Number Of Risk Alleles Research Articles

Associations Between Gene Variants of Lipid-Lowering Drug Targets and Adverse Outcomes After Ischemic Stroke.

The association of lipid-lowering drug targets and their gene variants with cardiovascular diseases has been previously clarified. However, the relationship between gene variants of lipid-lowering drug targets and the adverse prognosis of ischemic stroke patients remains unclear. Multiple single-nucleotide polymorphisms associated with 6 lipid-lowering drug targets were genotyped for patients with ischemic stroke. The primary outcome was death or major disability within 2 years after ischemic stroke. Genetic risk scorewas constructed from significant single-nucleotide polymorphismsidentified via additive models, which was calculated by multiplying the number of risk alleles at each locus by the corresponding beta coefficient and then summing the products. The rs2006760-C of the HMGCR, rs11206510-T of PCSK9, and rs1864163-G and rs9929488-G of CETP were associated with increased odds of adverse outcomes within 2 years after ischemic stroke. Each additional risk allele was associated with higher odds of adverse outcomes. Genetic risk scorewas positively associated with the odds of primary outcome (odds ratio [OR], 1.48 [95% CI, 1.15-1.90]; Ptrend = 0.001), major disability (OR, 1.56[95% CI, 1.16-2.08]; Ptrend = 0.002), death (hazard ratio [HR], 1.58[95% CI, 1.12-2.25]; Ptrend = 0.011), and the composite outcome of death or cardiovascular events (HR, 1.41[95% CI, 1.08-1.85]; Ptrend = 0.010) when 2 extreme quartiles were compared. rs2006760-C of HMGCR, rs11206510-T of PCSK9, and rs1864163-G and rs9929488-G of CETP were associated with increased odds of adverse outcomes within 2 years after ischemic stroke. Furthermore, higher GRS was positively related to the odds of poor outcomes in patients with ischemic stroke. Registration: URL: https://www.clinicaltrials.gov; Identifier: NCT01840072.

Combination of risk alleles of PNPLA3, TM6SF2, and HSD17B13 of donors can predict recurrence of steatotic liver disease after liver transplantation.

This study aimed to identify the genetic risk factors from donors or recipients that contribute to postliver transplantation (LT) steatotic liver disease (SLD), focusing on the genetic risk score (GRS) based on single nucleotide polymorphisms (SNPs) in SLD patients. This retrospective study included 55 Japanese SLD recipients and their respective donors. Genotyping of PNPLA3, TM6SF2, and HSD17B13 was undertaken, and the combined GRS was calculated. The relationship between the GRS and the incidence of posttransplant SLD was also evaluated. The SLD recipients had a high prevalence of post-LT graft steatosis/steatohepatitis (76.4% and 58.2%, respectively). Although the recipients had a high frequency of risk alleles, there was no relationship between the number of risk alleles for each SNP and the incidence of posttransplant SLD. In contrast, an increased number of risk alleles for any SNP in the donor was correlated with high incidence rates of both post-LT steatosis and steatohepatitis. A multivariable analysis showed that a high donor GRS was an independent risk factor for graft steatosis (odds ratio 8.77; 95% CI, 1.94-52.94; p=0.009). Similarly, a high donor GRS was an independent risk factor (odds ratio 6.76; 95% CI, 1.84-30.78; p=0.007) for post-LT graft steatohepatitis. Donor risk alleles of PNPLA3, TM6SF2, and HSD17B13, rather than recipient risk alleles, have been implicated in the development of posttransplant SLD. The combination of these donor risk alleles into a GRS could predict the development of posttransplant SLD.

The interaction between ultra-processed foods and genetic risk score on body adiposity index (BAI), appendicular skeletal muscle mass index (ASM), and lipid profile in overweight and obese women

