AKT1 Polymorphisms Research Articles

Association of PI3K/AKT/mTOR pathway autophagy-related gene polymorphisms with pulmonary tuberculosis susceptibility in a Chinese population.

Autophagy can inhibit the survival of intracellular microorganisms including Mycobacterium tuberculosis (Mtb), and the PI3K/AKT/mTOR pathway plays a crucial role. This study investigated the association between PI3K/AKT/mTOR pathway autophagy-related gene polymorphisms and pulmonary tuberculosis (PTB) susceptibility. KEGG pathway and gene ontology (GO) databases were searched for genes belonging to the PI3K/AKT/mTOR and autophagy pathways. Thirty SNPs in nine genes were identified and tested for their associations with tuberculosis in 130 patients with PTB and 271 controls. We constructed genetic risk scores (GRSs) and divided the participants into 3 subgroups based on their GRSs:0-5, 6-10, and 11-16. This analysis revealed that the AKT1 (rs12432802), RPTOR (rs11654508, rs12602885, rs2090204, rs2589144, and rs2672897), and TSC2 (rs2074969) polymorphisms were significantly associated with PTB risk. A decreasing trend was observed (P trend 0.020), in which a lower GRS was associated with a higher risk of PTB ([6-10] vs. [0-5]: OR (95%CI) 0.590 (0.374-0.931); [11-16] vs. [0-5]: OR (95%CI) 0.381 (0.160-0.906)). Polymorphisms in AKT1, RPTOR, and TSC2 may influence susceptibility to PTB.

Analysis of Functional Polymorphisms in Meningioma associated Genes

Meningioma is the most common benign intracranial tumour that develops in the meningeal protective covering of the central nervous system (CNS). Globally, every nine individuals out of 100,000 are diagnosed with this cancer. Basic risk factors of meningioma comprise ionizing radiation, hormonal imbalance, and genetic aberrations. In this study, various bioinformatics tools, specialized for consensus-based identification, sequence-homology, and supervised learning, were employed to analyze and screen the deleterious mutational landscape of commonly associated genes of meningioma/genes commonly associated with meningioma. This study employed an in-silico approach aimed to utilize thirteen different tools to benchmark pathogenic single nucleotide polymorphisms (SNPs) in SMARCB1, AKT1, SMO, SUFU, NF2 and MTHFR genes related to meningioma. We identified six highly pathogenic SNPs related to meningioma: SMARCB1 (rs387906812, rs387906811, rs267607072), AKT1 (rs121434592), SMO (rs121918347), and SUFU (rs202247756). Additionally, several deleterious missense variants of NF2 and MTHFR genes were also identified. Hence, this study is a gateway for research on SNPs since they can be utilized to conduct a type-based diagnosis of meningioma for its early prognosis. They can also be utilized as genomic targets for a targeted therapy by developing inhibitors against mutated proteins. For this purpose, further wet-lab experiments and genome-wide association studies are required to genotype these SNPs in a large number of samples, collected from different populations belonging to various ethnicities, for the development of SNP(s) gene panels.

AKT1 Polymorphism (rs10138227) and Risk of Colorectal Cancer in Moroccan Population: A Case Control Study.

Background:LMTK3 and AKT1 each have a role in carcinogenesis and tumor progression. The analysis of single nucleotide polymorphisms of AKT1 and LMTK3 could lead to more complete and accurate risk estimates for colorectal cancer. Aim:We evaluated the association between single nucleotide polymorphisms (SNPs) of AKT1 and LMTK3 and the risk of colorectal cancer in a case-control study in Moroccan population. Methods:Genomic DNA from 70 colorectal cancer patients and 50 healthy control subjects was extracted from whole blood. Genotyping was performed by direct sequencing after polymerase chain reactions for the 7 SNPs (AKT1rs1130214G/T, AKT1rs10138227C/T, AKT1rs3730358C/T, AKT1rs1000559097G/A, AKT1rs2494737A/T, LMTK3rs8108419G/A, and LMTK3rs9989661A/G.). Study subjects provided detailed information during the collection. All P values come from bilateral tests. Results:In the logistic regression analysis, a significantly high risk of colorectal cancer was associated with TC/TT genotypes of rs10138227 with adjusted odds ratio [OR] equal to 2.82 and 95% confidence interval [CI] of 1.15 to 6.91. Conclusion:Our results suggest that the SNP AKT1rs10138227 could affect susceptibility to CRC, probably by modulating the transcriptional activity of AKT1. However, larger independent studies are needed to validate our results.

