Significance Of Single Nucleotide Polymorphisms Research Articles

Associations of BDNF/BDNF-AS SNPs with Depression, Schizophrenia, and Bipolar Disorder.

Brain-Derived Neurotrophic Factor (BDNF) is crucial for various aspects of neuronal development and function, including synaptic plasticity, neurotransmitter release, and supporting neuronal differentiation, growth, and survival. It is involved in the formation and preservation of dopaminergic, serotonergic, GABAergic, and cholinergic neurons, facilitating efficient stimulus transmission within the synaptic system and contributing to learning, memory, and overall cognition. Furthermore, BDNF demonstrates involvement in neuroinflammation and showcases neuroprotective effects. In contrast, BDNF antisense RNA (BDNF-AS) is linked to the regulation and control of BDNF, facilitating its suppression and contributing to neurotoxicity, apoptosis, and decreased cell viability. This review article aims to comprehensively overview the significance of single nucleotide polymorphisms (SNPs) in BDNF/BDNF-AS genes within psychiatric conditions, with a specific focus on their associations with depression, schizophrenia, and bipolar disorder. The independent influence of each BDNF/BDNF-AS gene variation, as well as the interplay between SNPs and their linkage disequilibrium, environmental factors, including early-life experiences, and interactions with other genes, lead to alterations in brain architecture and function, shaping vulnerability to mental health disorders. The potential translational applications of BDNF/BDNF-AS polymorphism knowledge can revolutionize personalized medicine, predict disease susceptibility, treatment outcomes, and guide the selection of interventions tailored to individual patients.

DNA polymorphisms and expression profile of immune and antioxidant genes as biomarkers for reproductive disorders tolerance/susceptibility in Baladi goat

The objective of this study was to explore single nucleotide polymorphisms (SNPs) and gene expression of immune and antioxidant markers associated with reproductive disorders in Baladi goats. A total of one hundred adults Baladi does were allocated into two equal-sized groups: normal reproductive performance and does have a history of reproductive disorders. DNA sequencing of PRLR (304-bp), LTF (904-bp), TLR2 (420-bp), TLR4 (335-bp), CLA-DRB3.2 (285-bp), SOD3 (735-bp), CAT (1526-bp), GPX4 (782-bp), and GST (690-bp) revealed SNPs associated with reproductive disorders tolerance/susceptibility in investigated does. Nonetheless, DNA sequencing of beta defensin (483-bp), CCL5 (840-bp), and ATOX1 (374-bp) genes elicited a monomorphic pattern. Levels of PRLR, LTF, TLR2, TLR4, CLA-DRB3.2, beta defensin, and CCL5 genes were significantly up-regulated in does affect with reproductive disorders than tolerant ones; while SOD3, CAT, GPX4, GST and ATOX1 genes pattern elicited an opposite trend. The results herein confirmed the potential significance of SNPs in immune and antioxidant genes as genetic markers for reproductive disorders tolerance/susceptibility in Baladi does. The Gene expression profile of investigated genes could be also used as proxy biomarkers for the prediction of the most susceptible risk time for disease occurrence and for building up an effective management protocol.

Функціональне значення однонуклеотидного поліморфізму (RS11204981) в гені філагрину (FLG) для лікування бронхіальної астми у дітей з атопічним дерматитом

Мета. Метою даного дослідження було визначити зв’язок однонуклеотидного поліморфізму в гені філагрину й експресії мРНК філагрину в букальному епітелії з фенотипом бронхіальної астми з атопічним дерматитом в анамнезі у дітей. Методи. Генотипування філагрину (rs11204981) проводили в групі хворих із бронхіальною астмою і контрольній групі за допомогою ПЛР у реальному часі. Рівень експресії мРНК оцінювався з використанням зворотної транскрипції та наступної ПЛР у реальному часі. Результати. Ми виявили, що 5 % пацієнтів основної групи і 2 % контрольної групи мали мінорну алель (АА), 27 і 36 % відповідно мали гетерозиготну алель, 67 і 61 % відповідно — мажорну алель. Варіанти з генотипом АА з rs11204981 FLG виявилися в 2,4 раза частіше у пацієнтів основної, ніж контрольної групи. Гетерозиготний варіант мав значно вищу експресію філагрину в букальному епітелії. Висновки. Ми вважаємо, що поліморфізм в гені філагрину (rs11204981) може служити як важливий прогностичний маркер для фенотипу бронхіальної астми та атопічного дерматиту і що високий рівень експресії в гетерозиготному стані може свідчити про протекторну роль даного генотипу у розвитку алергії.