Background & aimsUltra-processed foods (UPF) are formulations of ingredients, resulting from a series of industrial processes. Excess intake of UPF is associated with an increased risk of obesity and chronic disease. The present study investigates the interaction between the consumption of UPF and genetic risk score with body composition, body adiposity index (BAI), and appendicular skeletal muscle mass (ASM) in overweight and obese women. MethodThe study is cross-sectional with 376 overweight and obese women aged 18–65 years. The food consumption was obtained with 147-item food frequency (FFQ), and food items were grouped according to the level of processing as per the NOVA classification. Three single nucleotide polymorphisms (SNPs), including Caveolin_1 (Cav_1), Melanocortin4 receptor (MC4R), and cryptochrome circadian regulator 1 (CRY1), were used to calculate GRS. The individual risk allele for each SNP was calculated using the incremental genetic model. Each SNP was recoded as 0, 1, or 2 based on the number of risk alleles associated with a higher body mass index (BMI). Subsequently, the unweighted GRS was computed by summing the number of risk alleles across the three SNPs. The GRS scale spans from 0 to 6, with each point representing a risk allele.Anthropometric measurements and some blood parameters were measured by standard protocols. ResultsAfter controlling for confounders such as age, energy intake, and BMI a significant interaction was found for appendicular skeletal muscle mass (β = −1.65, P = 0.04) and appendicular skeletal muscle mass index (β = −0.38, P = 0.07) on the NOVA classification system and GRS. ConclusionsThe findings of this study showed a significant interaction between GRS and the NOVA classification system on some body composition, including appendicular skeletal muscle mass. A higher intake of ultra-processed foods may be associated with lower appendicular skeletal muscle mass in people with high obesity-GRS.

Genetic risk score for insulin resistance based on gene variants associated to amino acid metabolism in young adults.

Circulating concentration of arginine, alanine, aspartate, isoleucine, leucine, phenylalanine, proline, tyrosine, taurine and valine are increased in subjects with insulin resistance, which could in part be attributed to the presence of single nucleotide polymorphisms (SNPs) within genes associated with amino acid metabolism. Thus, the aim of this work was to develop a Genetic Risk Score (GRS) for insulin resistance in young adults based on SNPs present in genes related to amino acid metabolism. We performed a cross-sectional study that included 452 subjects over 18 years of age. Anthropometric, clinical, and biochemical parameters were assessed including measurement of serum amino acids by high performance liquid chromatography. Eighteen SNPs were genotyped by allelic discrimination. Of these, ten were found to be in Hardy-Weinberg equilibrium, and only four were used to construct the GRS through multiple linear regression modeling. The GRS was calculated using the number of risk alleles of the SNPs in HGD, PRODH, DLD and SLC7A9 genes. Subjects with high GRS (≥ 0.836) had higher levels of glucose, insulin, homeostatic model assessment- insulin resistance (HOMA-IR), total cholesterol and triglycerides, and lower levels of arginine than subjects with low GRS (p < 0.05). The application of a GRS based on variants within genes associated to amino acid metabolism may be useful for the early identification of subjects at increased risk of insulin resistance.

Genome-wide association study implicates the role of TBXAS1 in the pathogenesis of depressive symptoms among the Korean population

Although depression is an emerging disorder affecting many people worldwide, most genetic studies have been performed in European descent populations. Herein, a genome-wide association study (GWAS) was conducted in Korean population to elucidate the genomic loci associated with depressive symptoms. Two independent cohorts were used as discovery datasets, which consisted of 6474 (1484 cases and 4990 controls) and 1654 (557 cases and 1097 controls) Korean participants, respectively. The participants were divided into case and control groups based on the Beck Depression Inventory (BDI). Meta-analysis using the two cohorts revealed that rs6945590 was significantly associated with the risk of depressive symptoms [P = 2.83 × 10−8; odds ratio (OR) = 1.23; 95% confidence interval (CI): 1.15–1.33]. This association was validated in other independent cohorts which were another Korean cohort (258 cases and 1757 controls) and the East Asian study of the Psychiatric Genomics Consortium (PGC) (12,455 cases and 85,548 controls). The predicted expression levels of thromboxane A synthase 1 gene (TBXAS1), which encodes the enzyme thromboxane A synthase 1 and participates in the arachidonic acid (AA) cascade, was significantly decreased in the whole blood tissues of the participants with depressive symptoms. Furthermore, Mendelian randomization (MR) analysis showed a causal association between TBXAS1 expression and the risk of depressive symptoms. In conclusion, as the number of risk alleles (A) of rs6945590 increased, TBXAS1 expression decreased, which subsequently caused an increase in the risk of depressive symptoms.