Effects of the MTOR and AKT1 genes polymorphisms on papillary thyroid cancer development

Papillary thyroid cancer (PTC) is the most common form of thyroid cancer, comprising 80% of all thyroid malignancies. The phosphoinositide-3-kinase-protein kinase B/Akt (PI3K-PKB/Akt) pathway is a main pathway in control of cell growth. Activated mTOR and Akt are involved in the development and progression of the PTC. This study aimed to evaluate the effects of MTOR (rs2536 and rs2295080) and AKT1 (rs2494732, rs1130214, and rs1130233) polymorphisms on PTC susceptibility. This study was conducted on 131 PTC patients and 144 healthy subjects. Genotype analysis was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Our results showed no statistically significant association between MTOR rs2536, AKT1 rs2494732, and rs1130214 polymorphisms and PTC development. However, MTOR rs2295080 polymorphism was found to be associated with a decreased risk of PTC in dominant and allelic models. The TT genotype of AKT1 rs1130233 was significantly higher in the PTC group in comparison to the controls, with a 3.5-fold increased risk for developing PTC. Furthermore, the allelic distribution also showed the T allele of rs1130233 as a risk factor for PTC occurrence. In conclusion, our results suggest the MTOR rs2295080 and AkT1 rs1130233 as the protective and risk factors for PTC development, respectively.

Akt1 genetic variants confer increased susceptibility to thyroid cancer.

The PI3K-Akt-mTOR pathway plays a central role in the development of non-medullary thyroid carcinoma (NMTC). Although somatic mutations have been identified in these genes in NMTC patients, the role of germline variants has not been investigated. Here, we selected frequently occurring genetic variants in AKT1, AKT2, AKT3, PIK3CA and MTOR and have assessed their effect on NMTC susceptibility, progression and clinical outcome in a Dutch discovery cohort (154 patients, 188 controls) and a Romanian validation cohort (159 patients, 260 controls). Significant associations with NMTC susceptibility were observed for AKT1 polymorphisms rs3803304, rs2494732 and rs2498804 in the Dutch discovery cohort, of which the AKT1 rs3803304 association was confirmed in the Romanian validation cohort. No associations were observed between PI3K-Akt-mTOR polymorphisms and clinical parameters including histology, TNM staging, treatment response and clinical outcome. Functionally, cells bearing the associated AKT1 rs3803304 risk allele exhibit increased levels of phosphorylated Akt protein, potentially leading to elevated signaling activity of the oncogenic Akt pathway. All together, germline encoded polymorphisms in the PI3K-Akt-mTOR pathway could represent important risk factors in development of NMTC.

FOXO3 polymorphisms were correlated with gefitinib-induced hepatotoxicity in patients with non-small cell lung cancer.

9578 Background: Drug-induced liver injury (DILI) is one of the most safety concern in drug development and clinical therapy. Severe hepatotoxicity of gefitinib often leads to acute/chronic liver injury, drug discontinuation and further treatment failure, however, the mechanism of gefitinib-induced hepatotoxicity remains unclear. AKT1/FOXO3 regulates expression of genes involved in multiple biological/pathological processes in liver cells, including apoptosis, oxidative stress, and cell-cycle transition, as well as expression of autophagy-related (Atg) genes. Therefore, we investigated the correlation between single nucleotide polymorphisms (SNP) in AKT1/ FOXO3 and gefitinib-induced hepatotoxicity in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 172 advanced NSCLC patients with activating EGFR mutations were enrolled and administered with gefitinib 250mg daily. 22 tag SNPs in AKT1/FOXO3 were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. The associations between polymorphisms of AKT1/FOXO3 and gefitinib-induced hepatotoxicity were analyzed by Chi square test. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: FOXO3 rs4946935 and FOXO3 rs75544369 were found to be associated with gefitinib-induced hepatotoxicity in NSCLC patients. FOXO3 rs4946935 AA carriers have higher risk of developing gefitinib-induced hepatotoxicity than those with FOXO3 rs4946935 AG/GG. ( P = 0.018, OR = 12.414, 95%CI (1.53-100.711)). Patients with FOXO3 rs75544369 GA have higher risk of developing hepatotoxicity with P of 0.0002 (OR = 5.241, CI%(1.85-14.851)), or developing severe hepatotoxicity with P of 0.033 (OR = 2.963, 95%CI (1.090-8.059)), than those with FOXO3 rs75544369 GG. Conclusions: FOXO3 rs4946935 and FOXO3 rs75544369 are predictive biomarkers for gefitinib-induced hepatotoxicity in NSCLC patients. The mechanism underlying the association between FOXO3 polymorphisms and gefitinib-induced hepatotoxicity are worth investigating in further studies. Clinical trial information: NCT01994057 .