Dysfibrinogenemia-Potential Impact of Genotype on Thrombosis or Bleeding.

The congenital dysfibrinogenemias, most often associated with bleeding disorders, encompass mutations in the amino-terminal end of fibrinogen α-chain consisting of Gly17-Pro18-Arg19-Val20, known as knob A, which is a critical site for fibrin polymerization. Here we review the studies reporting dysfibrinogenemia due to mutations affecting fibrinogen knob A and identified 29 papers. The number of reports on dysfibrinogenemias related to residues Gly17, Pro18, Arg19, and Val20 is 5, 4, 18, and 2, respectively. Dysfibrinogenemias related to residues Gly17, Pro18, and Val20 are exclusively associated with bleeding tendency. However, the clinical picture associated with dysfibrinogenemia related to residue Arg19 varies, with most patients suffering from bleeding tendencies, but also transitory ischemic attacks and retinal thrombosis may occur. The reason for this variation is unclear. To elaborate the genotype-phenotype associations further, we studied a Danish family with knob A-related dysfibrinogenemia caused by the Aα Arg19Gly (p.Arg19Gly) mutation using whole-exome sequencing and fibrin structure analysis. Our family is the first reported carrying the p.Arg19Gly mutation combined with one or more single nucleotide polymorphisms (SNP)s in FGA, FGB, and/or FGG and increased fibrin fiber thickness and fibrin mass-to-length ratio suffering from pulmonary emboli, suggesting that compound genotypes may contribute to the thrombogenic phenotype of these patients. Our review, accordingly, focuses on significance of SNPs, compound genotypes, and fibrin structure measures affecting the genotype-phenotype associations in fibrinogen knob A mutations.

Association of genetic variants in lncRNA GAS5/miR-21/mTOR axis with risk and prognosis of coronary artery disease among a Chinese population.

BackgroundAllowing for the significance of single nucleotide polymorphisms (SNPs) in reflecting disease risk, this investigation attempted to uncover whether SNPs situated in lncRNA GAS5/miR‐21/mTOR axis were associated with risk and prognosis of coronary heart disease (CHD) among a Chinese Han population.MethodsAltogether 436 patients with CHD were recruited as cases, and meanwhile, 471 healthy volunteers were included into the control group. Besides, SNPs of GAS5/MIR‐21/mTOR axis were genotyped utilizing mass spectrometry. Chi‐square test was applied to figure out SNPs that were strongly associated with CHD risk and prognosis, and combined effects of SNPs and environmental parameters on CHD risk were evaluated through multifactor dimensionality reduction (MDR) model.ResultsSingle nucleotide polymorphisms of GAS5 (ie, rs2067079 and rs6790), MIR‐21 (ie, rs1292037), and mTOR (rs2295080, rs2536, and rs1034528) were associated with susceptibility to CHD, and also Gensini score change of patients with CHD (P < .05). MDR results further demonstrated that rs2067079 and rs2536 were strongly interactive in elevating CHD risk (P < .05), while smoking, rs6790 and rs2295080 showed powerful reciprocity in predicting Gensini score change of patients with CHD (P < .05).ConclusionSingle nucleotide polymorphisms of lncRNA GAS5/miR‐21/mTOR axis might interact with smoking to regulate CHD risk, which was conducive to diagnosis and prognostic anticipation of CHD.

Genetic determinants of fracture non-union: A systematic review from the literature.

