional annotation and ESR1 expression analysis, respectively. RESULTS: The T allele of rs9383938 in ESR1 was significantly associated with an increased breast cancer risk (OR, 1.26; 95% CI, 1.05-1.50; P = .013). In genetic models, rs9383938 increased breast cancer risk in the codominant model (OR, 1.54; 95% CI, 1.07-2.22; P = .021), the dominant model (OR, 1.31; 95% CI, 1.01-1.68; P = .040), and the additive model (OR, 1.24; 95% CI, 1.04-1.48; P = .017). Stratification analysis showed that rs9383938 and rs2228480 raised the breast cancer susceptibility in individuals aged younger than 52 years old. Rs1801132 of ESR1 was significantly associated with the status of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 in the allele model and genetic models (P < .05). CONCLUSIONS: This study demonstrated that ESR1 polymorphisms might influence breast cancer susceptibility in the Chinese Han population. Further mechanism studies are needed to confirm the contribution of ESR1.

Transcriptome analysis of genes and metabolic pathways associated with nicotine degradation in Aspergillus oryzae 112822.

BACKGROUND: Nicotine-degrading microorganisms (NDMs) have recently received much attention since they can consume nicotine as carbon and nitrogen source for growth. In our previous work, we isolated an efficient nicotine-degrading fungus Aspergillus oryzae 112822 and first proposed a novel demethylation pathway of nicotine degradation in fungi. However, the underlying mechanisms of the demethylation pathway remain unresolved. In the present study, we performed a comparative transcriptome analysis to elucidate the molecular mechanisms of nicotine tolerance and degradation in A. oryzae 112822. RESULTS: We acquired a global view of the transcriptional regulation of A. oryzae 112822 exposed to nicotine and identified 4381 differentially expressed genes (DEGs) by nicotine treatment. Candidate genes encoding cytochrome P450 monooxygenases (CYPs), FAD-containing amine oxidase, molybdenum cofactor (Moco)-containing hydroxylase, and NADH-dependent and FAD-containing hydroxylase were proposed to participate in the demethylation pathway of nicotine degradation. Analysis of these data also revealed that increased energy was invested to drive nicotine detoxification. Nicotine treatment led to overproduction of reactive oxygen species (ROS), which formed intracellular oxidative stress that could induce the expression of several antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and peroxiredoxin (Prx). Thioredoxin system was induced to restore the intracellular redox homeostasis. Several glutathione S-transferases (GSTs) were induced, most likely to participate in phase II detoxification of nicotine by catalyzing the conjugation of glutathione (GSH) to active metabolites. The toxin efflux pumps, such as the ATP-Binding Cassette (ABC) transporters and the major facilitator superfamily (MFS) transporters, were overexpressed to overcome the intracellular toxin accumulation. By contrast, the metabolic pathways related to cellular growth and reproduction, such as ribosome biogenesis and DNA replication, were inhibited by nicotine treatment. CONCLUSION: These results revealed that complex regulation networks, involving detoxification, transport, and oxidative stress response accompanied by increased energy investment, were developed for nicotine tolerance and degradation in A. oryzae 112822. This work provided the first insight into the metabolic regulation of nicotine degradation and laid the foundation for further revealing the molecular mechanisms of the nicotine demethylation pathway in filamentous fungi.

Rational designed mutagenesis of levansucrase from Bacillus licheniformis 8-37-0-1 for product specificity study.

Levansucrases, which belong to the glycoside hydrolase family 68 (GH68), synthesize ß (2-6)-linked fructan levan with sucrose as substrate. We described the use of a levansucrase (Bl_SacB) from Bacillus licheniformis 8-37-0-1 for catalysis of fructosyl transfer to obtain high levan yield previously. In the present study, six variants (Y246A, N251A, K372A, R369A, R369S, and R369K) were constructed through sequence alignment and structural analysis to explore the synthesis mechanism of Bl_SacB. The selected residues were predicted to localize to the substrate-entering channel of the active cavity and close to or remote from the catalytic triad. The products of these variants ranged from homopolymers levan to fructo-oligosaccharides (FOSs). The primary FOSs were identified through MS and NMR analyses as neolevan-type neokestose [ß-D-Fru-(2-6)-α-D-Glc-(1-2)-ß-D-Fru], levan-type 6-kestose [ß-D-Fru-(2-6)-ß-D-Fru-(2-1)-α-D-Glc], and inulin-type 1-kestose [ß-D-Fru-(2-1)-ß-D-Fru-(2-1)-α-D-Glc]. The mutation at Tyr246 located remote from the catalytic triad led to the production of short-chain oligosaccharides with degree of polymerization (DP) of up to 25. The replaced Arg369 located close to the catalytic triad resulted in either elimination of polysaccharide synthesis or complete change in the dominant linkage of the products. The Michaelis constants (Km) of Y246A, N251A, K372A, and R369K were found to be similar to that of the wild type (WT). However, the turnover number (kcat) and the value of transfructosylation versus hydrolysis activity of the six variants decreased compared with those of the WT. Hence, the residues located on the surface of the substrate-entering channel of Bl_SacB can be critical in product linkage type and/or elongation mechanism.

Analysis and design of the transmitting mode on the pre-polarization surface nuclear magnetic resonance system.

Surface nuclear magnetic resonance (SNMR) technology is widely used in the detection of groundwater due to its non-invasive, qualitative, and quantitative advantages. Nonetheless, SNMR is difficult to employ in a high ambient noise level because of the weak level of nanovolt signals (10-9 V). To solve this problem, pre-polarization (PP) technology is utilized for SNMR detection. That is, the combination of direct current, i.e., PP pulse, with alternating current (AC) pulses is utilized to increase the signal amplitude of shallow hydrogen protons. However, the PP and AC pulses on the same transmitting coil should be output independently when using the PP SNMR system. Meanwhile, to avoid magnetization loss, the process of shutting down the PP field must be both rapid and adiabatic. To solve the above problems, we improved the transmitting part of the PP SNMR system and designed a discharge circuit for PP pulses. The feasibility of the design was demonstrated through both software simulation and actual testing. When the PP current is 91 A, it can be turned off within 3 ms. Via further water measurements in an electromagnetically shielded room, we demonstrated that a PP system with a PP pulse discharge circuit can effectively increase the initial amplitude of the signal.