Plasma Proteomic Signature Predicts Risk of Myeloid Neoplasm

Introduction The presence of clonally expanded mutant hematopoietic stem cells, clonal hematopoiesis (CH) is known to predispose to hematologic malignancy, particularly myeloid neoplasms (MN). However, the overall risk of developing MNs among individuals with CH is low (&amp;lt;1% per year). Limitations in our ability to predict who with CH will progress to MN is a barrier to prevention strategies. The human proteome reflects the downstream impact of complex interactions between genetic and epigenetic regulation of biologic systems. We hypothesized that plasma proteomic markers might be associated with MN risk and if so could inform our understanding of the mechanisms promoting the progression of CH to MN. Methods Among 46,237 individuals in the UK Biobank (UKB) with whole exome sequencing data and single nucleotide polymorphism (SNP) array profiling of the blood and plasma proteomic profiling using the Olink Explore platform (1,463 unique proteins), we jointly characterized CH and plasma proteomic profile. Cox proportional hazard models were used to assess the association between the level of each plasma protein and risk of MN; while controlling for age, sex, genetic ancestry, smoking status, blood counts, and sample collection year. The relative contribution of clinical, CH, and proteomics features in prediction of incident MN was assessed using lasso regression with 100-fold cross validation. We performed protein quantitative trait loci (pQTL) mapping to identify independent germline autosomal genetic loci that significantly regulate plasma proteomic levels (p &amp;lt;5x10 -8). We calculated genetically predicted risk scores for plasma protein levels as the as the sum of the effect estimates from linear regression analysis with additive genetic effect, multiplied by the number of risk alleles for each locus. As a validation cohort, we used an independent set of 427,614 individuals in the UKB to test for an association between genetically predicted levels of proteomic markers and MN risk. Results A total of 115 participants developed MN at least 3 months after study entry (median 83 months). As expected, participants who developed MN (cases) had a higher frequency of CH at the time of study entry compared to those free of hematologic malignancy (controls); 42 versus 6% for SNV/Indels and 23 versus 3% for mosaic copy number events in cases compared to controls respectively. We identified 115 proteins significantly associated (qFDR &amp;lt;0.05) with incident MN (Figure 1). These include known regulators of the adaptive immune system, innate immune system, leukocyte trafficking, hematopoietic stem cell self-renewal, and platelet activation. Given that CH is a genetic precursor to MN, we assessed the relationship between plasma proteomic markers of MN and CH. Among the 115 plasma proteins that were significantly associated with MN, 35 were significantly (qFDR &amp;lt;0.05) and 59 nominally (p &amp;lt;0.05) associated with CH. After adjusting for CH, the strength of the association between plasma protein markers and MN risk was generally reduced (mean 7%), but remained significant for many (N=44). We identified a total of 79 plasma proteins that were associated with the presence of CH at the time of study entry, 34 of which overlapped with MN risk proteins. Inclusion of proteomics features in a lasso regression model (AUC = 0.85) improved prediction of incident MN beyond clinical factors and CH (AUC = 0.80; Figure 2). There were 1,282 independent genetic loci that were significantly associated with 115 proteomic markers of MN risk. On average, genetic risk scores captured 12% of the total variance of plasma protein levels (range 0.1-64%). In an independent cohort of 427,614 UKB participants (1,099 of whom developed MN), we found that of the 110 plasma protein markers with a genetic risk score R 2 &amp;gt;1%, 12 were significantly associated with MN (p &amp;lt;0.05). Of the remaining, 63 were directionally consistent. Conclusions We show that plasma proteomic markers predict risk of MN. Some, but not all of the impact of plasma proteomic profile on MN risk is mediated by baseline CH. Inclusion of proteomic markers improves MN risk prediction beyond clinical and CH features. Genetic risk score analysis provides orthogonal validation of the plasma proteomic signature for MN risk. These data highlight the promise of protein and genetic biomarker integration for early diagnosis of MN and further support the role of immune cell regulation in early leukemogenesis.