Approximately 10-15% of fracture patients suffer impaired healing, which is either delayed or even results in non-union. We performed a Systematic Review, aiming to examine the types and frequency of specific genetic abnormalities in patients experiencing bone fracture and to ascertain whether a genetic association exists regarding the tendency for some patients to suffer fracture non-union or postoperative non-union events. GO and KEGG analyses were used to identify the likely function of the genes involved. Furthermore, we evaluated the functional significance of single nucleotide polymorphisms using RegulomeDB and GTEx. Seven eligible studies involving 29 genes and 89 SNPs were analyzed in this review. We found that the polymorphisms in gene NOS2, NOG, BMP4, CYR61, IL1β and FGFR1 apparently predisposed patients to fracture non-union, while the polymorphisms in gene MMP13, BMP6 and FAM5C appeared to provide protection from non-union. Bioinformatics analysis suggested that these genes were enriched in inflammatory pathways, suggesting that inflammation may be a potential factor involved in fracture non-union. Three SNPs (rs17563, rs3753793 and rs2853550) had smaller RegulomeDB scores, indicating significant biological function. In conclusion, we have identified a number of genes and their polymorphisms that might contribute to a genetic susceptibility to fracture non-union. Further studies with larger cohorts will enhance our understanding of fracture non-union and may inform and direct early interventions.

Clofarabine Improves Relapse-Free Survival of Acute Myeloid Leukemia in Younger Adults with Micro-Complex Karyotype.

Acute myeloid leukemia (AML) encompasses heterogeneous entities with dismal outcomes. Intermediate and unfavorable-risk AML represent the most difficult-to-treat entities. We recently reported the benefit of the clofarabine-based consolidation (CLARA) regimen compared to the standard high-dose cytarabine (HDAC) regimen in younger AML patients. Here, we aimed at assessing the clinical significance of single-nucleotide polymorphism (SNP)-array alterations and their interactions with chemotherapy regimens. A SNP-array was successfully performed in 187 out of the 221 intent-to-treat patients (CLARA arm: n = 92 patients, HDAC arm: n = 95 patients). The CLARA regimen did not significantly improve relapse-free survival (RFS) among patients who displayed a complex karyotype when compared to the HDAC regimen (4-year RFS (4y-RFS): 36.4% vs. 18.8%, respectively; p = 0.134). Defining micro-complex karyotypes from at least four SNP-array lesions enabled us to refine and enlarge the subset of adverse patients. In such patients, the CLARA regimen significantly improved RFS compared to the HDAC regimen (4y-RFS: 44.4% vs. 13.8%, respectively; p = 0.004). From our study cohort, 8% of patients displayed TP53 mutations, which were associated with an impaired RFS (4y-RFS: 20.0% vs 43.7%; p = 0.029). In a multivariate analysis, micro-complex karyotypes remained the sole poor prognostic factor in the HDAC arm (hazard ratio (HR) = 2.324 (95% confidence interval (CI) = 1.337–4.041), p = 0.003). The SNP array represents a powerful and reproductive approach to refine adverse AML patients that may benefit from alternative consolidation regimens.

Role of enterocyte-specific gene polymorphisms in adjuvant treatment for stage III colorectal cancer.

550 Background: Enterocyte subtype of the Colorectal Cancer (CRC) Assigner classifier is known as favorable to oxaliplatin-based adjuvant treatment for stage III CRC. We previously reported potential predictive value of single nucleotide polymorphisms (SNPs) in enterocyte-related genes in metastatic CRC (Suenaga, ASCO2018). In this study, we examined clinical significance of MS4A12 and CDX2 SNPs in adjuvant treatment (AT) for Stage III CRC. Methods: 350 patients with Stage III CRC were included in this study: 274 received AT (discovery cohort: median age = 62, median follow-up = 59.9 months) and 76 received surgery alone (control: median age = 75, median follow-up = 58.0 months). 68 and 206 patients received FOLFOX and oral fluoriopyrimidine, respectively. SNPs were analyzed by PCR-based direct sequencing. Disease-free survival and overall survival (OS) were analyzed using Kaplan-Meier curves, log-rank test, and Cox proportional hazards regression. Results: In discovery cohort, the G/G variant in MS4A12 rs4939378 was associated with lower 5-y survival rate than any A allele in uni- and multi-variate analyses (70% vs 90%, univariate: HR 2.29, 95% CI: 1.03-5.06, P = 0.035; multivariable: HR 2.58, 95% CI: 1.15-5.76, P = 0.021). Patients with the G/G variant in CDX2 rs3812863 had better OS than those with any A, though not significant in multivariable analysis (5 y-survival rate: 95% vs 82%, univariate: HR 0.34, 95% CI: 0.12-0.97, P = 0.034; multivariable: HR 0.39, 95% CI: 0.13-1.11, P = 0.078). There was no significance in the control, and significant interaction was observed between MS4A12 genotypes and groups (interaction P = 0.007). In addition, there was no interaction between MS4A12 rs4939378 and FOLFOX vs oral fluoropyrimidine. Conclusions: Our findings suggest that MS4A12 and CDX2 gene polymorphisms may predict outcome in patients with Stage III CRC. However, clinical significance of the SNPs for oxaliplatin seems to differ depending on tumor stage. Further research and validation study are warranted to explore the association of the SNPs with carcinogenesis or cancer progression.

