Specific Gene Variants Research Articles

Genomic insights into mRNA COVID-19 vaccines efficacy: Linking genetic polymorphisms to waning immunity

ABSTRACT Genetic polymorphisms have been linked to the differential waning of vaccine-induced immunity against COVID-19 following vaccination. Despite this, evidence on the mechanisms behind this waning and its implications for vaccination policy remains limited. We hypothesize that specific gene variants may modulate the development of vaccine-initiated immunity, leading to impaired immune function. This study investigates genetic determinants influencing the sustainability of immunity post-mRNA vaccination through a genome-wide association study (GWAS). Utilizing a hospital-based, test negative case-control design, we enrolled 1,119 participants from the Taiwan Precision Medicine Initiative (TPMI) cohort, all of whom completed a full mRNA COVID-19 vaccination regimen and underwent PCR testing during the Omicron outbreak. Participants were classified into breakthrough and protected groups based on PCR results. Genetic samples were analyzed using SNP arrays with rigorous quality control. Cox regression identified significant single nucleotide polymorphisms (SNPs) associated with breakthrough infections, affecting 743 genes involved in processes such as antigenic protein translation, B cell activation, and T cell function. Key genes identified include CD247, TRPV1, MYH9, CCL16, and RPTOR, which are vital for immune responses. Polygenic risk score (PRS) analysis revealed that individuals with higher PRS are at greater risk of breakthrough infections post-vaccination, demonstrating a high predictability (AUC = 0.787) in validating population. This finding confirms the significant influence of genetic variations on the durability of immune responses and vaccine effectiveness. This study highlights the importance of considering genetic polymorphisms in evaluating vaccine-induced immunity and proposes potential personalized vaccination strategies by tailoring regimens to individual genetic profiles.

Whole-exome sequencing uncovers the genetic complexity of bicuspid aortic valve in families with early-onset complications

Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with moderate or strong supportive evidence to cause developmental cardiac phenotypes were present in 107 EBAV-affected families (50% of total), including genes that cause BAV (9%) or heritable thoracic aortic disease (HTAD, 19%). After appropriate filtration, we also identified 129 variants in 54 candidate genes that are associated with autosomal-dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants drive early-onset presentations of BAV disease.

Identification of Pathogenic Pathways for Recurrence of Focal Segmental Glomerulosclerosis after Kidney Transplantation.

Primary focal segmental glomerulosclerosis (FSGS) is a disease of the podocytes and glomerulus, leading to nephrotic syndrome and progressive loss of renal function. One of the most serious aspects is its recurrence of disease in over 30% of patients following allogeneic kidney transplantation, leading to early graft loss. This research investigates the individual genetic predispositions and differences in the immune responses leading to recurrence of FSGS after transplantation. We performed exome sequencing on six patients with recurrent FSGS to identify variants in fifty-one genes and found significant variations in the alpha-2-macroglobulin (A2M). Immunoblotting was used to investigate effects of specific gene variants at the protein level. Further expression analysis identified A2M, exophilin 5 (EXPH5) and plectin (PLEC) as specific proteins linked to podocytes, endothelial cells, and the glomerulus. Subsequent protein array screening revealed the presence of non-HLA-specific antibodies, including TRIM21, after transplantation. Using Metascape for pathway and process enrichment analysis, we focused on the IL-17 signaling and chemotaxis pathways. ELISA measurements showed significantly elevated IL-17 levels in patients with recurrent FSGS (32.30 ± 9.12 pg/mL) compared to individuals with other glomerular diseases (23.16 ± 2.49 pg/mL; p < 0.01) and healthy subjects (22.28 ± 0.94 pg/mL; p < 0.01), with no significant difference in plasma CCL2/MCP-1 levels between groups. This study explores the molecular dynamics underlying recurrence of FSGS after transplantation, offering insights into potential biomarkers and therapeutic targets for the future development of individualized treatments for transplant patients.

