Common Gene Variants Research Articles

Exploring ALDH2 expression and immune infiltration in HNSC and its correlation of prognosis with gender or alcohol intake

The aldehyde dehydrogenase 2 point mutation (ALDH2*2) is a common frequent human gene variant, especially in East Asians. However, the expression and mechanism of action of ALDH2 in HNSC remain unknown. The present study explored the clinical significance and immune characteristics of ALDH2 in HNSC. The receiver operating characteristic curve was analysed to assess the diagnostic value of ALDH2 expression. ALDH2 expression in normal tissues and HNSC tissues was evaluated by IHC, and we also analysed ALDH2 gene expression in 4 HNSC cell lines. ALDH2 expression was significantly reduced in HNSC tissues compared to normal tissues (p < 0.05). HNSC patients with high ALDH2 expression had a better prognosis compared to patients with low ALDH2 expression (p < 0.05). GSEA indicated that these gene sets were correlated with signalling pathways, including the JAK-STAT signalling pathway. Unexpectedly, we found a significant prognostic effect of ALDH2 for HNSC based on alcohol consumption and the male sex. The correlation between ALDH2 expression and immune inhibitors showed an effect for ALDH2 in modifying tumour immunology in HNSC, and there may be a possible mechanism by which ALDH2 regulates the functions of T cells in HNSC. In addition, we developed a prognostic nomogram for HNSC patients, which suggested that low ALDH2 expression indicated poor prognosis in HNSC patients who were males and alcoholics.

Common variants in genes involved in islet amyloid polypeptide (IAPP) processing and the degradation pathway are associated with T2DM risk: A Chinese population study

AimTo explore the genetic effects of SLC30A8, IAPP, PCSK1, PCSK2, CPE, PAM and IDE, key genes involved in IAPP processing and degradation pathway on T2DM risk and metabolic traits in Chinese population. MethodsCommon variants were genotyped in 10936 Chinese subjects by Asian Screening Array and Multi-Ethnic Global Array. Associations of SNPs with occurrences of T2DM and related traits were evaluated through logistic and multiple linear regression. Genetic risk score (GRS) model was constructed based on 6 T2DM-variants, and its relationship with T2DM and related traits was assessed. ResultsSLC30A8-rs13266634, PCSK1-rs155980, PCSK2-rs6136035, CPE-rs532192464, PAM-rs7716941, and IDE-rs117929184 were the top SNPs significantly associated with T2DM after adjusting for age, sex, and BMI, associated with blood glucose level, insulin secretion, and insulin sensitivity (all FDR p < 0.05). GRS calculated based on the above SNPs was remarkably correlated with T2DM, blood glucose, and insulin secretion. Furthermore, there was a significant interaction between SLC30A8 and IAPP in patients with T2DM (P = 0.0083). ConclusionOur study showed that common variants in genes involved in IAPP processing and the degradation pathway were associated with T2DM in Chinese population. Subjects with high GRS exhibited poorer glucose metabolism and insulin secretion.

Genetic screening of common genetic deafness in 60,391 women of childbearing age and intervention of birth defects.

At least 60% of cases of severe hearing loss result from genetic factors. In this study genetic screening was carried out for common genetic deafness in women of childbearing age to prevent deafness and birth defects via providing genetic counseling and follow-up services for high-risk families. In total 60,391 pre-pregnancy/early-gestation women who received treatment in second-level or above hospitals in Weihai from February 2017 to December 2019 were selected. Venous or peripheral blood was collected to make dried blood slices on filter paper to extract genomic DNA, and high-throughput sequencing was applied to detect 20 variant sites in 4 common deafness genes (GJB2, GJB3, SLC26A4 and mitochondrial 12S rRNA) in the Chinese population. The spouses of women with deafness gene variants were sequenced. In total 3,761 carriers with deafness gene variants were detected in 60,391 women of childbearing age, with a carrier rate of 6.2%. Among them, 1,739 women (2.88%) only carried GJB2 pathogenic variants. The carrying rate of c.235delC in GJB2 pathogenic variants was the highest at 2.08%. 1,553 women (2.58%) only carried SLC26A4 pathogenic variants. The carrying rate of c.919-2A>G in SLC26A4 pathogenic variants was the highest at 1.63%. 300 women (0.5%) only carried GJB3 variants, and 125 women (0.2%) carried the mitochondrial drug-sensitive gene variant. This screening model will greatly reduce the birth rate of children with hearing disabilities and is an effective way to prevent newborn deafness. In addition, genetic screening provided the related knowledge of hereditary deafness, especially strengthening genetic counseling and the clinical decision making from the genetic screening.