No Association Between AKT1 Polymorphisms and Methamphetamine Addiction in Iranian Population.

Previous studies have shown a high level of heritability for most kinds of substance abuse. Certain single nucleotide polymorphisms (SNPs) or haplotypes have been shown to influence methamphetamine abuse or the related psychosis. Among the most related pathways in dependence to methamphetamine are dopaminergic system-related genes especially V-akt murine thymoma viral oncogene homolog 1 (AKT1). In the current investigation, we genotyped two intronic variants within the AKT1 gene (rs2494743 and rs2498794) in a population of Iranian methamphetamine-dependent individuals and controls. There were no significant differences in alleles, genotypes, or haplotype frequencies of rs2494743 and rs2498794 between cases and controls. Consequently, our study excludes participation of these SNPs in susceptibility to methamphetamine dependence. However, other variants within this gene might affect this trait, so future studies are needed to assess associations between other AKT1 variants and methamphetamine dependence.

Gene variants in AKT1, GCKR and SOCS3 are differentially associated with metabolic traits in Mexican Amerindians and Mestizos

Amerindian ancestry appears to be a risk factor for metabolic diseases (MetD), making Mexicans an ideal population to better understand the genetic architecture of metabolic health. In this study, we determine the association of genetic variants previously reported with metabolic entities, in two Mexican populations, including the largest sample of Amerindians reported to date.We investigated the association of eigth single-nucleotide polymorphisms (SNPs) in AKT1, GCKR, and SOCS3 genes with different metabolic traits in 1923 Mexican Amerindians (MAs) belonging to 57 ethnic groups, and 855 Mestizos (MEZs). The allele frequency of 7/8 SNPs showed significant differences between MAs and MEZs. Interestingly, some alleles were monomorphic in particular ethnic groups, and highly frequent in other ones. With the exception of GCKR rs1260326T, as expected, all SNP frequencies in the MEZ population had intermediate values between its two main ancestral populations (MAs and Iberian populations in Spain [IBS]). We detected ethnic differences in linkage disequilibrium patterns and haplotype structure between MAs and MEZs, possibly due to the high genetic heterogeneity in these populations. Remarkably, AKT1 was associated with hypertension in MEZs, but not in MAs. GCKR was associated with protection against type 2 diabetes (T2D) in MAs, and with hypertriglyceridemia and protection against low HDL Cholesterol (HDL-C) levels in MEZs. The CAT haplotype in SOCS3 was associated with metabolic syndrome (MetS) in MEZs, and correlated with protection against high blood pressure (HBP) and risk for high waist circumference and T2D in MAs. Our results show differential genetic associations with metabolic traits between MAs and MEZs, possibly due to the differences in genetic structure between these Mexican populations.

Association between single nucleotide polymorphisms in AKT1 and the risk of prostate cancer in the Chinese Han population.