Gene-gene and gene-environmental interaction of dopaminergic system genes in Pakistani children with attention deficit hyperactivity disorder

BackgroundAttention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder influenced by genetic and environmental factors. This study examined the specific gene variants, dopamine transporter 1 (DAT1) rs6350, dopamine receptor D3 (DRD3) rs6280, dopamine receptor D2 (DRD2) rs6277, and catechol-O-methyltransferase (COMT) rs4633, in relation to ADHD among Pakistani children by exploring the potential gene-gene and gene-environment interactions. MethodsA total of 100 cases of ADHD and 100 healthy children were recruited. The tetra-primer amplification refractory mutation system (ARMS) assays were designed for genotyping the selected variants in both groups, and their association with ADHD was determined in different genetic models. Gene-gene and gene-environmental interactions were determined by the multifactor dimensionality reduction (MDR) method. ResultsThe DAT1 rs6350 SNV AA genotype showed a significantly increased risk for ADHD in the codominant and recessive models. Conversely, the AG genotype demonstrated a protective factor for ADHD in the codominant and overdominant models. The DRD3 rs6280 T allele exhibited a decreased risk for ADHD, and the TT genotype showed a reduced risk in the recessive and log-additive models. No association between the DRD2 rs6277 and COMT rs4633 SNVs with ADHD was found in our population. The MDR analysis of the best three-fold interaction model showed redundancy between DAT1 rs6350 and DRD3 rs6280; however, the risk was increased with the gender variable, which showed a weak synergistic interaction with these SNVs. ConclusionGenes associated with dopaminergic neurotransmission may contribute to the occurrence of ADHD. Furthermore, gene-gene and gene-environmental interactions may increase ADHD susceptibility.

Carrier screening for 223 monogenic diseases in Chinese population: a multi-center study in 33 104 individuals

To investigate the epidemiological characteristics and mutation spectrum of monogenic diseases in Chinese population through a large-scale, multicenter carrier screening. This study was conducted among a total of 33 104 participants (16 610 females) from 12 clinical centers across China.Carrier status for 223 genes was analyzed using high-throughput sequencing and different PCR methods. The overall combined carrier frequency was 55.58% for 197 autosomal genes and 1.84% for 26 X-linked genes in these participants.Among the 16 669 families, 874 at-risk couples (5.24%) were identified.Specifically, 584 couples (3.50%) were at risk for autosomal genes, 306(1.84%) for X-linked genes, and 16 for both autosomal and X-linked genes.The most frequently detected autosomal at-risk genes included GJB2(autosomal recessive deafness type 1A, 393 couples), HBA1/HBA2(α-thalassemia, 36 couples), PAH (phenylketonuria, 14 couples), and SMN1(spinal muscular atrophy, 14 couples).The most frequently detected X-linked at-risk genes were G6PD (G6PD deficiency, 236 couples), DMD (Duchenne muscular dystrophy, 23 couples), and FMR1(fragile X syndrome, 17 couples).After excluding GJB2 c.109G>A, the detection rate of at-risk couples was 3.91%(651/16 669), which was lowered to 1.72%(287/16 669) after further excluding G6PD.The theoretical incidence rate of severe monogenic birth defects was approximately 4.35‰(72.5/16 669).Screening for a battery of the top 22 most frequent genes in the at-risk couples could detect over 95% of at-risk couples, while screening for the top 54 genes further increased the detection rate to over 99%. This study reveals the carrier frequencies of 223 monogenic genetic disorders in the Chinese population and provides evidence for carrier screening strategy development and panel design tailored to the Chinese population.In carrier testing, genetic counseling for specific genes or gene variants can be challenging, and the couples need to be informed of these difficulties before testing and provided with options for not screening these genes or gene variants.

Variations in the LINGO2 and GLIS3 Genes and Gene-Environment Interactions Increase Gestational Diabetes Mellitus Risk in Chinese Women.

Gestational diabetes mellitus (GDM) has been found to be a common complication in pregnant women, known to escalate the risk of negative obstetric outcomes. In our study, we genotyped 1,566 Chinese pregnant women for two single nucleotide polymorphisms (SNPs) in the LINGO2 gene and one SNP in the GLIS3 gene, utilizing targeted next-generation sequencing. The impact of two interacting genes, and the interaction of genes with the environment─including exposure to particulate matter (PM2.5), ozone (O3), and variations in prepregnancy body mass index (BMI)─on the incidence of GDM were analyzed using logistic regression. Our findings identify the variants LINGO2 rs10968576 (P = 0.022, OR = 1.224) and rs1412239 (P = 0.018, OR = 1.231), as well as GLIS3 rs10814916 (P = 0.028, OR = 1.172), as risk mutations significantly linked to increased susceptibility to GDM. Further analysis underscores the crucial role of gene-gene and gene-environment interactions in the development of GDM among Chinese women (P < 0.05). Particularly, the individuals carrying the rs10968576 G-rs1412239 G-rs10814916 C haplotype exhibit increased susceptibility to GDM during the prepregnancy period when interacting with PM2.5, O3, and BMI (P = 8.004 × 10-7, OR = 1.206; P = 6.3264 × 10-11, OR = 1.280; P = 9.928 × 10-7, OR = 1.334, respectively). In conclusion, our research emphasizes the importance of the interaction between specific gene variations─LINGO2 and GLIS3─and environmental factors in influencing GDM risk. Notably, we found significant associations between these gene variations and GDM risk across various environmental exposure periods.