Expected or unexpected clinical findings in liver glycogen storage disease type IX: distinct clinical and molecular variability.

To reveal the different clinical presentations of liver glycogen storage disease type IX (GSD IX), which is a clinically and genetically heterogeneous type of glycogenosis. The data from the electronic hospital records of 25 patients diagnosed with liver GSD IX was reviewed. Symptoms, clinical findings, and laboratory and molecular analysis were assessed. Of the patients, 10 had complaints of short stature in the initial presentation additionally other clinical findings. Elevated serum transaminases were found in 20 patients, and hepatomegaly was found in 22 patients. Interestingly, three patients were referred due to neurodevelopmental delay and hypotonia, while one was referred for only autism. One patient who presented with neurodevelopmental delay developed hepatomegaly and elevated transaminases during the disease later on. Three of the patients had low hemoglobin A1C and fructosamine values that were near the lowest reference range. Two patients had left ventricular hypertrophy. Three patients developed osteopenia during follow-up, and one patient had osteoporosis after puberty. The most common gene variant, PHKA2, was observed in 16 patients, 10 variants were novel and six variants were defined before. Six patients had variants in PHKG2, two variants were not defined before and four variants were defined before. PHKB variants were found in three patients. One patient had twonovel splice site mutations in trans position. It was revealed that one novel homozygous variant and one defined homozygous variant were found in PHKB. This study revealed that GSD IX may present with only hypotonia and neurodevelopmental delay without liver involvement in the early infantile period. It should be emphasized that although liver GSDIX is thought of as a benign disease, it might present with multisystemic involvement and patients should be screened with echocardiography, bone mineral densitometry, and psychometric evaluation.

Optical genome mapping identifies rare structural variations as predisposition factors associated with severe COVID-19

SummaryImpressive global efforts have identified both rare and common gene variants associated with severe COVID-19 using sequencing technologies. However, these studies lack the sensitivity to accurately detect several classes of variants, especially large structural variants (SVs), which account for a substantial proportion of genetic diversity including clinically relevant variation. We performed optical genome mapping on 52 severely ill COVID-19 patients to identify rare/unique SVs as decisive predisposition factors associated with COVID-19. We identified 7 SVs involving genes implicated in two key host-viral interaction pathways: innate immunity and inflammatory response, and viral replication and spread in nine patients, of which SVs in STK26 and DPP4 genes are the most intriguing candidates. This study is the first to systematically assess the potential role of SVs in the pathogenesis of COVID-19 severity and highlights the need to evaluate SVs along with sequencing variants to comprehensively associate genomic information with interindividual variability in COVID-19 phenotypes.

Whole Exome Sequencing Data Analysis for Detection of Breast Cancer Gene Variants and Pathway Study

Introduction: Whole Exome Sequencing (WES) involves sequencing, analysis of protein coding regions in genome. In present investigation, the potential gene variants were identified in human breast cancer genome using WES data analysis. Materials and Method: The NGS data samples with accession numbers (SRR1274896_1, SRR1274896_2) and (SRR1275000_1, SRR1275000_2) were collected from ENA database. The quality of the samples was assessed by using FastQC tool and followed by aligning samples with reference genome sequence hg38 using Bowtie2 tool. The results were retrieved in SAM format and converted to BAM format and then to sorted bam file using SAM tools, then duplicates were removed using Picard tool. Finally, Variant Calling format file was generated using BCF tools which projected the possible gene variants in the samples. Results: The results showed variant types out of them MUC3A1 showed an average of 53 mutations, highlighting its importance as a potential gene variant observed in breast cancer. Out of nonsynonymous mutations of samples, common gene variants in samples that possess 5 and more mutations were selected. The study was carried out on pathway analysis, domain analysis, gene involvement in biological processes and gene function. Conclusion: Majority of gene variants were involved in DNA Biosynthesis and Protein Biosynthesis and also resulted in tissue specific location. The location of these genes showed mutated genes in cytoplasm and in nucleus indicating the impact of gene variation on intracellular process.