Single Nucleotide Polymorphism (SNPs) in the Genes Associated with Tooth Agenesis

Objectives: The main focus of this review article was to collate up to date knowledge with regard to significance of single nucleotide polymorphisms (SNPs) in various genes associated with tooth agenesis. Failure to develop complete set of teeth also called tooth agenesis is a common developmental abnormality manifested mainly as an isolated condition. This anomaly is also associated with many developmental syndromes. Methods: We reviewed the evidence from the literature with regard to SNPs in many genes associated with this developmental anomaly. The information contained in this review deals only with non-syndromic form of tooth agenesis. This condition generally affects third molars or one or few other permanent teeth, however, in some cases its severity is relatively prevalent. Results and Conclusions: Mutations in genes such as Msh homeobox 1 (MSX1), Paired box gene 9 (PAX9), Axis inhibitor protein 2 (AXIN2) and Ectodysplasin A (EDA) have been identified that are associated with the familial form of the disease. It has been shown that the phenotypes associated with these mutations indicate the involvement of more complex mechanisms. Clinical Significance: Evidence collected so far has immense clinical significance to clinical dentists in providing comprehensive guide outlining the role of these gene mutations (SNPs) in various genes and also how the patients affected with this condition will be clinically diagnosed and managed in future.

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin.

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI.

Pathogenetic significance of single nucleotide polymorphisms in the gastric inhibitory polypeptide receptor gene for the development of carbohydrate metabolism disorders in obesity

Aim. To investigate the association of the GIPR gene polymorphisms rs2302382 and rs8111428 with increased risk of type 2 diabetes mellitus and abdominal obesity.Materials and methods. The study involved 163 patients with abdominal obesity (BMI, 39.5 ± 8.3 kg/m2; age, 44.7 ± 8.9 years; men, 61; women, 102), 72 with type 2 diabetes mellitus (BMI, 43.70 ± 9.32 kg/m2; age, 46.5 ± 10.1 years; men, 29; women, 43) and 91 patients without carbohydrate metabolism disorders (BMI, 36.13 ± 6.72 kg/m2; age, 43.93 ± 8.35 years; men, 32; women 59). The control group comprised 109 relatively healthy volunteers (BMI, 22.6 ± 2.7 kg/m2; age, 39.5 ± 7.6 years; men, 66; women, 43). Genotypes were analysed by real-time PCR and serum insulin and C-peptide levels were evaluated by ELISA.Results. The AA genotype in the rs2302382 polymorphism of GIPR was associated with an increased risk for type 2 diabetes mellitus in abdominal obesity and the CA genotype was associated with a reduced risk. In individuals with abdominal obesity and type 2 diabetes mellitus carrying the CA genotype in rs2302382 polymorphism of GIPR, serum insulin and C-peptide levels were elevated to 56.27 mU/L (55.49–58.41 mU/L) and 2.04 ng/ml (1.37–2.85 ng/ml), respectively (p 0.05). In obese patients with the same genotype and without type 2 diabetes, serum insulin levels and C-peptide levels were 22.73 mU/L (19.07–25.76 mU/L) and 0.73 ng/ml (0.53–1.03 ng/ml), respectively (p 0.05). The GIPR rs8111428 polymorphism was not associated with increased risk of type 2 diabetes mellitus in obesity for any of the groups examined.Conclusion. Serum insulin and C-peptide levels were increased in patients with abdominal obesity who were carriers of the CA genotype in the rs2302382 polymorphism of GIPR, which is associated with a decreased risk of type 2 diabetes mellitus in obesity compared with the CC genotype.