NGS panels' capture of biomarkers associated with targeted therapies in clinical trials.

e13508 Background: ASCO and NCCN guidelines strongly encourage participation in clinical trials though participation rates remain low. Although up to 60% of trials require biomarker information as a prerequisite to participation, guidelines are silent on biomarker testing to assess eligibility. To help inform policy development, we analyzed commercially available NGS panels to assess the capture rate of the specific gene variants required for targeted therapies in clinical trials. Methods: Publicly available gene variant information on 12 high volume NGS tissue and plasma commercial assays representative of panel size was accessed. The JAX-CKB database was queried to identify genomic prerequisites in active phase I-III clinical trials; mRNA and protein expression biomarkers were excluded. We used unpaired t-testing to compare the ability of large versus small panels to detect variants required for targeted treatments. (Somatic gene variant annotations and related content have been powered by The Jackson Laboratory Clinical Knowledgebase (JAX-CKBTM)). Results: Overall, 185 genes were linked to eligibility for targeted therapies in clinical trials (Table). Large panel assays (&gt;80 genes) had a higher average capture rate compared to smaller panels, (84% vs. 46%, p value &lt; 0.000002). Similarly, capture rates in select cancers were higher in larger panels: lung (85% vs 59%), breast (92% vs 54%), prostate (86% vs 34%), pancreatic (84% vs 54%), colorectal (88% vs 52%). All results were statistically significant (p &lt; 0.05). Smaller panels were more likely to exclude large genes (e.g. BRCA), genome-wide signatures (e.g. TMB), fusions, and copy number variants. Conclusions: NGS-based panels with more than 80 genes had higher capture rates for biomarkers required for clinical trials of targeted therapies. Clinicians searching for all relevant treatment options for patients should include large genomic sequencing panels to maximize identification of potential clinical trial eligibility. Professional societies and policy makers interested in enhancing clinical trial enrollment rates should consider the panel size-related variability in capture rates of genetic variants when developing recommendations. [Table: see text]

Exploring the Biological Overlapping Between Brain Calcifications and Tumorgenesis.

This article discusses a rare case of coexistent meningiomas and Primary familial brain calcification (PFBC). PFBC is a neurodegenerative disease characterized by brain calcifications and a variety of neuropsychiatric symptoms and signs, with pathogenic variants in specific genes. The study explores the potential link between PFBC and meningiomas, highlighting shared features like intralesional calcifications and common genes such as MEA6. The article also revisits PFBC patients developing other brain tumors, particularly gliomas, emphasizing the intersection of oncogenes like PDGFB and PDGFRB in both calcifications and tumor progression. In recent investigations, attention has extended beyond brain tumors to breast cancer metastasis, unveiling a noteworthy connection. These findings suggest a broader connection between brain calcifications and tumors, encouraging a reevaluation of therapeutic approaches for PFBC.

Abstract PO3-08-03: Comparing prognosis for BRCA1, BRCA2 and non-BRCA breast cancer