Functional Studies of Genetic Variants Associated with Human Diseases in Notch Signaling-Related Genes Using Drosophila.

Rare variants in the many genes related to Notch signaling cause diverse Mendelian diseases that affect myriad organ systems. In addition, genome- and exome-wide association studies have linked common and rare variants in Notch-related genes to common diseases and phenotypic traits. Moreover, somatic mutations in these genes have been observed in many types of cancer, some of which are classified as oncogenic and others as tumor suppressive. While functional characterization of some of these variants has been performed through experimental studies, the number of "variants of unknown significance" identified in patients with diverse conditions keeps increasing as high-throughput sequencing technologies become more commonly used in the clinic. Furthermore, as disease gene discovery efforts identify rare variants in human genes that have yet to be linked to a disease, the demand for functional characterization of variants in these "genes of unknown significance" continues to increase. In this chapter, we describe a workflow to functionally characterize a rare variant in a Notch signaling related gene that was found to be associated with late-onset Alzheimer's disease. This pipeline involves informatic analysis of the variant of interest using diverse human and model organism databases, followed by in vivo experiments in the fruit fly Drosophila melanogaster. The protocol described here can be used to study variants that affect amino acids that are not conserved between human and fly. By "humanizing" the almondex gene in Drosophila with mutant alleles and heterologous genomic rescue constructs, a missense variant in TM2D3 (TM2 Domain Containing 3) was shown to be functionally damaging. This, and similar approaches, greatly facilitate functional interpretations of genetic variants in the human genome and propel personalized medicine.

Common Variants in Neuraminidase Genes Contribute to Predisposition to and Progression of Chronic Heart Failure

Introduction: The role of neuraminidases in cardiovascular disease has recently gained increasing attention. However, the association between neuraminidase gene polymorphisms and heart failure (HF) has not yet been investigated. Methods and Results: Genotyping of nine single-nucleotide polymorphisms (SNPs) in the NEU2/NEU3/NEU4 genes was performed in 610 HF patients and 600 healthy controls from the Southwest Han Chinese population using TaqMan SNP Genotyping Assay. Individuals carrying the A allele of rs11545301 had decreased risk of HF (additive model: OR = 0.704, 95% CI = 0.511–0.97; p = 0.032). However, the C allele of rs2293763 increased the risk of HF in the recessive model (OR = 1.486, 95% CI = 1.095–2.012; p = 0.011). Rs2233384, rs2233394, and rs2293763 were significantly associated with the mortality risk of HF in the dominant model, both with and without adjustment for conventional risk factors (HR = 0.686, 95% CI = 0.52–0.906, p = 0.008 for rs2233384, HR = 1.357, 95% CI = 1.035–1.78, p = 0.027 for rs2233384, and HR = 0.76, 95% CI = 0.592–0.975, p = 0.031 for rs2293763). Conclusion: Our findings demonstrated the association between a series of variants in NEU2/NEU4 genes and the risk or prognosis of HF in the Han Chinese population. These data suggested an important role of NEU2 and NEU4 in the pathogenesis of HF.

Common disease-associated gene variants in a Saudi Arabian population.

BACKGROUND: Screening programs for the most prevalent conditions occurring in a country is an evidence-based prevention strategy. The burden of autosomal recessive disease variations in Saudi Arabia is high because of the highly consanguineous population. The optimal solution for estimating the carrier frequency of the most prevalent diseases is carrier screening.OBJECTIVES: Identify the most influential recessive alleles associated with disease in the Saudi population.DESIGN: We used clinical whole-exome sequencing data from an in-house familial database to evaluate the most prevalent genetic variations associated with disease in a Saudi population.SETTINGS: King Abdullah International Medical Research Center (KAIMRC) and King Abdulaziz Medical City.METHODS: Whole exome sequencing data obtained from clinical studies of family members, a cohort of 1314 affected and unaffected individuals, were filtered using the in-house pipeline to extract the most prevalent variant in the dataset.MAIN OUTCOME MEASURES: Most prevalent genetic variations associated with disease in the Saudi population.SAMPLE SIZE: 1314 affected and unaffected individuals.RESULTS: We identified 37 autosomal recessive variants and two heterozygous X-linked variants in 35 genes associated with the most prevalent disorders, which included hematologic (32%), endocrine (21%), metabolic (11%) and immunological (10%) diseases.CONCLUSION: This study provides an update of the most frequently occurring alleles, which support future carrier screening programs.LIMITATIONS: Single center that might represent the different regions but may be biased. In addition, most of the families included in the database are part of the proband's genetic identification for specific phenotypes.CONFLICT OF INTEREST: None.