AKT1, also known as v-akt murine thymoma viral oncogene homolog 1, is involved in the regulation of cell-survival and anti-apoptotic activities, which may affect the pathogenesis of various cancers. However, the association between genetic variants of AKT1 and the risk of developing prostate cancer has not been investigated before. This study investigated the associations between three polymorphisms (rs1130214, rs3730358, and rs2494732) in AKT1 and the risk of development of prostate cancer in the Chinese Han population. Sequenom MassARRAY & iPLEX technology were used to genotype these polymorphisms in 493 Chinese Han patients with prostate cancer and 309 age-matched healthy individuals. Compared to the CC genotype of the rs3730358 polymorphism, the CT genotype of the same polymorphism was strongly associated with a decreased risk of prostate cancer (OR = 0.617, 95%CI = 0.390-0.976, P = 0.037). However, there was no significant difference between the allele frequency of the rs3730358 polymorphism and those of the other two polymorphisms (P > 0.05). Moreover, no significant difference was found in the haplotype analysis (P > 0.05). Our study found that the variant genotype CT of rs3730358 of AKT1 was associated with a decreased risk of prostate cancer, which suggested that this polymorphism could play an important role in the development of the disease.

Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity

ObjectiveObesity is a chronic disease caused by both environmental and genetic factors. Epidemiological studies have documented that increased energy intake and sedentary lifestyle, as well as a genetic contribution, are forces behind the obesity epidemic. Knowledge about the interaction between genetic and environmental components can facilitate the choice of the most effective and specific measures for the prevention of obesity. The aim of this study was to assess the association between the FTO, AKT1, and AKTIP genes and childhood obesity and insulin resistance. MethodsThis was a case–control study in which SNPs in the FTO (rs99396096), AKT1, and AKTIP genes were genotyped in groups of controls and obese/overweight children. The study included 195 obese/overweight children and 153 control subjects. ResultsAs expected, the obese/overweight group subjects had higher body mass index, higher fasting glucose, HOMA‐IR index, total cholesterol, low‐density lipoprotein, and triglycerides. However, no significant differences were observed in genes polymorphisms genotype or allele frequencies. ConclusionThe present results suggest that AKT1, FTO, and AKTIP polymorphisms were not associated with obesity/overweight in Brazilians children. Future studies on the genetics of obesity in Brazilian children and their environment interactions are needed.

Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity

ObjectiveObesity is a chronic disease caused by both environmental and genetic factors. Epidemiological studies have documented that increased energy intake and sedentary lifestyle, as well as a genetic contribution, are forces behind the obesity epidemic. Knowledge about the interaction between genetic and environmental components can facilitate the choice of the most effective and specific measures for the prevention of obesity. The aim of this study was to assess the association between the FTO, AKT1, and AKTIP genes and childhood obesity and insulin resistance. MethodsThis was a case–control study in which SNPs in the FTO (rs99396096), AKT1, and AKTIP genes were genotyped in groups of controls and obese/overweight children. The study included 195 obese/overweight children and 153 control subjects. ResultsAs expected, the obese/overweight group subjects had higher body mass index, higher fasting glucose, HOMA-IR index, total cholesterol, low-density lipoprotein, and triglycerides. However, no significant differences were observed in genes polymorphisms genotype or allele frequencies. ConclusionThe present results suggest that AKT1, FTO, and AKTIP polymorphisms were not associated with obesity/overweight in Brazilians children. Future studies on the genetics of obesity in Brazilian children and their environment interactions are needed.

Association study of polymorphisms in FOXO3, AKT1 and IGF-2R genes with human longevity in a Han Chinese population.

FOXO3, AKT1 and IGF-2R are critical members of the insulin/IGF-1 signaling pathway. Previous studies showed that polymorphisms (SNPs) in FOXO3, AKT1 and IGF-2R were associated with human longevity in Caucasian population. However, the association of these SNPs in different ethnic groups is often inconsistent. Here, we investigated the association of genetic variants in three genes with human longevity in Han Chinese population. Twelve SNPs from FOXO3, AKT1 and IGF-2R were selected and genotyped in 1202 long-lived individuals (nonagenarians and centenarians) and younger individuals. Rs9486902 of FOXO3 was found to be associated with human longevity in both genders combined in this study (allelic P = 0.002, corrected P = 0.024). The other eleven SNPs were not significantly associated with human longevity in Han Chinese population. The haplotypes TTCTT, CCTTC and CTCCT of FOXO3 as well as GGTCGG and GGTCAG of AKT1 were shown to have a significant difference between case and control (P =0.006, 2.78×10-5, 4.68×10-6, 0.003,0.005, respectively). The estimated prevalence of diabetes and prediabetes in long-lived individuals was significantly lower than in common adult populations (P = 0.001, 2.3×10-26) .Therefore, the search for longevity-associated genes provides the identification of new potential targets beneficial for the treatment of diabetes.