Abstract BACKGROUND Breast Cancer (BC) is the most diagnosed malignancy and the leading cause of cancer death in women worldwide. Approximately 10% of BC cases are hereditary, and up to 25% have been linked to germline variants of specific genes. Germline pathogenic variants (PV) in BRCA1 and BRCA2 genes, which account for 20% of familial BC cases, are highly penetrant and are associated with Hereditary Breast/Ovarian Cancer Syndrome. BRCA1 e BRCA2 are tumor suppressor genes, which interact with recombination/DNA repair proteins in pathways that participate in preserving intact chromosome structure, particularly on the DNA double chain. So far, more than 7000 PV were identified on these genes, including the Portuguese founder mutation (BRCA2 c.156_157insAlu), which accounts for a great proportion of BC cases in our country. BRCA1 and BRCA2 associated BC have distinct clinicopathological characteristics. Long-term follow-up data related to prognosis and survival of either BRCA1 or BRCA2 BC patients is conflicting. Two large meta-analysis report worse overall survival for both, when compared to sporadic BC, whereas two other large meta-analysis concluded on worse overall survival only for BRCA1 patients, with similar overall survival for BRCA2 patients. One meta-analysis reports similar survival for both groups. We report the analysis of our cohort of BRCA1/2 BC patients included in our multidisciplinary program. Our goal is to compare clinicopathological characteristics and prognosis between BRCA1 and BRCA2 BC and with a control group without germline PV (non-BRCA). METHODS Prospective follow-up was proposed to patients with a diagnosed BRCA1/2 PV. This study included BRCA1/2 patients with BC as first cancer diagnosis, observed between January 2000-May 2023. A control group, with similar phenotype and histological characteristics, without germline PV was used. Statistical analysis was performed to compare characteristics and prognosis between BRCA1 and BRCA2 and non-BRCA BC. ANOVA test was used to compare the age at diagnosis; chi-square was used to compare categorical variables, such as histological subtype and clinical staging at diagnosis; log rank was used to compare the primary and secondary endpoints – overall survival (OS) and invasive disease-free survival (iDFS), respectively. RESULTS From 1077 individuals who tested positive for BRCA1/2 PV, 345 patients had BC, mostly with a BRCA2 PV (66.4%). A control group of 339 individuals was assembled. BRCA2 BC was mostly luminal, as non-BRCA patients, compared with BRCA1 (73.8% vs. 65.8% vs. 25.9%, p&amp;lt; 0.001) and BRCA1 was mostly triple negative, compared with non-BRCA and BRCA2 (65.5% vs. 16.5% vs. 13.3%, p&amp;lt; 0.001). For a mean follow-up time of 10.6 years (±5.6), recurrence was similar, with central nervous system (CNS) metastases being more frequent for BRCA1 (66.7% vs. 23.7% in non-BRCA, and vs. 9.1% in BRCA2, p&amp;lt; 0.001), and bone metastases were predominant for BRCA2 BC (57.5% vs 33.3% in non-BRCA, and vs. 9.1% in BRCA1, p=0.003). Non-BRCA BC showed longer time to recurrence (99.3 months vs. 76.5 months in BRCA2 BC, and vs. 61.2 months in BRCA1 BC, p=0.010), although longer OS was observed in BRCA2 BC (136.2 months vs. 121.7 months in BRCA1 BC, and vs. 113.2 months in non-BRCA, p&amp;lt; 0.001). Development of second primary tumors was more frequent in BRCA2 patients, compared with BRCA1 (20.9% vs 9.2%, p=0.002). DISCUSSION In the Portuguese population, BRCA2 BC is more frequent than BRCA1 BC. Relapses occurred later for BRCA2 BC, affecting mostly the bone, whereas BRCA1 BC relapsed in CNS. As it is stated in the literature, BRCA1 BC is consistent with triple negative, as BRCA2 BC is more associated with luminal subtype. Differences in iDFS favored non-BRCA patients, whereas OS was significantly improved in BRCA2 BC patients. This is the biggest cohort presented in the Portuguese population and one of the biggest presenting BRCA2 BC patients. Table 1 Characteristics of patients according to BRCA1/2 mutation status (n = 684) Citation Format: Pedro Antunes Meireles, Catarina Bexiga, Sofia Fragoso, Sidónia Santos, Teresa Duarte, Fátima Vaz. Comparing prognosis for BRCA1, BRCA2 and non-BRCA breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-08-03.

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies.

Novel therapies for the treatment of familial dilated cardiomyopathy (DCM) are lacking. Shaping research directions to clinical needs is critical. Triggers for the progression of the disorder commonly occur due to specific gene variants that affect the production of sarcomeric/cytoskeletal proteins. Generally, these variants cause a decrease in tension by the myofilaments, resulting in signaling abnormalities within the micro-environment, which over time result in structural and functional maladaptations, leading to heart failure (HF). Current concepts support the hypothesis that the mutant sarcomere proteins induce a causal depression in the tension-time integral (TTI) of linear preparations of cardiac muscle. However, molecular mechanisms underlying tension generation particularly concerning mutant proteins and their impact on sarcomere molecular signaling are currently controversial. Thus, there is a need for clarification as to how mutant proteins affect sarcomere molecular signaling in the etiology and progression of DCM. A main topic in this controversy is the control of the number of tension-generating myosin heads reacting with the thin filament. One line of investigation proposes that this number is determined by changes in the ratio of myosin heads in a sequestered super-relaxed state (SRX) or in a disordered relaxed state (DRX) poised for force generation upon the Ca2+ activation of the thin filament. Contrasting evidence from nanometer-micrometer-scale X-ray diffraction in intact trabeculae indicates that the SRX/DRX states may have a lesser role. Instead, the proposal is that myosin heads are in a basal OFF state in relaxation then transfer to an ON state through a mechano-sensing mechanism induced during early thin filament activation and increasing thick filament strain. Recent evidence about the modulation of these mechanisms by protein phosphorylation has also introduced a need for reconsidering the control of tension. We discuss these mechanisms that lead to different ideas related to how tension is disturbed by levels of mutant sarcomere proteins linked to the expression of gene variants in the complex landscape of DCM. Resolving the various mechanisms and incorporating them into a unified concept is crucial for gaining a comprehensive understanding of DCM. This deeper understanding is not only important for diagnosis and treatment strategies with small molecules, but also for understanding the reciprocal signaling processes that occur between cardiac myocytes and their micro-environment. By unraveling these complexities, we can pave the way for improved therapeutic interventions for managing DCM.