Common ALDH3A1 Gene Variant Associated with Keratoconus Risk in the Polish Population.

Background: ALDH3A1 protein is important in maintaining corneal physiology and protecting the eye from UV damage. However, none of the genome-wide association studies has indicated that the ALDH3A1 locus is associated with keratoconus. In this study, we examined the potential role of ALDH3A1 variants as risk factors for keratoconus incidence and severity in a large group of Polish keratoconus patients. Methods: In the first stage we analyzed the coding region sequence of the ALDH3A1 in a subgroup of keratoconus. Then, we genotyped three selected ALDH3A1 variants in a larger KC group of patients (n = 261) and healthy controls (n = 317). Results: We found that the rs1042183 minor allele A is a risk factor for keratoconus in the dominant model (OR = 2.06, 95%CI = 1.42–2.98, p = 0.00013). The rs2228100 variant genotypes appear to be associated with an earlier age of KC diagnosis in the Polish population (p = 0.055 for comparison of three genotypes and p = 0.022 for the dominant inheritance model). Conclusions: The rs1042183 variant in ALDH3A1 is associated with keratoconus risk in the Polish population. The differences in the allele frequency between both populations could be partially responsible for the difference in the disease prevalence.

GENETIC DIVERSITY OF ENTEROCOCCUS FAECALIS ISOLATES FROM CHILDREN WITH URINARY TRACT INFECTION IN PRIMORSKY KRAI OF RUSSIA

Background: Escherichia coli is the most common cause of urinary tract infections (UTI). However, Enterococcus faecalis has been shown to be the most common causative agent of UTI among children and newborns in Primorsky Krai of Russia warranting further research. Aim: To study the occurrence of pathogenicity factor genes in the E. faecalis isolates from children with UTI in the Primorsky Krai of the Russian Far East. Methods: Forty-two E. faecalis clinical isolates from children under the age of 16 with UTI identified in 2013-2017 were studied. Phylogenetic diversity of the strains was assessed by the ultilocus sequence typing. Six genes, namely, cylA, aggA, efaA, eep, gelE, esp were tested in the isolates by polymerase chain reaction . Results: CylA, aggA, efaA, eep, gelE and esp genes occurred in 50.0 %, 80.95 %, 100 %, 100 %, 76.2 % and 71.4 % of the isolates, respectively. Eleven different gene variants were detected for the combination of pathogenicity factor genes. The most common gene variants were (aggA, cylA, efaA, eep, gelE, esp) and (aggA, efaA, eep, gelE). Among the uropathogenic E. faecalis. Fourteen sequence-types were identified (ST6, ST16, ST21, ST25, ST40, ST41, ST64, ST116, ST133, ST151, ST179, ST480, ST537, ST774), with ST179, ST774, ST6 being the most common. Conclusions: The identified diversity of sequence-types indicates the genetic heterogeneity of uropathogenic enterococci isolated in the Primorsky Krai. The detection of a large amount of pathogenicity factors and their combinations causes the predominance of E. faecalis in the region as a clinically relevant etiological agent of UTI among children. The identification of highly virulent sequence types such as E. faecalis ST6, ST179 and ST774 warrants further research to determine the population structure of enterococci.

Abstract 11051: A Common Variant Near the Fibrinogen Gamma Chain Gene is an Independent Risk Factor for Thrombosis After Congenital Heart Surgery

