Risk Genotypes Research Articles

High risk APOL1 genotypes and kidney disease among treatment naïve HIV patients at Kano, Nigeria.

Racial disparities are known in the occurrence of kidney disease with excess risks found among people of African descent. Apolipoprotein L1 (APOL1) gene variants G1 and G2 are associated with kidney disease among HIV infected individuals of African descent in the USA as well as among black population in South Africa. We set out to investigate the prevalence of these high-risk variants and their effects on kidney disease among HIV infected patients in Northern Nigeria with hitherto limited information despite earlier reports of high population frequencies of these alleles from the Southern part of the country. DNA samples obtained from the whole blood of 142 participants were genotyped for APOL1 G1 and G2 variants after initial baseline investigations including assessment of kidney function. Participants comprised 50 HIV positive patients with no evidence of kidney disease, 52 HIV negative individuals with no kidney disease and 40 HIV positive patients with chronic kidney disease (CKD) evidenced by persistent proteinuria and/or reduced eGFR, who also had a kidney biopsy. All the HIV positive patients were newly diagnosed and treatment naïve. The distribution of the APOL1 genotypes among the study participants revealed that 24.6% had a G1 risk allele and 19.0% a G2. The frequency of the High Risk Genotype (HRG) was 12.5% among those with CKD compared to 5.8% in the HIV negative group and zero in the HIV positive no CKD group. Having the HRG was associated with a higher odds for developing HIV Associated Nephropathy (HIVAN) (2 vs 0 risk alleles: OR 10.83, 95% CI 1.38-84.52; P = 0.023; 2 vs 0 or 1 risk alleles: OR 5.5, 95% CI 0.83-36.29; P = 0.07). The HRG was also associated with higher odds for Focal Segmental Glomerulosclerosis (FSGS) (2 vs 0 risk alleles: OR 13.0, 95% CI 2.06-81.91; P = 0.006 and 2 vs 0 or 1 risk alleles: OR 9.0, 95%CI 1.62-50.12; P = 0.01) when compared to the control group. This study showed a high population frequency of the individual risk alleles of the APOL1 gene with higher frequencies noted among HIV positive patients with kidney disease. There is high association with the presence of kidney disease and especially FSGS and HIVAN among treatment naive HIV patients carrying two copies of the HRG.

Transcription factor 21 and prognosis in a coronary population

Abstract Introduction TCF21 is a member of the basic helix-loop-helix (bHLH) transcriptor factor family, being critical for embryogenesis of the heart. It regulates epicardium-derived cells differentiation into smooth muscle (SMC) and fibroblast lineages. The biological roles of TCF21 in epicardial fate determination and the progression of atherosclerosis remains a controversial issue. Purpose Investigate the impact of the TCF21 rs12190287 G>C variant on the prognosis of a coronary artery disease (CAD) cohort. Methods A prospective study was performed with 1,713 CAD patients (mean age 53.3±7.8; 78.7% male) surveyed in terms of MACE occurrence in an extended follow-up of 5.0±4.3. TCF21 rs12190287 was genotyped and analysed using the dominant model (GC+CC) and, subsequently, compared with the wild-type GG to evaluate the survival probability by Kaplan-Meier. A Cox regression analysis with all the risk factors and genetic models was performed to assess the independent variables associated with the prognosis of CAD patients. Results GG wild genotype was present in 9.5% of the population, GC in 43.2% and the risk genotype CC accounted for 47.3% of the CAD patients. The dominant model GC+CC showed a worse survival throughout the follow-up period. After multivariate Cox regression analysis, this model remained in the equation as an independent risk factor for MACE occurrence with an HR of 1.41 (p=0.033) together with multivessel disease, physical inactivity, chronic kidney disease (CKD) and diabetes. Conclusion TCF21 rs12190287 is a risk factor for prognosis in our population. The role of this gene may influence fundamental SMC processes in response to vascular stress, accelerating atherosclerosis progression and may represent a target for future therapies. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

TCF7L2 gene associated postprandial triglyceride dysmetabolism- a novel mechanism for diabetes risk among Asian Indians.