ERAP1 and ERAP2 gene variants as potential clinical biomarkers of anti-interleukin-17A response in psoriasisvulgaris.

Interleukin (IL)-17A is a proinflammatory cytokine that plays an essential role in the development of psoriasis. Although treatment with anti-IL-17A monoclonal antibodies has demonstrated high efficacy in patients with psoriasis, not all patients respond equally well, highlighting the need for biomarkers to predict treatment response. Specific single-nucleotide polymorphisms (SNPs) in the genes encoding endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) have been associated with psoriasis and other immune-mediated diseases. To investigate the association between the ERAP1 and ERAP2 genotypes and response to secukinumab treatment in patients with psoriasis. In total, 75 patients with plaque psoriasis were included. All patients were genotyped for the ERAP1 rs27524, rs27044, rs30187, rs2287987 and rs26653 SNPs, the ERAP2 rs2248374 SNP, and the status of the human leucocyte antigen HLA-C*06:02 gene. Our results demonstrated that individuals with specific ERAP1 and ERAP2 genotypes had a considerably lower response rate to secukinumab treatment. Patients with the ERAP2 rs2248374 GG genotype had a more than sixfold increased risk of treatment failure compared with patients with the rs2248374 AG or AA genotypes. Stratifying for HLA-C*06:02 status, the ERAP2 GG genotype pointed towards an increased risk of treatment failure among HLA-C*06:02-positive patients, although this was not statistically significant. Taken together, this unique study breaks new ground by identifying distinct ERAP1 and ERAP2 gene variants that may serve as potential biomarkers for predicting the treatment response to secukinumab in patients with psoriasis. Notably, our data extend existing knowledge by linking specific ERAP1 and ERAP2 gene variants to treatment outcome.

Whole-Exome Sequencing (WES) Reveals Novel Sex-Specific Gene Variants in Non-Alcoholic Steatohepatitis (MASH).

Non-alcoholic steatohepatitis (NASH, also known as MASH) is a severe form of non-alcoholic fatty liver disease (NAFLD, also known as MASLD). Emerging data indicate that the progression of the disease to MASH is higher in postmenopausal women and that genetic susceptibility increases the risk of MASH-related cirrhosis. This study aimed to investigate the association between genetic polymorphisms in MASH and sexual dimorphism. We applied whole-exome sequencing (WES) to identify gene variants in 8 age-adjusted matched pairs of livers from both male and female patients. Sequencing alignment, variant calling, and annotation were performed using standard methods. Polymerase chain reaction (PCR) coupled with Sanger sequencing and immunoblot analysis were used to validate specific gene variants. cBioPortal and Gene Set Enrichment Analysis (GSEA) were used for actionable target analysis. We identified 148,881 gene variants, representing 57,121 and 50,150 variants in the female and male cohorts, respectively, of which 251 were highly significant and MASH sex-specific (p < 0.0286). Polymorphisms in CAPN14, SLC37A3, BAZ1A, SRP54, MYH11, ABCC1, and RNFT1 were highly expressed in male liver samples. In female samples, Polymorphisms in RGSL1, SLC17A2, HFE, NLRC5, ACTN4, SBF1, and ALPK2 were identified. A heterozygous variant 1151G>T located on 18q21.32 for ALPK2 (rs3809983) was validated by Sanger sequencing and expressed only in female samples. Immunoblot analysis confirmed that the protein level of β-catenin in female samples was 2-fold higher than normal, whereas ALPK2 expression was 0.5-fold lower than normal. No changes in the protein levels of either ALPK2 or β-catenin were observed in male samples. Our study suggests that the perturbation of canonical Wnt/β-catenin signaling observed in postmenopausal women with MASH could be the result of polymorphisms in ALPK2.

Understanding the Genetic and Non-genetic Interconnections in the Aetiology of Isolated Congenital Heart Disease: An Updated Review: Part 1.