Genetic variants in glucose-6-phosphate isomerase gene as prognosis predictors in hepatocellular carcinoma

Metabolic reprogramming is an important hallmark of cancer cells, including the alterations of activity and expression of enzymes in glucose metabolism. Previous studies have demonstrated the critical role of glucise-6-phosphate isomerase (GPI) in cancer initiation, metastasis and progression. However, the significance of single nucleotide polymorphisms (SNPs) in GPI gene has not been investigated in hepatocellular carcinoma (HCC). In this study, a total of 3 functional SNPs in GPI gene were genotyped in 492 HCC patients with surgical treatment. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the analysis of overall survival (OS) and recurrence-free survival (RFS). The homozygous variant genotypes of rs7248411 in mRNA splice sites of GPI gene were significantly associated with an increased risk of death in the multivariate analysis (Hazard ratio [HR], 2.07; 95% confidence interval [95% CI]: 1.16-3.68 in a recessive model). In stratified analysis, the association remained significant in patients with high α-fetal protein (AFP) level (HR=2.37, 95% CI 1.25-4.49). Moreover, we identified the interaction between rs7248411 and AFP level in predicting the prognosis of HCC patients (P for interaction<0.001). Our data suggest that GPI gene polymorphism may serve as potential biomarkers to predict the OS of HCC. Further studies with different ethnicities are needed to validate our findings and generalize its clinical utility.

Functional significance of single nucleotide polymorphisms in the lactase gene in diverse US patients and evidence for a novel lactase persistence allele at -13909 in those of European ancestry.

Recent data from mainly homogeneous European and African populations implicate a 140-bp region 5' to the transcriptional start site of LCT (the lactase gene) as a regulatory site for lactase persistence and nonpersistence. Because there are no studies of US nonhomogeneous populations, we performed genotype/phenotype analysis of the -13910 and -22018 LCT single nucleotide polymorphisms (SNPs) in New England children, mostly of European ancestry. Duodenal biopsies were processed for disaccharidase activities, RNA quantification by reverse transcription polymerase chain reaction (RT-PCR), allelic expression ratios by PCR, and genotyping and SNP analysis. Results were compared with clinical information. Lactase activity and mRNA levels, and sucrase-to-lactase ratios of enzyme activity and mRNA, showed robust correlations with genotype. None of the other LCT SNPs showed as strong a correlation with enzyme or mRNA levels as did -13910. Data were consistent, with the -13910 being the causal sequence variant instead of -22018. Four individuals heterozygous for -13910T/C had allelic expression patterns similar to individuals with -13910C/C genotypes; of these, 2 showed equal LCT expression from the 2 alleles and a novel variant (-13909C>A) associated with lactase persistence. The identification of -13910C/C genotype is likely to predict lactase nonpersistence, consistent with prior published studies. A -13910T/T genotype will frequently, but not perfectly, predict lactase persistence in this mixed European-ancestry population; a -13910T/C genotype will not predict the phenotype. A long, rare haplotype in 2 individuals with -13910T/C genotype but equal allele-specific expression contains a novel lactase persistence allele present at -13909.

Genetic variants in genes of tricarboxylic acid cycle key enzymes are associated with prognosis of patients with non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is characterized by poor prognosis and only a few molecular markers may be potentially used to predict the outcome. Metabolic reprogramming is a hallmark of cancer, including the alterations of tricarboxylic acid (TCA) cycle key enzymes. However, the significance of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes has not been investigated in NSCLC. In this study, we genotyped 18 potentially functional SNPs in 7 genes belonging to 3 TCA cycle enzyme families (SDH, FH and IDH) using Sequenom iPLEX genotyping system in a cohort of 500 NSCLC patients. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the survival analysis. Our results showed that SDHC gene: SNP rs12064957, IDH2 gene: SNP rs11540478 and FH gene: SNP rs1414493 were associated with overall survival (OS) and SDHA gene: SNP rs13173911, IDH2 gene: SNP rs4932158 were associated with recurrence-free survival (RFS) of NSCLC patients. Unfavorable genotypes of these SNPs showed a significant cumulative effect on OS and RFS of NSCLC patients (both P<0.001). Furthermore, survival tree analysis indicated that FH: rs1414493 was the primary risk factor contributing to OS of NSCLC patients and the IDH2: rs4932158 was the primary risk factor contributing to RFS of NSCLC patients. Our data suggest that SNPs in TCA cycle key enzyme genes may serve as potential biomarkers to predict the outcomes of NSCLC. Further studies with different ethnicities are needed to validate our findings and generalize their clinical utility.