Aim TCF7L2 gene is believed to increase the risk of T2DM by its effects on insulin secretion. However, the exact mechanism of this enhanced risk is not clearly known. While TCF7L2 gene has been shown to affect lipid metabolism, these effects have remained largely unexplored in the context of diabetes risk.MethodsPostprandial lipid responses to a standardized fat challenge test were performed in 620 Asian Indian subjects (310 with NGT and 310 with T2DM/prediabetes) and compared between the risk and wild genotypes of the rs7903146 TCF7L2 gene. In 30 subjects scheduled to undergo abdominal surgery (10 each with NGT, Prediabetes and T2DM), adipocyte TCF7L2 gene expression was also performed by real time qPCR and confirmed by protein expression in western blot.ResultsT allele of rs7903146 TCF7L2 gene was confirmed as the risk allele for T2DM (OR=1.8(1.2-2.74), p=0.005). TT+CT genotypes of rs7903146 TCF7L2 gene showed significantly higher 4hrTg (p<0.01), TgAUC (p<0.01), peakTg (p<0.01) as well as higher postprandial plasma glucose (p=.006) levels and HOMA-IR (p=0.03) and significantly lower adiponectin levels (p=0.02) as compared to CC genotype. The expression of TCF7L2 gene in VAT was 11-fold higher in prediabetes group as compared to NGT (P<0.01) and 5.7-fold higher in T2DM group as compared to NGT group(P=0.003) and was significantly associated with PPTg and glucose levels.ConclusionThere is significant PPTg dysmetabolism associated with the risk allele of rs7903146 polymorphism as well as adipocyte expression of TCF7L2 gene. Significant upregulation of TCF7L2 gene expression in VAT that correlates with PPTg and glycaemia is also seen in Asian Indians with glucose intolerance. Modulation of PPTg metabolism by TCF7L2 gene and the resultant PPHTg may be a novel mechanism that contributes to its diabetes risk in them.

Pancreatitis-Associated PRSS1-PRSS2 Haplotype Alters T-Cell Receptor Beta (TRB) Repertoire More Strongly Than PRSS1 Expression

Pancreatitis-Associated PRSS1-PRSS2 Haplotype Alters T-Cell Receptor Beta (TRB) Repertoire More Strongly Than PRSS1 Expression

A literature embedding model for cardiovascular disease prediction using risk factors, symptoms, and genotype information

Accurate prediction of cardiovascular disease (CVD) requires multifaceted information consisting of not only a patient’s medical history, but genomic data, symptoms, lifestyle, and risk factors which are often not incorporated into a decision making process as the data are vast, difficult to obtain, and require complex algorithms. However, given the vast amount of publicly available information and recent advances in machine and deep learning techniques, acquiring multifaceted data for accurate diagnosis and medical decision making via artificial intelligence has become more attainable. In this work we illustrate a literature embedding model, which identifies various risk factors, symptoms, mechanisms, and genes associated with CVD using a query word (i.e., “stroke”), and then based on the collected information the model predicts whether or not a person will be susceptible to CVD. For this purpose, we collected published literature from PubMed using search keywords consisting of a word such as “heart” and 19,264 human gene names, then trained our literature embedding model using the collected abstracts. For the intrinsic evaluation, we analyzed whether or not the captured words and genes were correctly identified as risk factors and associated symptoms for the input query words. For the extrinsic evaluation, we used our embedding model as feature selection and dimensionality reduction tasks on cohort data for CVD prediction. Our model accurately (average accuracy of >96 %) captured associated risk factors, symptoms, and genes for a given input query word (intrinsic evaluation). Using the selected features and reduced dimensions, our method provided better performance for CVD prediction with less computational time when compared with other popular methods (extrinsic evaluation). Our model provided outstanding results for both evaluation tasks, which enables accurate risk factor identification for CVD prediction. Our model has the potential to facilitate easier collation of multifaceted information for better data mining of vast publicly available data so that efficient and accurate risk factors and symptoms can be identified, which enables better-informed decisions for CVD prediction and treatment.

Pattern recognition receptor CD14 gene polymorphisms in alcohol use disorder patients and its Influence on liver disease susceptibility.