Congenital heart disease (CHD) is the most frequently occurring birth defect. Majority of the earlier reviews focussed on the association of genetic factors with CHD. A few epidemiological studies provide convincing evidence for environmental factors in the causation of CHD. Although the multifactorial theory of gene-environment interaction is the prevailing explanation, explicit understanding of the biological mechanism(s) involved, remains obscure. Nonetheless, integration of all the information into one platform would enable us to better understand the collective risk implicated in CHD development. Great strides in novel genomic technologies namely, massive parallel sequencing, whole exome sequencing, multiomics studies supported by system-biology have greatly improved our understanding of the aetiology of CHD. Molecular genetic studies reveal that cardiac specific gene variants in transcription factors or signalling molecules, or structural proteins could cause CHD. Additionally, non-hereditary contributors such as exposure to teratogens, maternal nutrition, parental age and lifestyle factors also contribute to induce CHD. Moreover, DNA methylation and non-coding RNA are also correlated with CHD. Here, we inform that a complex combination of genetic, environmental and epigenetic factors interact to interfere with morphogenetic processes of cardiac development leading to CHD. It is important, not only to identify individual genetic and non-inherited risk factors but also to recognize which factors interact mutually, causing cardiac defects.

Personalization of treatment based on obesity phenotypes

Introduction:&#x0D; Obesity is a significant clinical problem worldwide. The disease exhibits remarkable heterogeneity, leading to diverse pathogenesis among individuals. Despite a growing selection of weight-reducing medications and increased awareness of the importance of a healthy lifestyle, the effectiveness of obesity therapy often remains insufficient. This raises the question of whether tailoring obesity pharmacotherapy to specific phenotypes and individual patient characteristics results in improved treatment outcomes.&#x0D; Objective:&#x0D; To review literature on the effectiveness of obesity treatment based on the personalization of pharmacotherapy according to its underlying causes.&#x0D; Current Knowledge:&#x0D; Currently, the early outcome of weight loss is closely linked to the long-term effectiveness of obesity pharmacotherapy. However, due to the diversity of obesity pathogenesis, it is not helpful in selecting therapy at the initiation of treatment. Specific characteristics are sought to indicate the appropriate drug during therapy planning.&#x0D; In a U.S. study (Acosta et al., 2021) results showed that phenotype-guided obesity pharmacotherapy resulted in clinically more significant absolute weight loss than in the non-phenotyped group.&#x0D; Other studies demonstrated that for very rare types of obesity dependent on specific genetic mutations, targeted treatment addressing these defects yielded the best therapeutic outcomes (recombinant human leptin therapy for patients with leptin gene mutation – Farooqi et al., 2002; setmelanotide therapy for individuals with proopiomelanocortin deficiency – Clément et al., 2020).&#x0D; The impact of specific gene variants on therapeutic response should also be considered, leading to variability in treatment effects for different patients using the same drug.&#x0D; Conclusion:&#x0D; The concept of basing therapy on obesity phenotypes may currently serve as a guide for treatment selection, although it still requires confirmation in randomized clinical trials.&#x0D;

RAS mutation specific survival in patients with metastatic colorectal cancer treated with trifluridine/tipiracil.

197 Background: Trifluridine/tipiracil (T/T) is effective in patients with pretreated metastatic colorectal cancer (mCRC). RAS mutational status could predict magnitude of T/T effect (van de Haar et al, Nat Med. 2023), but the data are conflicting. Methods: We retrospectively reviewed the clinical data of 402 patients consecutively treated with T/T in two institutions in the Czech Republic and analysed the potential predictive value of different RAS mutations. Results: Baseline characteristics: median age 65 (range 28-84), female 32.8%, ECOG PS 0 in 32.8% and 1 in 64.9%, primary tumor location left colon in 76.3%. The median line in which T/T was administered was 3 (range 2-8). Median number of T/T cycles administered was 3 (range 2-27). Median follow-up was 32.4 months, 358 patients died (89.1%). Overall survival (OS) was 9.3 months (95% CI 8.7 to 10.3) and progression-free survival (PFS) 3.5 months (3.2 to 3.6). RAS mutation was detected in 54.2% patients. KRAS G12 mutation was found in 117 patients (29.1%), KRAS G13 in 19 (4.7%), other RAS mutation in 25 (6.2%), non-specified RAS mutation in 57 (14.2%), and BRAF mutation in 14 (4.8%). No difference in OS in RAS wildtype (wt) vs mutated group (P=.50) was observed. OS in the defined groups was found: wtRAS group (9.1 months), KRAS G12 (9.1 m), KRAS G13 (5.6 m), and other RAS mutations (10.6 m, P=.180). Patients with KRAS G13 had worse OS vs all other patients (P=.029; HR 1.97), vs wt (P=.02; HR 2.08), vs other mutated (P=0.067; HR 1.75), vs KRAS G12 mutated patients (P=.069; HR 1.75). Patients with KRAS G12 had no OS difference vs other groups of patients. In KRAS G12 group we found that specific gene variants have different OS (for G12C, 7 patients, OS was 6.0 months; for G12D, 41 patients, 9.0 m; for G12V, 45 patients, 10.5 m; for G12S, 7 patients, 16.1 m; for G12A, 11 patients, 7.6; other G12 variants, 5 patients, 10.0 months, P=.028). BRAF mutation was associated with worse OS (6.6 vs 9.1 months, P=.02, HR 2.46). Conclusions: We did not confirm the negative predictive value of KRAS G12 mutation in patients treated with T/T, however, OS depends on the specific G12 mutation. In contrast, patients with KRAS G13 mutation had worse survival.