Genetic variations in the PI3K/AKT pathway predict platinum-based neoadjuvant chemotherapeutic sensitivity in squamous cervical cancer.

Cervical cancer is one of the most frequent malignant tumours in women. The PI3K/Akt pathway plays a role in chemoresistance to platinum-based neoadjuvant chemotherapy (NAC). The objective of this study was to evaluate the association between genetic polymorphisms in the PI3K/Akt pathway and chemotherapeutic outcomes following platinum-based NAC in Northwestern Chinese Han patients with squamous cervical cancer (SCC). In total, 17 tagging single nucleotide polymorphisms (tSNPs) in four genes (PIK3CA, Akt1, Akt2, PTEN) were identified as being associated with chemotherapeutic response in 259 patients with stage IB2-IIB SCC. Each of these patients received more than two cycles of NAC. These tSNPs were genotyped by the Sequenom MassArray system. The heterozygous genotype of two loci in the PIK3CA gene (rs3729679: uncorrected P=0.022 and rs12494623: uncorrected P=0.018) was associated with an increased risk of chemoresistance in SCC patients. The stratified analysis also showed that these same SNP polymorphisms were associated with a poor response to NAC in the cisplatin-based subgroup. Furthermore, NAC non-responders had a higher frequency of the rs10416620 and rs62107593 G alleles in the Akt2 gene (rs10416620 and rs62107593: uncorrected P=0.037). The rs34716810 A allele was associated with a poor response to chemotherapy (uncorrected P=0.037). Moreover, rs2498786 (uncorrected P=0.036) and the GGCC haplotype of polymorphisms in Akt1 showed a high risk for non-response to NAC (uncorrected P=0.018). The findings from this study demonstrate that genetic polymorphisms in the PI3K/Akt pathway are associated with sensitivity to platinum-based chemotherapy in SCC patients.

Association Between Genetic Variants of Akt1 and Endometrial Cancer.

Akt isoforms have critical roles in the cause and regulation of cancer cells invasive, migration, and metastatic dissemination. In the present study, the association between Akt1 polymorphisms and endometrial cancer was investigated in patients with endometrial cancer and controls. Thirty premenopaused patients diagnosed with endometrial cancer and 30 premenopaused women with no clinically documented abnormalities of the endometrium undergoing hysterectomy were included in this study. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism. There was no significant difference between Akt1 gene polymorphisms of patients (SNP1, SNP2 and SNP3) with endometrial cancer and controls (p>0.05). Difference between alleles frequency of SNP1, SNP2, SNP3 of patients with endometrial cancer and controls was not significant (p>0.05). SNPs (rs72715985), (rs2494750), and (rs74090038) of Akt1 gene are not associated with endometrial cancer in Iranian subjects.

Polymorphisms in epidermal growth factor receptor (EGFR) and AKT1 as possible predictors of clinical outcome in advanced non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors.

This study aimed to investigate the association of epidermal growth factor receptor (EGFR) gene polymorphism and AKT1 polymorphism with the clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). The clinical outcome and the survival of NSCLC of 230 patients after treatment with EGFR-TKIs were measured. The rs712829, rs1468727 of the EGFR gene and rs1130214 of the AKT1 gene from peripheral blood cell were detected by a multiplexed single nucleotide polymorphism (SNP) MassEXTEND assay. The relationship between genetic polymorphisms and clinical outcomes of treatment with EGFR-TKIs was analyzed. The response rates and the disease control rate of patients with genotype GG, GT, and TT in EGFR rs712829 were statistically very significant difference(19.7 vs 36.1 vs 50.0%, P = 0.016 and 57.7 vs 77.8 vs 83.3%, P = 0.026, respectively). Better disease control was also achieved in patients with the GG genotype of AKT1 rs1130214 than those with the GT and TT genotypes (65.6 vs. 48.7%, P = 0.043). Patients carrying the EGFR rs712829 TT genotype had significantly longer PFS and OS than those with the GT or GG genotypes (9.0 vs. 7.0 vs. 5.0months, P = 0.001 and 13.1 vs. 14.6 vs. 18.8months, P = 0.008, respectively). In addition, patients carrying the AKT1 rs1130214 GG genotype also had significantly longer PFS than those with the GT and TT genotypes (5.5 vs. 4.5months, P = 0.008). EGFR rs712829 polymorphism and AKT1 rs1130214 could influence the response to EGFR-TKIs therapy in patients with advanced NSCLC.