BackgroundAlcohol use disorders (AUDs) leading to liver disease is major concern over other spectrum of disorder. Excessive alcohol consumption resulting in leaky gut syndrome is attributed to alcohol-induced liver injury through portal translocation of bacterial endotoxin. Susceptibility to alcoholic liver disease (ALD) in AUD patients could be dependent upon genes responsible for inflammation and alcohol metabolism. The pattern recognition receptor CD14 gene is a major player in endotoxin-mediated inflammation and susceptibility to ALD. This study investigated the genetic association of CD14 polymorphisms and other mechanisms relevant to altered inflammatory responses leading to ALD.MethodsPatients with alcohol use disorder with ALD (n = 128) and without liver disease (ALC, n = 184) and controls without alcohol use disorder (NALC, n = 152) from North India were enrolled. The CD4 gene polymorphisms in the North Indian population were evaluated by RFLP and sequencing. Secretory CD14 (sCD14), LBP, TLR4, MD2, TNFα, IL1b, IFNγ, IL6, IL10, and IL4 levels in serum were measured by ELISA among groups. The influence of polymorphisms on CD14 gene promoter activity and circulatory bacterial DNA level was determined.ResultsThe CD14 gene promoter and exonic region SNPs were found to be monomorphic, except for SNP rs2569190 for the North Indian population. The genetic association of SNP rs2569190(C/T) with the risk of developing ALD was found significant for TT genotype [ORTT, 95% CI = 2.19, 1.16–4.13 for ALD vs. ALC and OR, 2.09, 1.18–3.72 for ALD vs. NALC]. An increased sCD14 level was observed in AUD patients compared to NALC control. Increased levels of LBP, TLR4, TNFα, IL1β, IFNγ, and IL6 and reduced levels of MD2, IL10, and IL4 were observed among the ALD patients compared to the other two control groups. Elevated levels of pro-inflammatory and reduced levels of anti-inflammatory cytokines were observed in the risk genotype TT groups of ALD patients and the ALC group compared to NALC. Promoter activity was observed in the intronic region flanking SNPs and risk genotype can influence reporter activity, indicating CD14 gene expression.ConclusionEnhanced CD14 expression associated with inflammatory responses increases susceptibility to ALD in the TT genotype of AUD patients.

APOL1 variant-expressing endothelial cells exhibit autophagic dysfunction and mitochondrial stress.

Polymorphisms in the Apolipoprotein L1 (APOL1) gene are common in ancestrally African populations, and associate with kidney injury and cardiovascular disease. These risk variants (RV) provide an advantage in resisting Trypanosoma brucei, the causal agent of African trypanosomiasis, and are largely absent from non-African genomes. Clinical associations between the APOL1 high risk genotype (HRG) and disease are stronger in those with comorbid infectious or immune disease. To understand the interaction between cytokine exposure and APOL1 cytotoxicity, we established human umbilical vein endothelial cell (HUVEC) cultures representing each APOL1 genotype. Untreated HUVECs were compared to IFNɣ-exposed; and APOL1 expression, mitochondrial function, lysosome integrity, and autophagic flux were measured. IFNɣ increased median APOL1 expression across all genotypes 22.1 (8.3 to 29.8) fold (p=0.02). Compared to zero risk variant-carrying HUVECs (0RV), HUVECs carrying 2 risk variant copies (2RV) showed both depressed baseline and maximum mitochondrial oxygen consumption (p<0.01), and impaired mitochondrial networking on MitoTracker assays. These cells also demonstrated a contracted lysosomal compartment, and an accumulation of autophagosomes suggesting a defect in autophagic flux. Upon blocking autophagy with non-selective lysosome inhibitor, hydroxychloroquine, autophagosome accumulation between 0RV HUVECs and untreated 2RV HUVECs was similar, implicating lysosomal dysfunction in the HRG-associated autophagy defect. Compared to 0RV and 2RV HUVECs, HUVECs carrying 1 risk variant copy (1RV) demonstrated intermediate mitochondrial respiration and autophagic flux phenotypes, which were exacerbated with IFNɣ exposure. Taken together, our data reveal that IFNɣ induces APOL1 expression, and that each additional RV associates with mitochondrial dysfunction and autophagy inhibition. IFNɣ amplifies this phenotype even in 1RV HUVECs, representing the first description of APOL1 pathobiology in variant heterozygous cell cultures.

Study on the Relationship between MMP-2, MMP-9 Gene Polymorphisms, and the Risk of Colorectal Cancer.