Introduction: Postoperative thrombosis is a common complication after congenital heart disease (CHD) surgery in children, and is associated with increased mortality and morbidity. Identification of risk factors may allow preventive therapy and improved outcomes. Hypothesis: We tested the hypothesis that genetic variants are associated with postoperative thrombosis after CHD surgery in children. Methods: Children with CHD were prospectively enrolled in an observational cohort study at the time of initial surgical repair/palliation. Clinically detected thrombosis within 30 days of surgery while in hospital was the primary outcome. Patients were genotyped on the Axiom Precision Medicine Research Array. Clinical and genetic (8 common variants in candidate genes) factors were assessed for association with the primary outcome with univariate and multivariate analysis. A two-tailed P-value of &lt; 0.05 was considered statistically significant. Results: A total of 2,398 unique patients (median age 6 months, median weight 6.7 kg) had complete clinical and genetic data for analysis. Postoperative thrombosis occurred in 242 (10.1%). Patients with thrombosis were younger (P&lt;0.001), with longer bypass time (P&lt;0.001) and higher initial postoperative lactate (P&lt;0.001). Thrombosis was also associated with longer hospital stay (50 ± 59 days vs 16 ± 31days, P&lt;0.001) and mortality (15.3% vs 2.9%, P&lt;0.001). One common variant near fibrinogen gamma ( FGG , rs7659024, NC_000004.12:g.154599778G&gt;A) was associated with postoperative thrombosis, with a gene-dose effect (thrombosis observed in 8.9% GG, n=1370, 11% AG, n=869, 15.1% AA, n=159, P=0.025). In multivariate analysis age (per year older OR 0.7, 95% CI 0.61-0.79), bypass time (per hour OR 1.24, 95% CI 1.09-1.39), lactate (per mmol/L OR 1.15, 95% CI 1.19-1.32) and FGG genotype (GG reference, AG OR 1.51, 95% CI 1.09-2.08; AA OR 2.35, 95% CI 1.39-3.97) were each independently associated with postoperative thrombosis. Conclusions: A common variant near FGG previously associated with fibrinogen γ′ levels is an independent risk factor for postoperative thrombosis after CHD surgery. Preoperative genotyping with thromboprophylaxis for patients at sufficient risk may be considered.

Association of serum surfactant protein D and SFTPD gene variants with asthma in Danish children, adolescents, and young adults.

BackgroundSurfactant Protein D (SP‐D) is a pattern recognition molecule belonging to the family of collectins expressed in multiple human organ systems, including the lungs. Previous studies have shown that SP‐D levels in bronchoalveolar lavage samples decrease and serum levels increase in patients suffering from asthma, possibly due to a combination of induced SP‐D synthesis and decreased air–blood barrier integrity. The aims of this study were to investigate whether serum levels of SP‐D and common variants in the SP‐D gene were associated with asthma in adolescents and young adults.MethodsProspective observational study including 449 adolescents and young adults (age 11–27 years) previously diagnosed with asthma during a 2‐year period from 2003 to 2005 (0–16 years). At follow‐up from 2016 to 2017, 314 healthy controls with no history of asthma were recruited. Serum SP‐D was analyzed on samples obtained at baseline as well as samples obtained at follow‐up. SP‐D genotyping was performed for rs721917, rs2243639, and rs3088308.ResultsNo differences were found in mean levels of sSP‐D and SFTPD genotype among subjects with current asthma, no current asthma, and controls. Serum SP‐D and SFTPD genotype were not associated with any clinical parameters of asthma. Furthermore, baseline sSP‐D was not associated with asthma at follow‐up.ConclusionSerum surfactant protein D and common SP‐D gene variants were not associated with asthma in Danish adolescents and young adults with mild to moderate asthma. Serum surfactant protein D did not demonstrate any value as a clinical biomarker of asthma.

Sensitive period-regulating genetic pathways and exposure to adversity shape risk for depression.

Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects on brain structure or function, behavior, and disease. Although sensitive periods for depression likely arise through a complex interplay of genes and experience, this possibility has not yetbeen exploredin humans. We examined the effect of genetic pathways regulating sensitive periods, alone and in interaction with common childhood adversities, on depression risk. Guided by a translational approach, we: (1) performed association analyses of three gene sets (60 genes) shown in animal studies to regulate sensitive periods using summary data from a genome-wide association study of depression (n = 807,553); (2) evaluated the developmental expression patterns of these genes using data from BrainSpan (n = 31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay (dGxE)by analyzing the combined effect of common variants in sensitive period genes and time-varying exposure to two types of childhood adversity within a population-based birth cohort (n = 6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, 6 of the 15 genes in this set showed developmentally regulated gene-level expression. We also identified astatistical interaction between caregiver physical or emotional abuse during ages 1-5 years and genetic risk for depression conferred by the opening genes. Genes involved in regulating sensitive periods are differentially expressed across the life course and may be implicated in depression vulnerability. Our findings about gene-by-development interplay motivate further research in large, more diverse samples to further unravel the complexity of depression etiologythrough a sensitive period lens.