Characterising the Genetic Landscape of Amyotrophic Lateral Sclerosis: A Catalogue and Assessment of Over 1,000 Published Genetic Variants.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with genetic and phenotypic heterogeneity. Pathogenic genetic variants remain the only validated cause of disease, the majority of which were discovered in familial ALS patients. While causal gene variants are a lesser contributor to sporadic ALS, an increasing number of risk alleles (low penetrance genetic variants associated with a small increase in disease risk) and variants of uncertain significance have been reported. To examine the pathogenic potential of genetic variation in ALS, we sought to characterise variant- and gene-level attributes of previously reported ALS-implicated variants. A list of 1,087 genetic variants reported in ALS to March 2021 was compiled through comprehensive literature review. Individual variants were annotated using in silico tools and databases across variant features including pathogenicity scores, localisation to protein domains, evolutionary conservation, and minor allele frequencies. Gene level attributes of genic tolerance, gene expression in ALS-relevant tissues and gene ontology terms were assessed for 33 ALS genes. Statistical analysis was performed for each characteristic, and we compared the most penetrant variants found in familial cases with risk alleles exclusive to sporadic cases, to explore genetic variant features that associate with disease penetrance. We provide spreadsheet (hg19 and GRCh38) and variant call format (GRCh38) resources for all 1,087 reported ALS-implicated variants, including detailed summaries for each attribute. We demonstrate that the characteristics of variants found exclusively in sporadic ALS cases are less severe than those observed in familial ALS. We provide a comprehensive, literature-derived catalogue of genetic variation in ALS thus far and reveal crucial attributes that contribute to ALS pathogenicity. Our variant- and gene-level observations highlight the complexity of genetic variation in ALS, and we discuss important implications and considerations for novel variant interpretation.

Genetic variants associated with SARS-CoV-2 infection also affect lung function and asthma severity

BackgroundHost genetic factors may be associated with COVID-19 unfavourable outcomes. The first genome-wide association study (GWAS) conducted in individuals with respiratory failure due to COVID-19 revealed susceptibility loci close to six genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1) and the ABO blood-group gene. We aimed to investigate how polymorphisms in those genes could relate to lung function and severe asthma in a Brazilian population. MethodsDNA samples of 784 individuals following the ProAR (Programa para Controle da Asma e Rinite Alérgica da Bahia) were genotyped by the Multi-Ethnic Global Array panel with ∼2 million polymorphisms (Illumina). Polymorphisms in SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1 and the ABO blood-group gene were evaluated. Logistic regression for severe asthma, airway obstruction and lack of FEV1 reversibility was performed using PLINK software 1.9, in the additive model and was adjusted for sex, age and PCA-1. Pairwise Linkage disequilibrium analyses were performed using Haploview 4.2. The haplotypes and gene score analyses were performed in the SNPstat tool. In silico functions of polymorphisms were analysed using rSNPbase and RegulomeDB plataforms. ResultsWe identified the rs8176733 (G allele) and rs8176725 (A allele) in the ABO blood-group gene as risk factors for severe asthma, lower pulmonary obstruction and lack of FEV1 reversibility. Polymorphisms in CCR9 are risk factors for both severe asthma (A allele of rs34338823) and airway obstruction (A allele of rs6806802). The markers rs13079478 (A allele) and rs75817942 (A allele) in FYCO1 are related to more severe asthma and a lack of FEV1 reversibility, respectively. We identified the A allele of both rs35731912 and rs34338823 in LZTFL1 as risk factors for severe asthma. The marker rs6806802 (C allele) was associated with airway obstruction and rs7614952 (A allele), rs7625839 (G allele) and rs112509260 (A allele) are related to a lack of FEV1 reversibility. The A allele of rs2531747 in the SLC6A20 gene is also associated with severe asthma. Conversely, polymorphisms in XCR1 play a protective role in relation to severe asthma (A allele of rs2036295) and airway obstruction (A allele of rs2036295). Additionally, we found that individuals with a higher number of risk alleles have a greater risk of severe asthma, airway obstruction and FEV1 reversibility. ConclusionOur study suggests that polymorphisms in genes associated with respiratory failure in SARS-CoV-2-infected individuals are associated with greater susceptibility to severe asthma and reduced lung function in subjects with asthma.

Cumulative effect of AOC1 gene variants on symptoms and pathological conditions in adult women with fibromyalgia: a pilot study.