Objective The aim of the study is to explore the relationship between matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) gene polymorphisms and the risk of colorectal cancer. Methods From January 2019 to December 2021, 308 patients with colorectal cancer in our hospital were selected to be included in the colorectal cancer group and 300 normal healthy people were included in the control group. We perform genotyping, compare the genotype frequencies between the colorectal cancer group and the control group, calculate the relationship between MMP-2 and MMP-9 gene polymorphisms and disease risk, and analyze the genotype distribution characteristics of colorectal cancer patients with different pathological stages and lymph node metastasis status. The expression levels of serum MMP-2 and MMP-9 in patients with different genotypes were compared. Results The frequency of CC genotype and C gene at the MMP-2 gene−735 (C/T) locus in the colorectal cancer group was higher than that of the control group, and the frequency of TT genotype and T gene at MMP-9 gene−1562 (C/T) locus was a higher control group (P < 0.05). The comparison of genotype and gene frequency distribution of MMP-2 gene−1306 (C/T), −790 (T/G), and MMP-9 gene R668Q and P574R between the colorectal cancer group and the control group (P > 0.05); MMP-2 gene−735 (C/T) locus CC genotype and MMP-9 gene−1562 (C/T) locus TT genotype are dangerous genotypes for colorectal cancer. OR values were 1.490 (95% CI: 1.085–2.047), 1.519 (95% CI: 1.061–2.174); TNM stage III-IV, the proportion of CC genotype and TT genotype at MMP-9 gene−1562 (C/T) locus in patients with lymph node metastasis is higher than that without lymph node metastasis of TNM stage I-II patients (P < 0.05); MMP-2 gene in colorectal cancer patients. Serum MMP-2 levels in patients with CC genotype at 735 (C/T) locus were higher than those with CT + TT genotype, and serum MMP-9 levels in patients with TT genotype at MMP-9 gene−1562 (C/T) locus were higher CT + CC genotype patients (P < 0.05). Conclusion The CC genotype at −735 (C/T) locus of the MMP-2 gene and the TT genotype at−1562 (C/T) locus of the MMP-9 gene are risk genotypes for the development of colorectal cancer.

Gut microbiota modulates differential lipid metabolism outcomes associated with FTO gene polymorphisms in response to personalized nutrition intervention.

BackgroundInterindividual differences in response to personalized nutrition (PN) intervention were affected by multiple factors, including genetic backgrounds and gut microbiota. The fat mass and obesity associated (FTO) gene is an important factor related to hyperlipidemia and occurrence of cardiovascular diseases. However, few studies have explored the differences in response to intervention among subjects with different genotypes of FTO, and the associations between gut microbiota and individual responses.ObjectiveTo explore the differential lipid metabolism outcomes associated with FTO gene polymorphisms in response to PN intervention, the altered taxonomic features of gut microbiota caused by the intervention, and the associations between gut microbiota and lipid metabolism outcomes.MethodsA total of 400 overweight or obese adults were recruited in the study and randomly divided into the PN group and control group, of whom 318 completed the 12-week intervention. The single nucleotide polymorphism (SNP) of rs1121980 in FTO was genotyped. Gut microbiota and blood lipids were determined at baseline and week 12. Functional property of microbiota was predicted using Tax4Fun functional prediction analysis.ResultsSubjects with the risk genotype of FTO had significantly higher weight and waist circumference (WC) at baseline. Generalized linear regression models showed that the reduction in weight, body mass index (BMI), WC, body fat percentage, total cholesterol (TCHO), and low-density lipoprotein (LDL) was greater in subjects with the risk genotype of FTO and in the PN group. Significant interaction effects between genotype and intervention on weight, BMI, WC, TCHO, and LDL were found after stratifying for specific genotype of FTO. All subjects showed significant increasement in α diversity of gut microbiota after intervention except for those with the non-risk genotype in the control group. Gut microbiota, including Blautia and Firmicutes, might be involved in lipid metabolism in response to interventions. The predicted functions of the microbiota in subjects with different genotypes were related to lipid metabolism-related pathways, including fatty acid biosynthesis and degradation.ConclusionSubjects with the risk genotype of FTO had better response to nutrition intervention, and PN intervention showed better amelioration in anthropometric parameters and blood lipids than the control. Gut microbiota might be involved in modulating differential lipid metabolism responses to intervention in subjects with different genotypes.Trial registration[Chictr.org.cn], identifier [ChiCTR1900026226].

Early glucose metabolism in children at risk for type 1 diabetes based on islet autoantibodies compared to low-risk control groups.

BackgroundAnatomic variation or early differences in glucose metabolism have been linked to the development of type 1 diabetes. We aimed to describe early glucose metabolism based on HbA1c, oral glucose tolerance test (OGTT), and random plasma glucose years before the presentation of type 1 diabetes in five risk groups based on autoantibody combinations. For the first time, we were able to include for comparison children with very low risk of progression to type 1 diabetes.MethodsThe Finnish Diabetes Prediction and Prevention birth cohort study screened newborn infants for HLA susceptibility to type 1 diabetes since 1994. Those carrying a risk genotype were prospectively followed up with islet autoantibody testing. Glucose parameters were obtained starting from the time of seroconversion. By 31 August 2014, 1162 children had developed at least one islet autoantibody and were included in the current study. Type 1 diabetes was diagnosed in 335 children (progressors). In the non-progressor groups, 207 developed multiple (≥2) biochemical islet autoantibodies, 229 a single biochemical autoantibody, 370 ICA only, and 64 transient autoantibodies. Children were divided into five risk groups. Glucose metabolism was evaluated.ResultsWe observed lower HbA1c values in early follow-up 4.5 to 6.0 years before diagnosis in the progressors when compared to the same time in children with a single biochemical autoantibody or low-risk (ICA only and transient) participants, who did not progress to clinical type 1 diabetes. However, no such differences were observed in OGTTs or random plasma glucose. The variation was minimal in glucose values in the low-risk groups.ConclusionWe report the possibility of early alteration in glucose metabolism in future progressors. This could suggest early defects in multiple glucose-regulating hormones.