Association between Polymorphisms of the AKT1 Gene Promoter and Risk of the Alzheimer's Disease in a Chinese Han Population with Type 2 Diabetes.

Alzheimer's disease (AD) is a multifactor disease that has been reported to have a close association with type 2 diabetes (T2D) where the v-akt murine thymoma viral oncogene homolog 1 (AKT1) plays an important role in the protein synthesis pathways and cell apoptosis processes. Evidence has been shown that AKT1 protein may be related to AD risk among patients with T2D. The aim of this study was to analyze the potential association between single nucleotide polymorphisms of AKT1 promoter and the risk of AD among patients with T2D. The association between AKT1 polymorphisms and AD risk in patients with T2D was assessed among 574 consecutive unrelated subjects including 112 AD patients with T2D, 231 patients with AD, and 231 healthy controls in a case-control study. The cognitive function of all subjects was assessed using MMSE. Six single nucleotide polymorphisms with minor allele frequency >0.2 (rs2498786, rs74090038, rs2494750, rs2494751, rs5811155, and rs2494752) in AKT1 promoter were analyzed by polymerase chain reaction (PCR), and the concentration of AKT1 protein in serum was tested using enzyme-linked immunosorbent assay (ELISA). Overall, there was statistically significant difference in AKT1 rs2498786 polymorphism. The CC frequency of AKT1 rs2498786 polymorphism in AD with T2D group and AD control group was significantly higher than that in healthy control group (PAD+T2D vs. health < 0.0001, PAD vs. health < 0.0001). However, the difference was not found between AD with T2D group and AD control group. Compared with healthy control group, the plasma levels of AKT1 protein in AD with T2D group (PAD+T2D vs. health < 0.0001) and AD control group (PAD vs. health = 0.0003) decreased significantly. Among genotypes of AKT1 rs2498786 polymorphism, the AKT1 protein level in GG genotype was significantly higher than that in GC genotype (PGG vs. GC < 0.0001) and CC genotype (PGG vs. CC < 0.0001). The study suggests that AKT1 rs2498786 polymorphism in insulin signaling pathway may be associated with AD risk and different genotypes may affects levels of protein expression. However, the polymorphism is not shown to be exclusive in AD patients with T2D.

PI3K/PTEN/AKT/mTOR polymorphisms: Association with clinical outcome in patients with head and neck squamous cell carcinoma receiving cetuximab‐docetaxel

The purpose of this study was to determine whether single nucleotide polymorphisms (SNPs) in AKT1, AKT2, FRAP1, PIK3CA, and PTEN were associated with treatment response and clinical outcome in patients with head and neck squamous cell carcinoma (HNSCC). Genomic DNA was extracted from formalin-fixed tissue of 45 patients with recurrent or initially metastatic HNSCC, and SNPs were genotyped by means of real-time polymerase chain reaction (PCR) system or direct sequencing. The AKT2:rs8100018 and the PTEN:rs12569998 homozygous variants resulted as associated with an increased risk of progression (hazard ratio [HR], 4.83; 95% confidence interval [CI], 1.11-21.03; and HR, 2.36; 95% CI, 1.24-4.50, respectively). An additive effect on risk of progression was observed. The AKT2:rs8100018 homozygous variant was significantly associated with a higher risk of death (HR, 3.57; 95% CI, 1.06-12.00), whereas the presence of at least one variant allele of AKT1:rs3803304 was associated with a lower risk of death (HR, 0.51; 95% CI, 0.27-0.97). We identified combined genotypes associated with outcome of HNSCC, which might have an impact for identification of a target population for cetuximab-docetaxel treatment. Results should be considered as an initial finding and warrant validation in larger clinical trials.