Introduction: The amine oxidase copper-containing 1 (AOC1) gene encodes for the diamine oxidase (DAO) enzyme. DAO is an enzyme that catabolizes some molecules, including histamine, and is the degradative enzyme in the polyamine catabolic pathway that is active in intestinal mucosal cells. Variants of AOC1 are associated with reduced DAO activity, resulting in accumulation of high levels of histamine and causing a wide range of neurological, gastrointestinal, and epidermal disorders, which are present in people with fibromyalgia. This study aimed to evaluate the impact of four AOC1 gene variants, namely, rs10156191, rs1049742, rs1049793, and rs2052129, on fibromyalgia symptoms measured by the Fibromyalgia Impact Questionnaire (FIQ), such as sleep disorders, atopic dermatitis, migraine, gastrointestinal (GI) disorders, allergies, and intolerances, in adult women with fibromyalgia. Methods: The sample consisted of 100 unrelated women with fibromyalgia between 33 and 60years of age (48.48years ±7.35), whose were diagnosed by a rheumatologist based on symptoms such as pain, stiffness, and fatigue. Single-nucleotide polymorphisms (SNPs) of AOC1 were identified using oral mucosa samples collected following a standard hygiene protocol. DNA was extracted, and gene variants of interest were analyzed using multiplex single-nucleotide primer extension (SNPE). Clinical data were collected using the FIQ and a series of variables that quantified the intensity and frequency of the symptoms. Results: The minor allele frequencies of rs10156191, rs1049742, rs1049793, and rs2052129 were 31.5, 10, 32.5, and 27%, respectively. Each variant was found to be in Hardy-Weinberg equilibrium, but partial linkage disequilibrium between AOC1 SNPs is suspected. The results show that fibromyalgia symptoms measured using the FIQ tend to increase with the number of risk alleles and that the intensity of dry skin and low stool consistency may be associated with an increase in the number of these alleles. Conclusion: This study constitutes the first step in investigating associations between fibromyalgia symptoms and candidate variants of the AOC1 gene in DAO enzyme activity. Identification of reduced DAO activity may improve the quality of life and treatment of symptoms in fibromyalgia patients.

Genetic Prediction of Lifetime Risk of Fracture.

Fragility fracture is a significant public health problem because it is associated with increased mortality. We want to find out whether the risk of fracture can be predicted from the time of birth. To examine the association between a polygenic risk score (PRS) and lifetime fracture risk. This population-based prospective study involved 3515 community-dwelling individuals aged 60+ years who have been followed for up to 20 years. Femoral neck bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry. A PRS was created by summing the weighted number of risk alleles for each single nucleotide polymorphism using BMD-associated coefficients. Fragility fractures were radiologically ascertained, whereas mortality was ascertained through a state registry. Residual lifetime risk of fracture (RLRF) was estimated by survival analysis. The mortality-adjusted RLRF for women and men was 36% (95% CI, 34%-39%) and 21% (18%-24%), respectively. Individuals with PRS > 4.24 (median) had a greater risk (1.2-fold in women and 1.1-fold in men) than the population average risk. For hip fracture, the average RLRF was 10% (95% CI, 8%-12%) for women and ∼5% (3%-7%) for men; however, the risk was significantly increased by 1.5-fold and 1.3-fold for women and men with high PRS, respectively. A genetic profiling of BMD-associated genetic variants is associated with the residual lifetime risk of fracture, suggesting the potential for incorporating the polygenic risk score in personalized fracture risk assessment.

KCNQ1 rs2237892 polymorphism modify the association between short-term ambient particulate matter exposure and fasting blood glucose: A family-based study

BackgroundThe association between particulate matter and fasting blood glucose (FBG) has shown conflicting results. Genome-wide association studies have shown that KCNQ1 rs2237892 polymorphism is associated with the risk of diabetes. Whether KCNQ1 rs2237892 polymorphism might modify the association between particulate matter and FBG is still uncertain. MethodsData collected from a family-based cohort study in Northern China, were used to perform the analysis. A generalized additive Gaussian model was used to examine the short-term effects of air pollutants on FBG. We further conducted interaction analyses by including a cross-product term of air pollutants by rs2237892 within KCNQ1 gene. ResultsA total of 4418 participants were included in the study. In the single pollutant model, the FBG level increased 0.0031 mmol/L with per 10 μg/m3 elevation in fine particular matter (PM2.5) for lag 0 day. After additional adjustments for nitrogen dioxide (NO2) and sulfur dioxide (SO2), similar results were observed for lag 0–2 days. As for particulate matter with particle size below 10 μm (PM10), the significant association between the daily average concentration of the pollutant and FBG level was observed for lag 0–3 days. Additionally, rs2237892 in KCNQ1 gene modified the association between PM and FBG level. The higher risk of FBG levels associated with elevations in PM10 and PM2.5 were more evident as the number of risk allele C increased. Individuals with a CC genotype had the highest risk of elevation in FBG levels. ConclusionShort-term exposures to PM2.5 and PM10 were associated with higher FBG levels. Additionally, rs2237892 in KCNQ1 gene might modify the association between the air pollutants and FBG levels.