Rrp1B gene polymorphism (1307T&gt;C) in metastatic progression of breast cancer

Rrp1B (ribosomal RNA processing1 homolog B) is a novel candidate metastasis modifier gene in breast cancer. Functional gene assays demonstrated that a physical and functional interaction existing between Rrp1b and metastasis modifier gene SIPA1 causes reduction in the tumor growth and metastatic potential. Ectopic expression of Rrp1B modulates various metastasis predictive extra cellular matrix (ECM) genes associated with tumor suppression. The aim of this study is to determine the functional significance of single nucleotide polymorphism (SNP) in human Rrp1B gene (1307 T>C; rs9306160) with breast cancer development and progression. The study consists of 493 breast cancer cases recruited from Nizam's Institute of Medical Sciences, Hyderabad, and 558 age-matched healthy female controls from rural and urban areas. Genomic DNA was isolated by non-enzymatic method. Genotyping was done by amplification refractory mutation system (ARMS-PCR) method. Genotypes were reconfirmed by sequencing and results were analyzed statistically. We have performed Insilco analysis to know the RNA secondary structure by using online tool m fold. The TT genotype and T allele frequencies of Rrp1B1307 T>C polymorphism were significantly elevated in breast cancer (χ (2); p = <0.008) cases compared to controls under different genetic models. The presence of T allele had conferred 1.75-fold risk for breast cancer development (OR = 1.75; 95% CI = 1.15-2.67). The frequency of TT genotype of Rrp1b 1307T>C polymorphism was significantly elevated in obese patients (χ (2); p = 0.008) and patients with advanced disease (χ (2); p = 0.01) and with increased tumor size (χ (2); p = 0.01). Moreover, elevated frequency of T allele was also associated with positive lymph node status (χ (2); p = 0.04) and Her2 negative receptor status (χ (2); p = 0.006). Presence of Rrp1b1307TT genotype and T allele confer strong risk for breast cancer development and progression.

Genetic variants in genes of tricarboxylic acid cycle key enzymes predict postsurgical overall survival of patients with hepatocellular carcinoma.

Metabolic reprogramming is a hallmark of cancer, including the alterations of activity and expression in tricarboxylic acid (TCA) cycle key enzymes. However, the significance of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes has not been investigated in hepatocellular carcinoma (HCC). In this study, 17 SNPs in seven genes encoding three TCA cycle enzyme families (SDH, FH, and IDH) were genotyped in 492 HCC patients with surgical treatment and their association with overall survival (OS) was analyzed. Five SNPs in four genes were identified to be associated with OS in HCC patients. Among them, rs3935401 in the 3' untranslated region of SDHC exhibited the most significant association (P < 0.001). The unfavorable genotype of these five SNPs showed a significant accumulative effect on the prognosis of HCC patients, with a P for trend of <0.001. Furthermore, the haplotype group consisting of wild type in rs4131826 and variant in rs3935401 was significantly associated with increased risk of death in HCC patients. Survival tree analysis indicated that variant genotype of rs3935401 was the primary risk factor contributing to the prediction of OS in HCC patients. SNPs in TCA cycle key enzyme genes may serve as potential biomarkers to predict the OS in HCC patients.

Global evolution of multidrug-resistant Acinetobacter baumannii clonal lineages

The rapid expansion of Acinetobacter baumannii clinical isolates exhibiting resistance to carbapenems and most or all available antibiotics during the last decade is a worrying evolution. The apparent predominance of a few successful multidrug-resistant lineages worldwide underlines the importance of elucidating the mode of spread and the epidemiology of A. baumannii isolates in single hospitals, at a country-wide level and on a global scale. The evolutionary advantage of the dominant clonal lineages relies on the capability of the A. baumannii pangenome to incorporate resistance determinants. In particular, the simultaneous presence of divergent strains of the international clone II and their increasing prevalence in international hospitals further support the ongoing adaptation of this lineage to the hospital environment. Indeed, genomic and genetic studies have elucidated the role of mobile genetic elements in the transfer of antibiotic resistance genes and substantiate the rate of genetic alterations associated with acquisition in A. baumannii of various resistance genes, including OXA- and metallo-β-lactamase-type carbapenemase genes. The significance of single nucleotide polymorphisms and transposon mutagenesis in the evolution of A. baumannii has been also documented. Establishment of a network of reference laboratories in different countries would generate a more complete picture and a fuller understanding of the importance of high-risk A. baumannii clones in the international dissemination of antibiotic resistance.