The Role of Ion Channel-Related Genes in Autism Spectrum Disorder: A Study Using Next-Generation Sequencing.

The clinical heterogeneity of autism spectrum disorder (ASD) is closely associated with the diversity of genes related to ASD pathogenesis. With their low effect size, it has been hard to define the role of common variants of genes in ASD phenotype. In this study, we reviewed genetic results and clinical scores widely used for ASD diagnosis to investigate the role of genes in ASD phenotype considering their functions in molecular pathways. Genetic data from next-generation sequencing (NGS) were collected from 94 participants with ASD. We analyzed enrichment of cellular processes and gene ontology using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). We compared clinical characteristics according to genetic functional characteristics. We found 266 genes containing nonsense, frame shift, missense, and splice site mutations. Results from DAVID revealed significant enrichment for “ion channel” with an enrichment score of 8.84. Moreover, ASD participants carrying mutations in ion channel-related genes showed higher total IQ (p = 0.013) and lower repetitive, restricted behavior (RRB)-related scores (p = 0.003) and mannerism subscale of social responsiveness scale scores, compared to other participants. Individuals with variants in ion channel genes showed lower RRB scores, suggesting that ion channel genes might be relatively less associated with RRB pathogenesis. These results contribute to understanding of the role of common variants in ASD and could be important in the development of precision medicine of ASD.

Inflammatory Pathways Are Impaired in Alzheimer Disease and Differentially Associated With Apolipoprotein E Status.

Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-ε4 significantly increases AD risk, APOE-ε3 is the most common gene variant, and APOE-ε2 protects against AD. However, the underlying mechanisms of APOE-ε4 on AD risk remains unclear, with APOE-ε4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-ε3/3 (n = 9) or APOE-ε4/4 (n = 10) participants with AD pathology and APOE-ε3/3 (n = 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-ε4/4-AD individuals compared to APOE-ε3/3-AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-ε3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-ε4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.

Host genetic factors determining COVID-19 susceptibility and severity.

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) poses an unprecedented challenge to humanity. SARS-CoV-2 infections range from asymptomatic to severe courses of COVID-19 with acute respiratory distress syndrome (ARDS), multiorgan involvement and death. Risk factors for disease severity include older age, male sex, increased BMI and pre-existing comorbidities. Ethnicity is also relevant to COVID-19 susceptibility and severity. Host genetic predisposition to COVID-19 is now increasingly recognized and whole genome and candidate gene association studies regarding COVID-19 susceptibility have been performed. Several common and rare variants in genes related to inflammation or immune responses have been identified. We summarize research on COVID-19 host genetics and compile genetic variants associated with susceptibility to COVID-19 and disease severity. We discuss candidate genes that should be investigated further to understand such associations and provide insights relevant to pathogenesis, risk classification, therapy response, precision medicine, and drug repurposing.

Hereditary vascular cognitive decline

A number of monogenic forms of cerebral small vessel disease (SVD) cause early onset lacunar stroke and dementia. By far the most common of these is CADASIL due to NOTCH3 mutations, although other underlying genes causing similar diseases include HTRA1 and COL4A1/2. Characteristic MRI features include white matter hyperintensities, lacunar infarcts, and cerebral microbleeds. The pattern of cognitive impairment usually shows prominent executive dysfunction and information processing speed. Diagnosis depends on family history, characteristic clinical features, and characterised MRI markers, and is confirmed by genetic testing, made much simpler with newer gene arrays. Although there is little evidence based management, recent European Neurological Association guidelines provide a useful management framework. Increasing evidence has implicated a key role of disruption in the matrisome and extracellular matrix (ECM) of the small perforating arteries within the brain in disease pathogenesis, with disruption in different genes converging on shared pathways. Recent evidence suggests that more common variants in the same genes can predispose to sporadic younger onset stroke and dementia. Interestingly study of community cohorts has demonstrated that the mutations causing familial SVD are much commoner in the general population than would be expected from familial SVD prevalence. Why mutations sometimes result in early onset disease and on other occasions do not is still being investigated. However these population variants have also been associated with an increased risk of sporadic stroke and sporadic vascular dementia.

Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs.

Cross-hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is a relatively common, non-allergic, adverse drug event triggered by two or more chemically unrelated NSAIDs. Current evidence point to COX-1 inhibition as one of the main factors in its etiopathogenesis. Evidence also suggests that the risk is dose-dependent. Therefore it could be speculated that individuals with impaired NSAID biodisposition might be at increased risk of developing cross-hypersensitivity to NSAIDs. We analyzed common functional gene variants for CYP2C8, CYP2C9, and CYP2C19 in a large cohort composed of 499 patients with cross-hypersensitivity to NSAIDs and 624 healthy individuals who tolerated NSAIDs. Patients were analyzed as a whole group and subdivided in three groups according to the main enzymes involved in the metabolism of the culprit drugs as follows: CYP2C9, aceclofenac, indomethacin, naproxen, piroxicam, meloxicam, lornoxicam, and celecoxib; CYP2C8 plus CYP2C9, ibuprofen and diclofenac; CYP2C19 plus CYP2C9, metamizole. Genotype calls ranged from 94 to 99%. No statistically significant differences between patients and controls were identified in this study, either for allele frequencies, diplotypes, or inferred phenotypes. After patient stratification according to the enzymes involved in the metabolism of the culprit drugs, or according to the clinical presentation of the hypersensitivity reaction, we identified weak significant associations of a lower frequency (as compared to that of control subjects) of CYP2C8*3/*3 genotypes in patients receiving NSAIDs that are predominantly CYP2C9 substrates, and in patients with NSAIDs-exacerbated cutaneous disease. However, these associations lost significance after False Discovery Rate correction for multiple comparisons. Taking together these findings and the statistical power of this cohort, we conclude that there is no evidence of a major implication of the major functional CYP2C polymorphisms analyzed in this study and the risk of developing cross-hypersensitivity to NSAIDs. This argues against the hypothesis of a dose-dependent COX-1 inhibition as the main underlying mechanism for this adverse drug event and suggests that pre-emptive genotyping aiming at drug selection should have a low practical utility for cross-hypersensitivity to NSAIDs.

APOE Genotype Modifies the Plasma Oxylipin Response to Omega-3 Polyunsaturated Fatty Acid Supplementation in Healthy Individuals

The omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), mediate inflammation in large part by affecting pro-inflammatory and anti-inflammatory/pro-resolving oxylipin concentrations. Common gene variants are thought to underlie the large inter-individual variation in oxylipin levels in response to n-3 PUFA supplementation, which in turn is likely to contribute to the overall heterogeneity in response to n-3 PUFA intervention. Given its known role in inflammation and as a modulator of the physiological response to EPA and DHA, here we explore, for the first time, the differential response of plasma hydroxy-, epoxy- and dihydroxy-arachidonic acid, EPA and DHA oxylipins according to apolipoprotein E (APOE) genotype using samples from a dose-response parallel design RCT. Healthy participants were given doses of EPA+DHA equivalent to intakes of 1, 2, and 4 portions of oily fish per week for 12 months. There was no difference in the plasma levels of EPA, DHA or ARA between the wildtype APOE3/E3 and APOE4 carrier groups after 3 or 12 months of n-3 PUFA supplementation. At 12 months, hydroxy EPAs (HEPEs) and hydroxy-DHAs (HDHAs) were higher in APOE4 carriers, with the difference most evident at the highest EPA+DHA intake. A significant APOE*n-3 PUFA dose effect was observed for the CYP-ω hydroxylase products 19-HEPE (p = 0.027) and 20-HEPE (p = 0.011). 8-HEPE, which, along with several other plasma oxylipins, is an activator of peroxisome proliferator activated receptors (PPARs), showed the highest fold change in APOE4 carriers (14-fold) compared to APOE3/E3 (4-fold) (p = 0.014). Low basal plasma EPA levels (EPA < 0.85% of total fatty acids) were associated with a greater change in 5-HEPE, 9-HEPE, 11-HEPE, and 20-HEPE compared to high basal EPA levels (EPA > 1.22% of total fatty acids). In conclusion, APOE genotype modulated the plasma oxylipin response to increased EPA+DHA intake, with APOE4 carriers presenting with the greatest increases following high dose n-3 PUFA supplementation for 12 months.