The PTGS1 (rs1330344) CC Genotype Contributes to Susceptibility to Kawasaki Disease in Southern Chinese Children.

Kawasaki disease (KD) is an acute systemic vascular disease complicated by coronary artery injury. Although polymorphisms in prostaglandin-endoperoxide synthase 1 (PTGS1) are being increasingly explored in cardiovascular diseases, little is known regarding the connection between PTGS1 polymorphisms and KD risk. We evaluated 834 KD patients and 1474 healthy controls to explore the relationship between PTGS1 polymorphisms (rs1330344 and rs5788) and KD risk. Our results showed that the rs1330344 CC genotype was significantly associated with KD risk and coronary artery injury in children with KD. In combined analysis, individuals with 1-2 unfavorable genotypes had an increased risk of KD, compared with those with no risk genotype. Stratified analysis indicated that the rs1330344 CC genotype is strongly associated with increased risk of KD in children aged ≤60months and females. Moreover, carrying 1-2 of these SNP genotypes had a higher risk of KD than those who harbored none of them in children ≤60months of age and females; the risk of coronary artery dilatations/small aneurysms and medium/giant aneurysms was also significantly increased in KD patients. In summary, the PTGS1 rs1330344 CC genotype is associated with increased susceptibility to KD, which may contribute to KD pathogenesis and serve as a genetic biomarker.

Potentially functional variants of MAP3K14 in the NF-κB signaling pathway genes predict survival of HBV-related hepatocellular carcinoma patients.

BackgroundThe NF-κB signaling pathway plays an important role in associating inflammation with tumor development and progression. However, few studies have reported that roles of genetic variants of the NF-κB signaling pathway genes in survival of patients with HBV-related hepatocellular carcinoma (HBV-HCC), especially with regards to potentially functional SNPs.MethodsWe used multivariate Cox proportional hazards regression to evaluate associations between 2,060 single nucleotide polymorphisms (SNPs) in 20 NF-κB signaling pathway genes and survival of 866 HBV-HCC patients, which were randomly split (1:1) into discovery and validation datasets. Expression quantitative trait loci (eQTL) analysis was conducted to identify associations between survival-associated SNPs and mRNA expression of corresponding genes. Furthermore, online database was used to assess mRNA expression of corresponding genes and survival. Finally, receiver operating characteristic (ROC) curves were used to assess the prediction accuracy of models integrating both clinical and genetic variables on HCC survival.ResultsA total of 6 SNPs in MAP3K14 remained significantly associated with OS of HBV-HCC patients (P<0.05, BFDP<0.8). Further eQTL analysis demonstrated that significant correlations between the rs2074292 (G>A) A allele was associated with higher mRNA expression levels of MAP3K14 (P=0.044) in normal liver tissue, which was associated with worse survival of HBV-HCC patients. In the additive model, after adjusting for age, sex, smoking status, drinking status, AFP level, cirrhosis, embolus and BCLC stage, the combined dataset showed that HBV-HCC patients carrying the rs2074292 AA and GA genotypes (HR=1.71, 95%CI= 1.29-2.27, P=0.000) (HR=1.40, 95%CI=1.10-1.77, P=0.005) have worse OS than GG genotype, respectively. The addition of risk genotypes to the prediction models increased the AUC significantly from 71.15% to 73.11% (P=0.012) and from 72.55% to 74.21% (P=0.010) for 1-year and 3-year OS, respectively.ConclusionOur study indicated that MAP3K14 rs2074292 A allele may be a potential predictor of HBV-HCC survival, likely regulating MAP3K14 mRNA expression.

The Associated of the Risk of IVIG Resistance in Kawasaki Disease with ZNF112 Gene and ZNF180 Gene in a Southern Chinese Population.