Role of genotype-based personalized antiplatelet therapy in the era of potent P2Y12 receptor inhibitors

Therapy with clopidogrel and aspirin, commonly known as dual antiplatelet therapy, is a widely adapted secondary prevention strategy among coronary artery disease patients treated with percutaneous coronary intervention. However, in addition to response variability and high on-treatment platelet reactivity and their relation to increased adverse events during clopidogrel therapy, candidate gene studies and genome-wide association studies have highlighted the significance of single nucleotide polymorphisms of genes associated with clopidogrel metabolism in coronary artery disease patients. Genotyping may have an emerging role in personalized antiplatelet therapy, particularly with the advent of new P2Y12 receptor blockers that have more rapid and potent pharmacodynamic properties than clopidogrel. The current review discusses the role of genotyping in personalizing P2Y12 receptor-blocker therapy.

Genetic regulation of parasite infection: empirical evidence of the functional significance of an IL4 gene SNP on nematode infections in wild primates.

BackgroundSusceptibility to parasite infection affects fitness-related processes, such as mate choice and survival, yet its genetic regulation remains poorly understood. Interleukin-4 (IL4) plays a central role in the humoral immune defence against nematode parasite infections, inducing IgE switch and regulation of worm expulsion from the intestines. The evolutionary and functional significance of single nucleotide polymorphisms (SNPs) in IL4-genes is known, yet empirical information on the effect of IL4 SNPs on gastro-intestinal infections is lacking. Using samples from a population of wild red-fronted lemurs (Eulemur fulvus rufus, Primates: Lemuridae), from western Madagascar, we explored the association of IL4-gene promoter polymorphisms with nematode infections and investigated a possible functional role of the IL4 polymorphism on male reproductive success.ResultsUsing sequence analyses of lemur DNA we detected a new SNP in the IL4 gene promoter area. Carriers of the genotype T/T showed higher nematode infection intensities than individuals of genotypes C/T and C/C. Genetic population analyses using data from more than 10 years, suggested higher reproductive success of T/T males than expected.ConclusionsOur results suggest a regulatory effect of an IL4 gene promoter polymorphism on the intensity of parasite infections in a natural population of red-fronted lemurs, with a seemingly disadvantageous genotype represented in low frequencies. Long-term population analyses, however, point in the direction of a negative frequency-dependent association, giving a fitness advantage to the rare genotype. Due to low frequencies of the genotype in question conclusive evidence of a functional role of IL4 polymorphism cannot be drawn here; still, we suggest the use of IL4 polymorphism as a new molecular tool for quick assessment of individual genetic constitution with regard to nematode infection intensities, contributing to a better understanding of the actual components of the immune response that mediate protection against gastro-intestinal parasites.

The significance of single nucleotide polymorphisms (SNPs) in Eucalyptus globulus breeding programs

Summary Eucalyptus globulus (Labill.) is the most widely planted eucalypt for pulpwood in temperate regions of the world. Breeding to improve pulp properties of this species has been hampered by the long time between planting and pulp trait assessment and the high cost of estimating pulp traits. Identifying and employing allelic variants that associate with superior pulp yield and quality has the potential to assist breeding programs. Before this strategy can deliver benefits, detailed knowledge of population structure, nucleotide diversity, haplotype diversity and linkage disequilibrium (LD) must be collected. To address this, 20 wood quality candidate genes were sequenced in 8 to 28 Eucalyptus globulus individuals. Relative to other tree species where such studies have been conducted, single nucleotide polymorphism (SNP) frequencies were high. Decay of linkage disequilibrium was rapid at all loci tested, with linkage rarely extending beyond 500 base pairs. Regions within many candidate genes exhibited significant positive or negative selection signatures, indicative of purifying or balancing selection, respectively. Our findings have implications for association mapping in Eucalyptus species. The potential for E. globulus pedigree reconstruction and whole-genome association approaches in eucalypts in general are discussed.