AKT1 and SELP polymorphisms predict the risk of developing cachexia in pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) patients have the highest risk of developing cachexia, which is a direct cause of reduced quality of life and shorter survival. Novel biomarkers to identify patients at risk of cachexia are needed and might have a substantial impact on clinical management. Here we investigated the prognostic value and association of SELP-rs6136, IL6-rs1800796 and AKT1-rs1130233 polymorphisms with cachexia in PDAC. Genotyping was performed in DNA from blood samples of a test and validation cohorts of 151 and 152 chemo-naive locally-advanced/metastatic PDAC patients, respectively. The association of SELP-rs6136, IL6-rs1800796 and AKT1-rs1130233 polymorphisms with cachexia as well as the correlation between cachexia and the candidate polymorphisms and overall survival were analyzed. Akt expression and phosphorylation in muscle biopsies were evaluated by specific ELISA assays. SELP-rs6136-AA and AKT1-rs1130233-AA/GA genotypes were associated with increased risk of developing cachexia in both cohorts (SELP: p = 0.011 and p = 0.045; AKT1: p = 0.004 and p = 0.019 for the first and second cohorts, respectively), while patients carrying AKT1-rs1130233-GG survived significantly longer (p = 0.002 and p = 0.004 for the first and second cohorts, respectively). In the multivariate analysis AKT1-rs1130233-AA/GA genotypes were significant predictors for shorter survival, with an increased risk of death of 1.7 (p = 0.002) and 1.6 (p = 0.004), in the first and second cohorts, respectively. This might be explained by the reduced phosphorylation of Akt1 in muscle biopsies from patients harboring AKT1-rs1130233-AA/GA (p = 0.003), favoring apoptosis induction. In conclusion, SELP and AKT1 polymorphisms may play a role in the risk of cachexia and death in PDAC patients, and should be further evaluated in larger prospective studies.

Genetic Variation in Akt1 and Risk of Tuberculosis Among Iranian Population

Results: Frequencies of genotypes GG, GA, and AA of the Akt1 726 G/A polymorphism were 45.6%, 47.4%, and 7% in the patients with pulmonary tuberculosis, and 53.9%, 37.0% and 9.1% in the control group, respectively. G allele frequency was 69.2% in patients with PTB and 72.4% in healthy controls. We observed no significant difference in allele and genotype frequencies of the Akt1 polymorphism between patients with PTB and healthy controls. Conclusions: Our finding showed that Akt1 726 G/A polymorphism was not associated with risk of PTB in our population. More studies are necessary to validate our results.

Genetic variant of AKT1 and AKTIP associated with late‐onset depression in a Brazilian population

Examine the association between polymorphisms in the AKT1 and AKTIP genes and late-onset depression (LOD). Major depressive disorder is one of the most prevalent neuropsychiatric diseases. LOD is a disorder that starts after 65 years old. AKT1 is a downstream enzyme that has been implicated in the pathogenesis of neurotransmitter-related disorders, such as depression. The identification of a novel AKT1-binding protein (AKTIP) was pointed as an important new target. AKTIP binds directly to AKT1, enhancing the phosphorylation of regulatory sites, and this modulation are affected by AKT1 activation. The association of AKT1 and AKTIP polymorphisms with depressive symptoms was not investigated in LOD. Genotype tagSNPs in the AKT1 and AKTIP in LOD patients and controls. An academic medical center. Sample composed by 190 outpatients with LOD and 77 healthy individuals. The participants were evaluated using Diagnostic and Statistical Manual IV criteria, MINI-PLUS and the Geriatric Depression Scale. Our findings suggested an association between the tagSNP rs3730358 homozygous A/A (p = 0.006) and LOD. A strong association of allele A and increased association for LOD was demonstrated with tagSNP rs3730358 (p-value = 0.003). Limitation include composition of our control group, where the exclusion criteria generated a kind of super-healthy older group what might have produced a hidden stratification when compared with the LOD. This study is the first one to establish the association of the AKT1/AKTIP genes and LOD, and further studies are necessary to clarify the functional role of these proteins.