Interaction of environmental factors with the polygenic risk scores of thinness-related genes in preventing obesity risk in middle-aged adults: The KoGES.

Some persons are genetically resistant to obesity, but only a few studies have evaluated thinness genes for preventing obesity. We aimed to investigate the association of polygenic variants with being underweight and their interaction with the lifestyles of middle-aged and elderly persons and identify potential new genetic approaches for managing body weight. In total, 58,701 participants aged 40-77 years were recruited from urban hospitals in Korea. Underweight (case) was defined as body mass index (BMI) < 18.5 kg m2 (n = 991) and normal weight (control, n = 21,921) was defined as 18.5 ≤ BMI < 23 kg m2 . A genome-wide association study was run to identify thinness-related single nucleotide polymorphisms (SNPs) after adjustment for compound factors using Gplink. The generalised multifactor dimensionality reduction program was used to identify the genetic variants with SNP-SNP interactions. The polygenic risk score (PRS) was calculated by summing up the number of risk alleles in each SNP and classifying them into low-, medium- and high-PRS. The best model included the ANK2_rs7656666, CAST_rs28042, SLC1A3_rs928431867, CHST12_rs2906173, ALOX5_rs1051713, RGS6_rs17180754, ST8SIA5_rs79491311 and DCC_rs35721894 alleles. The participants with high-PRS had a lower BMI (p < 0.0001) than those with low-PRS and were 3.834 (2.58-5.70) times more likely to be underweight after multivariate adjustment (p < 0.001). The selected SNPs were correlated with each other and highly expressed in brain-related genes. The genes with minor alleles of CAST_rs28042 and CHST12_rs2906173 exhibited a higher expression frequency in brain-related tissues. PRS had significant interactions with protein, sodium, indigestible carbohydrates, calcium intake and exercise (p < 0.05), influencing the underweight state. People with a high-PRS were more underweight than those with low-PRS under high protein, sodium, high calcium, low indigestible carbohydrate intake and low exercise by 3.75, 3.88, 7.05, 3.18 and 3.80 times, respectively (p < 0.0001). In conclusion, adults having a high-PRS were significantly correlated with being underweight, especially in combination with a particular nutritional status. These results show the potential for thinness genes to be applied to personalised nutrition for preventing obesity through targeted gene therapy.

Effect of genetic polymorphisms on outcomes following nivolumab for advanced renal cell carcinoma in the SNiP-RCC trial.

Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.

PNPLA3 and TM6SF2 genetic variants and hepatic fibrosis and cirrhosis in Pakistani chronic hepatitis C patients: a genetic association study

BackgroundThe present study investigates if common missense functional variants p.I148M and p.E167K in PNPLA3 and TM6SF2 genes, respectively, associate with development of hepatic fibrosis and cirrhosis in a geographically novel cohort of Pakistani chronic hepatitis C (CHC) patients.MethodsIn total, 502 Pakistani CHC patients [242 males, median age 40 years, 220 with significant hepatic fibrosis, including 114 with cirrhosis] were genotyped for PNPLA3 and TM6SF2 variants using TaqMan genotyping assays. Associations between genotypes, biochemical and clinical parameters were evaluated.ResultsGenotypic distributions for PNPLA3 and TM6SF2 polymorphisms conformed to Hardy–Weinberg equilibrium and did not associate with fibrosis grades ≥ F2 or cirrhosis in any of the genetic models tested (all p = > 0.05). PNPLA3 and TM6SF2 variants did not modulate baseline characteristics and serum markers of liver injury in CHC patients. Similarly, increasing number of risk alleles of PNPLA3 and TM6SF2 polymorphisms had no trend effect on serum liver enzyme activities or proportion of CHC patients with significant or advanced fibrosis or cirrhosis (p = > 0.05). The same trend of no association with hepatic fibrosis or cirrhosis persisted in the multivariate logistic regression models adjusting for age, gender, body mass index and HCV viral load (p = > 0.05).ConclusionsPNPLA3 and TM6SF2 variants do not appear to modulate development of hepatic fibrosis or cirrhosis in present CHC patients of Pakistani origin, and may be of more relevance in liver pathology involving abnormalities in hepatic fat accumulation. These results also reflect the divergent associations observed for different genetic modifiers of hepatic fibrosis and cirrhosis in distinct ethnicities.