BackgroundKawasaki disease (KD) was one of the most common primary vasculitis. IVIG resistance was associated with an increased risk of coronary artery aneurysm. Accumulating evidences demonstrated that inflammatory gene polymorphisms might play important roles in IVIG resistance, and zinc finger proteins were closely related to immune inflammation regulation, but the effect of ZNF112/rs8113807 and ZNF180/rs2571051 on IVIG resistance in KD patients has not been reported.MethodsA total of 996 KD patients were recruited, and the assay of TaqMan-real-time polymerase chain reaction was used for ZNF112/rs8113807 and ZNF180/rs2571051 genotyping. Odds ratio (OR) and 95% confidence interval (CI) were calculated for estimating the relationship between the polymorphisms of the both SNPs (ZNF112/rs8113807 and ZNF180/rs2571051) and the risk of IVIG resistance.ResultsBoth of the ZNF112/rs8113807 CC/TC genotype and the ZNF180/rs2571051 TT/CT genotype increased the risk of IVIG resistance in KD (rs8113807: CC vs TT: adjusted OR = 1.83, 95% CI = 1.06–3.16, p = 0.0293; CC/TC vs TT adjusted: OR = 1.49, 95% CI = 1.10–2.02, p = 0.0094. rs2571051: TT vs CC adjusted: OR = 2.64, 95% CI = 1.62–4.29, p < 0.0001; TT/CT vs CC adjusted: OR = 2.14, 95% CI = 1.37–3.37, p = 0.0009; TT vs CC/CT adjusted: OR = 1.66, 95% CI = 1.22–2.27, p = 0.0014). Furthermore, the combinative analysis of risk genotypes in ZNF112/rs8113807 and ZNF180/rs2571051 showed that patients with two unfavorable genotypes were more likely to increase risk of IVIG resistance than those who carried with zero or one unfavorable genotypes (adjusted: OR = 1.68, 95% CI = 1.24–2.27, p = 0.0008).ConclusionOur findings enriched the genetic background of IVIG resistance risk in the KD development and suggested that the ZNF112/rs8113807 C-carrier and the ZNF180/rs2571051 T-carrier were associated with increased risk of IVIG resistance in KD patients in Chinese southern population.

METTL1 gene polymorphisms synergistically confer hepatoblastoma susceptibility

IntroductionHepatoblastoma is a rare but devastating pediatric liver malignancy. Overexpressed methyltransferase-like 1 (METTL1) is a methyltransferase that catalyzes essential N7-methylguanosine (m7G) modification of eukaryotic mRNA. Accumulating evidence has revealed the oncogenic potential of METTL1. However, whether METTL1 gene polymorphisms confer susceptibility to hepatoblastoma has not been reported. This study aimed to identify causal relationships between genetic variants of this gene and susceptibility to hepatoblastoma.Materials and methodsUsing the TaqMan assay, we genotyped three METTL1 polymorphisms (rs2291617 G > T, rs10877013 T > C, rs10877012 T > G) in germline DNA samples from 1759 Chinese children of Han ethnicity (313 cases vs. 1446 controls).ResultsNone of these polymorphisms were associated with hepatoblastoma risk. However, combination analysis showed that children with 1 to 3 risk genotypes were associated with increased hepatoblastoma risk (adjusted odds ratio = 1.47, 95% confidence interval 1.07–2.02; P = 0.018). Stratified analyses revealed significant effects of combined polymorphisms mainly among young children (< 17 months of age), boys, and those with advanced hepatoblastoma.ConclusionWe identified some potential functional METTL1 gene polymorphisms that work together to increase the risk of hepatoblastoma among Chinese Han children; single polymorphism showed only weak effects. These METTL1 polymorphisms may be promising biomarkers for screening high-risk individuals for hepatoblastoma. These findings are inspiring and deserve to be validated among individuals of different ethnicities.Graphical

Combined effects of nitric oxide synthase 3 genetic variant and childhood emotional abuse on earlier onset of suicidal behaviours