Novel Pathogenic Variants in POLR3K Cause POLR3‐Related Leukodystrophy

POLR3‐related hypomyelinating leukodystrophy (POLR3‐HLD) is a rare inherited neurological disorder caused by biallelic pathogenic variants in specific genes encoding subunits of RNA polymerase III (Pol III). Here, we report the third patient worldwide with pathogenic variants in POLR3K and clinical features consistent with POLR3‐HLD. The female patient presented with mild intellectual and behavioural disturbances in childhood, as well as growth delay, with brain MRI revealing diffuse hypomyelination and a pattern consistent with POLR3‐HLD. In adolescence, she manifested minor motor dysfunction. Next‐generation sequencing revealed a paternally inherited missense variant in POLR3K (c.322G&gt;T; p.D108Y) and a maternally inherited large deletion, spanning approximately 17.8 kb from chr16:30,362‐48,162. The missense variant is located at the C‐terminus position of the protein and is predicted to impair residue interactions and cause steric interference in enzyme conformational changes. The large deletion encompasses the third and last exon of POLR3K, leading to a likely amorphic truncated protein product lacking the final 42 amino acids from the total 108 amino acid–length protein. Studies of RNA‐level expression showed a significant reduction in the levels of POLR3K RNA in the patient compared to the control. In considering whether the transcriptional function of Pol III was affected, the expression of several Pol III‐transcribed RNAs was measured, where the levels of several distinct tRNAs were significantly reduced in the patient while the expression of other RNA transcripts was not decreased, suggesting that Pol III retains partial function. This study provides further evidence for the association of pathogenic variants in POLR3K with POLR3‐HLD, expanding the spectrum of pathogenic variants in genes encoding for Pol III subunits associated with this disease.

Impact of single-nucleotide variants and individual characteristics on adverse events of L-asparaginase in children with acute lymphoblastic leukemia.

L-Asparaginase (L-Asp) is a key drug in the treatment of acute lymphoblastic leukemia (ALL); however, it is commonly associated with the occurrence of adverse events (AE). Risk factors such as age, sex, nutritional status, and some single nucleotide variants (SNVs) in specific genes could be related to hypersensitivity reactions to L-Asp. The objective of this study was to identify the influence of individual characteristics and three SNVs in the GRIA1 and NFATC2 genes on the occurrence of the most significant adverse events caused by the use of L-Asp in Mexican children with ALL. Eighty-five children from ages 0-17years old diagnosed with ALL were included. The patients were treated at two hospital centers in Mexico. The SNV genotypes of the GRI1A and NFATC2 genes studied were examined using real-time qPCR. The evaluation of AE was carried out according to the Common Terminology Criteria for adverse events, and the determination of anti-L-Asp antibodies was conducted using Western blot immunoassay. Homozygosity (AA) of the GRIA1 rs4958351 SNV was significantly associated with the occurrence of AE with the use of L-Asp (OR = 4.05; 95% CI = 1.06 to 15.40, p = 0.04) and was strongly associated with the development of anti-L-Asp antibodies (OR = 3.4375, 95% CI = 1.04 to 11.25, p = 0.04). With this, we found a significant risk association for the SNV rs4958351 of the GRIA1 gene. On the other hand, we did not find significant risk associations for the GRIA1 rs6889909 and NFATC2 rs6021191 SNVs, although other populations have shown a significant risk. Our study has some limitations, such as the small sample size, the heterogeneity in adverse events due to the patients' different regions of origin, and the limited ability to conduct a more detailed follow-up on pancreatitis. Additionally, since no significant associations were found between the NFATC2 rs6021191 and GRIA1 rs6889909 SNVs and the development of adverse events or the presence of antibodies due to the use of L-Asp, it is necessary to investigate new specific SNVs that may improve the efficacy and safety of treatment in Mexican children with ALL.