Joint Effect of Multiple Prothrombotic Genotypes and Mean Platelet Volume on the Risk of Incident Venous Thromboembolism.

A high mean platelet volume (MPV), a marker of increased platelet reactivity, is a risk factor for venous thromboembolism (VTE). Whether established prothrombotic single nucleotide polymorphisms (SNPs) further increase the VTE risk in subjects with high MPV because of biological interaction remains unknown. To investigate the joint effect of high MPV and prothrombotic genotypes, comprising a 5-SNP genetic risk score (GRS), on the risk of VTE in a population-based case-cohort. Incident VTE cases (n = 653) and a subcohort (n = 1,774) were derived from the Tromsø Study (1994-2012). DNA was genotyped for rs8176719 (ABO), rs6025 (F5), rs1799963 (F2), rs2036914 (F11), and rs2066865 (FGG). Hazard ratios (HRs) for VTE with 95% confidence intervals (CIs) were estimated according to predefined MPV-strata (<8.5, 8.5-9.5, ≥9.5 fL) and number of risk alleles for each individual SNP and the GRS (0-1, 2-3, ≥4 risk alleles) in models adjusted for age, sex, body mass index, and platelet count. The combination of high MPV and risk alleles, either as individual SNPs or the GRS, had an additive effect on VTE risk. Compared with subjects with MPV <8.5 fL and 0-1 risk allele, those with high MPV (≥9.5 fL) and ≥4 risk alleles had HRs of 2.80 (95% CI: 1.77-4.43) for overall VTE and 4.60 (95% CI: 2.20-9.60) for unprovoked events, respectively, but there was no supra-additive effect on risk estimates. The combination of high MPV and prothrombotic genotypes had an additive effect on VTE risk, suggesting there is no biological interaction between these risk factors in the pathogenesis of VTE.

Genetic variants in RNA m5 C modification genes associated with survival and chemotherapy efficacy of colorectal cancer.

Colorectal cancer is one of the most common malignant digestive tract tumors with a poor prognosis. RNA 5-methylcytosine (m5 C) is an important posttranscriptional widespread modification involved in many biological processes. However, the association between genetic variations of m5 C modification genes and the prognostic value of colorectal cancer remains unclear. We investigated the association between candidate single nucleotide polymorphisms (SNPs) in 13 m5 C modification genes and colorectal cancer overall survival (OS) after chemotherapy by the Cox regression model. The combined effect of selected SNPs on OS, progression-free survival (PFS), and disease control rate (DCR) was assessed by the number of risk alleles (NRA). The GTEx and TCGA database were used to perform expression qualitative trait locus (eQTL) analysis. We identified that two SNPs in YBX1 were associated with OS after chemotherapy (HR=1.43, p=0.001 for rs10890208; HR=1.36, p=0.025 for rs3862218). A striking dose-response effect between NRA and OS after chemotherapy was found (ptrend =0.002). The DCR of patients receiving oxaliplatin chemotherapy in the 3-4 NRA group was markedly reduced in comparison to that in the 0-2 NRA group (OR=1.49, p=0.036). Moreover, YBX1 mRNA expression was significantly overexpressed in tumor tissues (p < 0.05) in the TCGA database, and eQTL analysis demonstrated that the two SNPs were associated with YBX1 (p=0.003 for rs10890208 and p=0.024 for rs3862218). Our study indicates that genetic variants in m5 C modification genes may mediate changes in YBX1 mRNA levels and affect the chemotherapeutic efficacy of colorectal cancer patients.

Polygenic risk score in prostate cancer.

This study was conducted in order to review the outcomes regarding polygenic risk score (PRS) in prediction of prostate cancer (PCa). With the increasing proficiency of genetic analysis, assessment of PRS for prediction of PCa has been performed in numerous studies. Genetic risk prediction models for PCa that include hundreds to thousands of independent risk-associated variants are under development. For estimation of additive effect of multiple variants, the number of risk alleles carried by an individual is summed, and each variant is weighted according to its estimated effect size for generation of a PRS. Currently, regarding the accuracy of PRS alone, PCa detection rate ranged from 0.56 to 0.67. A higher rate of accuracy of 0.866-0.880 was observed for other models combining PRS with established clinical markers. The results of PRS from Asian populations showed a level of accuracy that is somewhat low compared with values from Western populations (0.63-0.67); however, recent results from Asian cohorts were similar to that of Western counterparts. Here, we review current PRS literature and examine the clinical utility of PRS for prediction of PCa. Emerging data from several studies regarding PRS in PCa could be the solution to adding predictive value to PCa risk estimation. Although commercial markers are available, development of a large-scale, well validated PRS model should be undertaken in the near future, in order to translate hypothetical scenarios to actual clinical practice.