Marked heterogeneity in suicide attempters has been observed, with earlier onset being linked to stronger heritability, more childhood maltreatment. Nitric oxide signalling system might be implicated in this relationship through its role in the stress response/adaptation. This study examined how NOS genetic variants and childhood maltreatment were associated with age at first suicide attempt (SA). Adult patients with SA history (N = 414) filled in the Childhood Trauma Questionnaire, and six functionally relevant NOS2 and NOS3 polymorphisms were genotyped. Analyses included χ2, Mann-Whitney U tests, Kendall's regression, multivariate linear and Cox survival regressions, and a moderation analysis. The NOS3 promotor 27-bp variable number tandem repeat (VNTR) bb homozygous state and childhood emotional abuse were independently associated with earlier age at first SA, which was robust after controlling for confounders [regression coefficient − 3.975, 95% CI −6.980 – (−0.970), p = 0.010, and − 1.088, 95% CI −2.172 – (−0.004), p = 0.049]. No interaction was observed. In the Cox proportional hazards model for age at first SA, the hazard ratio for patients with childhood emotional abuse and NOS3 27-bp VNTR bb was 0.533 (95% CI 0.394–0.720, p < 0.001) compared to patients without. Intermediate scores were observed with either only the risk genotype or only childhood emotional abuse. A graded relationship was also observed for repeated SA, family history of SA, and severe SA history. These results are preliminary due to a low statistical power and call for replication and further characterization of the role of nitric oxide system in the susceptibility to early-onset SB.

TMEM106B Acts as a Modifier of Cognitive and Motor Functions in Amyotrophic Lateral Sclerosis.

The transmembrane protein 106B (TMEM106B) gene is a susceptibility factor and disease modifier of frontotemporal dementia, but few studies have investigated its role in amyotrophic lateral sclerosis. The aim of this work was to assess the impact of the TMEM106B rs1990622 (A–major risk allele; G–minor allele) on phenotypic variability of 865 patients with amyotrophic lateral sclerosis. Demographic and clinical features were compared according to genotypes by additive, dominant, and recessive genetic models. Bulbar onset was overrepresented among carriers of the AA risk genotype, together with enhanced upper motor neuron involvement and poorer functional status in patients harboring at least one major risk allele (A). In a subset of 195 patients, we found that the homozygotes for the minor allele (GG) showed lower scores at the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen, indicating a more severe cognitive impairment, mainly involving the amyotrophic lateral sclerosis-specific cognitive functions and memory. Moreover, lower motor neuron burden predominated among patients with at least one minor allele (G). Overall, we found that TMEM106B is a disease modifier of amyotrophic lateral sclerosis, whose phenotypic effects encompass both sites of onset and functional status (major risk allele), motor functions (both major risk and minor alleles), and cognition (minor allele).

Risk Prediction of Type 2 Diabetes Mellitus (T2DM) in Indian Families Using Antioxidant Gene Variants

Background: Type 2 diabetes mellitus (T2DM) is a complex metabolic disease that is caused by insulin dysfunction. It is an output of oxidative stress that results from defective redox reactions and increased reactive metabolites (RMs) and is neutralized by antioxidant enzymes. It has been reported that decreased levels of antioxidant enzymes are due to genetic alterations in the respective genes. Therefore, the present study has undertaken a genetic analysis of antioxidant genes and their interaction in the family to assess T2DM risk. Objective: This study aimed to investigate the individual susceptibility/risk to T2DM using antioxidant gene variants and their interactions in family members with a diabetic history. Methods: Genotypic analysis of antioxidant genes was done by polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP), haplotype analysis, and gene-gene interactions using statistical tools. Pedigrees were constructed by face-to-face interviews with members of nine families. Results: Genotypes AT (CAT-21A&gt;T), IV (GSTP1+313(105I&gt;V), and CT (GPx1 +599C&gt;T) were found to be frequent in diabetic individuals. For instance, in one family, if only the mother had diabetes, all siblings were found to have the risk genotypes AT (CAT- 21A&gt;T) and CT (GPx1 +599C&gt;T) with 2.12- and 2.11-folds risk of developing T2DM. The risk haplotypes, NNV (GSTM1 N&gt;P(Null&gt;Present), GSTT1 N&gt;P(Null&gt;Present), GSTP1105I&gt;V and TCC (CAT-21A&gt;T, SOD2+47C&gt;T, GPx1+599C&gt;T) were observed in most of the diabetic individuals and non-diabetics possessing the risk haplotypes manifested altered BMI. Conclusion: The present study suggests that the GSTP1105I&gt;V, CAT-21A&gt;T, SOD2+47C&gt;T and GPx1+599C&gt;T gene variants can be prognostic biomarkers for the assessment of T2DM risk in healthy individuals.

The correlation between transcription factor 7-like 2 gene polymorphisms and susceptibility of gestational diabetes mellitus in the population of central China: A case-control study.