ЭМПИРИЧЕСКАЯ ТЕОРИЯ ФОРМИРОВАНИЯ ЭМОЦИОНАЛЬНОГО И ВОЛЕВОГО ДЕФИЦИТА ПРИ ШИЗОФРЕНИИ С ПРЕОБЛАДАНИЕМ НЕГАТИВНЫХ РАССТРОЙСТВ, ПОЛУЧЕННАЯ НА ОСНОВЕ АНАЛИЗА СВЯЗИ КЛИНИЧЕСКИХ И ГЕНЕТИЧЕСКИХ ДАННЫХ С ПРИМЕНЕНИЕМ ДСМ-МЕТОДА АВТОМАТИЗИРОВАННОЙ ПОДДЕРЖКИ ИССЛЕДОВАНИЙ

The study attempted to test experts' assumptions about the difference in the genetic mechanisms of the formation of emotional and volitional deficits in schizophrenia with predominance of negative disorders. The aim of the study is to create empirical theory of these two phenomena using an approach based on JSM-method for automated research support (JSM-method ARS). Polymorphisms of four genes associated with schizophrenia (BDNF, 5HTR2A, HTTLPR, ZNF804A) and clinical data presented as PANSS score were used as empirical data. The use of generalized JSM-method ARS, which generates ternary relationships “cause-blocker-effect”, allows us considering in detail the interaction of specific gene variants for emotional and volitional deficits in negative schizophrenia. The result of the study is confirmation of the experts' hypothesis about the difference in the mechanisms of these clinical manifestations. This conclusion was based on a comparison of knowledge fragments for two phenomena. The utilized approach can be extrapolated to a larger number of genes. We suggest that the use of the generalized JSM-method ARS is a promising approach to studying gene interactions in schizophrenia.

Estimating the efficacy of pharmacogenomics over a lifetime.

It is well known that common variants in specific genes influence drug metabolism and response, but it is currently unknown what fraction of patients are given prescriptions over a lifetime that could be contraindicated by their pharmacogenomic profiles. To determine the clinical utility of pharmacogenomics over a lifetime in a general patient population, we sequenced the genomes of 300 deceased Marshfield Clinic patients linked to lifelong medical records. Genetic variants in 33 pharmacogenes were evaluated for their lifetime impact on drug prescribing using extensive electronic health records. Results show that 93% of the 300 deceased patients carried clinically relevant variants. Nearly 80% were prescribed approximately three medications on average that may have been impacted by these variants. Longitudinal data suggested that the optimal age for pharmacogenomic testing was prior to age 50, but the optimal age is greatly influenced by the stability of the population in the healthcare system. This study emphasizes the broad clinical impact of pharmacogenomic testing over a lifetime and demonstrates the potential application of genomic medicine in a general patient population for the advancement of precision medicine.

Genotype Prevalence of Lactose Deficiency, Vitamin D Deficiency, and the Vitamin D Receptor in a Chilean Inflammatory Bowel Disease Cohort: Insights from an Observational Study.

Lactose intolerance (LI) and vitamin D deficiency (VDD) have been linked to inflammatory bowel disease (IBD). We conducted an observational study in 192 Chilean IBD patients to investigate the prevalence of a specific gene variant (LCT-13910 CC genotype) associated with LI and the prevalence of VDD/Vitamin D Receptor (VDR) gene variants. Blood samples were analyzed using Illumina's Infinium Global Screening Array. The LCT-13910 CC genotype was found in 61% of IBD patients, similar to Chilean Hispanic controls and lower than Chilean Amerindian controls. The frequency of the LCT-13910-C allele in Chilean IBD patients (0.79) was comparable to the general population and higher than Europeans (0.49). Regarding VDR and VDD variants, in our study, the rs12785878-GG variant was associated with an increased risk of IBD (OR = 2.64, CI = 1.61-4.32; p-value = 0.001). Sixty-one percent of the Chilean IBD cohort have a genetic predisposition to lactose malabsorption, and a significant proportion exhibit genetic variants associated with VDD/VDR. Screening for LI and VDD is crucial in this Latin American IBD population.