How Variation in Risk Allele Output and Gene Interactions Shape the Genetic Architecture of Schizophrenia.

Schizophrenia is a highly heritable polygenic psychiatric disorder. Characterization of its genetic architecture may lead to a better understanding of the overall burden of risk variants and how they determine susceptibility to disease. A major goal of this project is to develop a modeling approach to compare and quantify the relative effects of single nucleotide polymorphisms (SNPs), copy number variants (CNVs) and other factors. We derived a mathematical model for the various genetic contributions based on the probability of expressing a combination of risk variants at a frequency that matched disease prevalence. The model included estimated risk variant allele outputs (VAOs) adjusted for population allele frequency. We hypothesized that schizophrenia risk genes would be more interactive than random genes and we confirmed this relationship. Gene–gene interactions may cause network ripple effects that spread and amplify small individual effects of risk variants. The modeling revealed that the number of risk alleles required to achieve the threshold for susceptibility will be determined by the average functional locus output (FLO) associated with a risk allele, the risk allele frequency (RAF), the number of protective variants present and the extent of gene interactions within and between risk loci. The model can account for the quantitative impact of protective variants as well as CNVs on disease susceptibility. The fact that non-affected individuals must carry a non-trivial burden of risk alleles suggests that genetic susceptibility will inevitably reach the threshold for schizophrenia at a recurring frequency in the population.

Combined Performance of Fecal Immunochemical Tests and a Genetic Risk Score for Advanced Neoplasia Detection

In our study, combining polygenic risk score with fecal immunochemical test (FIT) did not improve diagnostic accuracy for advanced colorectal neoplasia detection compared with FIT alone. So far, such a combination cannot be recommended because it would come at extra costs and effort despite no relevant gain in neoplasia detection.

Contribution of a genetic risk score to ethnic differences in fatty liver disease.

Background and aims:Susceptibility to fatty liver disease (FLD) varies among individuals and between racial/ethnic groups. Several genetic variants influence FLD risk, but whether these variants explain racial/ethnic differences in FLD prevalence is unclear. We examined the contribution of genetic risk factors to racial/ethnic-specific differences in FLD.Methods:A case–control study comparing FLD patients (n = 1194) and population-based controls (n = 3120) was performed. Patient characteristics, FLD risk variants (PNPLA3-rs738409 + rs6006460, TM6SF2-rs58542926, HSD17B13-rs80182459 + rs72613567, MBOAT7/TMC4-rs641738, and GCKR-rs1260326) and a multi-locus genetic risk score (GRS) were examined. The odds of FLD for individuals with different risk factor burdens were determined.Results:Hispanics and Whites were over-represented (56% vs. 38% and 36% vs. 29% respectively) and Blacks under-represented (5% vs. 23%) among FLD patients, compared to the population from which controls were selected (p < .001). Among cases and controls, Blacks had a lower and Hispanics a greater, net number of risk alleles than Whites (p < .001). GRS was associated with increase odds of FLD (ORQ5vsQ1 = 8.72 [95% CI = 5.97–13.0], p = 9.8 × 10−28), with the association being stronger in Hispanics (ORQ5vsQ1 = 14.8 [8.3–27.1]) than Blacks (ORQ5vsQ1 = 3.7 [1.5–11.5], P-interaction = 0.002). After accounting for GRS, the odds of FLD between Hispanics and Whites did not differ significantly (OR = 1.06 [0.87–1.28], p = .58), whereas Blacks retained much lower odds of FLD (OR = 0.21, [0.15–0.30], p < .001).Conclusions:Blacks had a lower and Hispanics a greater FLD risk allele burden than Whites. These differences contributed to, but did not fully explain, racial/ethnic differences in FLD prevalence. Identification of additional factors protecting Blacks from FLD may provide new targets for prevention and treatment of FLD.