ObjectiveTo investigate the correlation between transcription factor 7-like 2 (TCF7L2) gene polymorphisms and gestational diabetes mellitus (GDM) risk in the central Chinese population.MethodsThis case–control study examined the association of seven TCF7L2 gene single-nucleotide polymorphisms (SNPs) (rs11196218, rs4506565, rs7895340, rs7901695, rs11196205, rs12243326, and rs290487) with GDM risk in the central Chinese population (843 GDM and 877 controls). The clinical information and blood samples were collected by trained interviewers and nurses. Genotyping of SNPs was conducted on the Sequenom MassARRAY platform. Statistical analyses including t-test, ANOVA, chi-square test, Fisher’s exact test, and logistic regression were performed.ResultsDifferences in age, pre-pregnant body mass index (BMI), and family history of type 2 diabetes mellitus (T2DM) between the case and control groups were significant (p < 0.05). Compared with the wild-type genotype, pregnant women with genotypes of rs4506565-AT (OR = 1.89, 95%CI: 1.18–3.02), rs7895340 GA (OR = 1.93, 95%CI: 1.06–3.54), rs7901695-TC (OR = 1.79, 95%CI: 1.11–2.88), and rs11196205-GC (OR = 2.15, 95%CI: 1.16–3.98) had a significantly higher risk of GDM, adjusted by age, pre-pregnant BMI, and family history of T2DM. Functional annotation showed that all these four SNPs fell in the functional elements of human pancreatic islets. Further cumulative effects analysis concluded that when participants carried all these four risk genotypes, the risk of GDM was 3.51 times (OR = 3.51, 95%CI: 1.38–8.90) than that of those without any risk genotypes.ConclusionsThe findings of this study suggested that rs4506565, rs7895340, rs7901695, and rs11196205 were the genetic susceptibility SNPs of GDM in the central Chinese population. Further studies are needed to validate our findings and clarify the underlying mechanisms.

PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP (ADCYAP1)-PAC1R (ADCYAP1R1) are highly expressed in the hypothalamus. Here, we show that female mice subjected to acute stress immobilization (IMO) have fear extinction impairments related to Adcyap1 and Adcyap1r1 mRNA upregulation in the hypothalamus, PACAP-c-Fos downregulation in the Medial Amygdala (MeA), and PACAP-FosB/ΔFosB upregulation in the Ventromedial Hypothalamus dorsomedial part (VMHdm). DREADD-mediated inhibition of MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism have impaired fear extinction.

Association Between Polymorphisms in Estrogen Receptor Genes and Depression in Women: A Meta-Analysis.

Objective: It is suggested that estrogen receptors (ERs) might be associated with the disproportionate vulnerability of women to depressive episodes. Several variants in ER-alpha (ERα) and ER-beta (ERβ) have been linked to depression, but the results were not consistent. Hence, we conducted a meta-analysis to evaluate the association between ERα/ERβ and depression in a cohort of women. Methods: A comprehensive literature search was performed in public databases. The genetic association between polymorphisms in Erα/ERβ and depression risk in a cohort of women was evaluated by odds ratios (ORs) and 95% confidence intervals (CIs). Cochran’s Q test and the I2 index were used to evaluate heterogeneity. Results: In total, 10 studies and 4 SNPs (rs2234693, rs9340799, rs4986938, rs1256049) were included in our meta-analysis. rs2234693 genotype was significantly associated with the risk of depression in women by dominant model (CC + CT vs TT, OR = 1.30, 95% CI: 1.09–1.55, p = 0.0031), recessive model (CC vs CT + TT, OR = 1.64, 95% CI: 1.00–2.67, p = 0.0478), additive model (CC vs TT, OR = 1.93, 95% CI: 1.12–3.35, p = 0.0189) and allelic model (C vs T, OR = 1.24, 95% CI: 1.10–1.39, p = 0.0003). For rs9340799, the frequencies of risk genotypes according to the dominant (GG + GA vs AA, OR = 1.47, 95% CI = 1.10–1.98, p = 0.0096, I2 = 0%, p = 0.43) and allelic (G vs A, OR = 1.33, 95% CI: 1.04–1.69, p = 0.0236, I2 = 0%, p = 0.39) models were significantly lower in women with depression than in controls within the Asian subgroup. For rs1256049, risk genotypes were significantly more frequent in depressed subjects than in controls under the dominant model (AA+ GA vs GG, OR = 1.62, 95% CI: 1.19–2.21, p = 0.0024) and the allelic model (A vs G, OR = 1.35, 95% CI: 1.07–1.72, p = 0.012) after sensitivity analysis by omitting one study which induce the heterogeneity. Conclusions: The current meta-analysis is the first and most comprehensive investigation of the association between ERs and depression in women, and the findings support the concept that ERs participate in the etiology of sex heterogeneity in depression.