Aug 2026· European Heart Journal, Supplement· 0 citations
TL;DR
Findings indicate that the variant rs72705424 is associated with higher circulating PD-L1 levels and that elevated PD-L1 increases the risk of incident CVD, and highlight how genetic variation can affect circulating factors and the subsequent CVD risks.
Abstract
Immune checkpoint (IC) inhibitors have revolutionised the cancer field by targeting immunomodulatory properties of tumours. However, these targeted therapies are also known for their cardiotoxic effect. Immune checkpoint ligand, programmed death-ligand 1 (PD-L1), specifically, has been implicated in cardiac pathophysiology. Despite this, little is known about the impact of genetic variations on IC signalling and their contribution to cardiovascular disease (CVD). Therefore, we performed a large-scale biobank study examining the effect of a single nucleotide polymorphism (SNP) on protein expression and CVD outcomes.
First, 490 541 participants in the UK Biobank were genotyped using the pre-processed whole-genome sequencing files. Carriers of the PD-L1 (CD274) SNP were defined by having either one or two copies of the minor allele of the intronic variant rs72705424 (chr9: 5456083G>A) with a population allele frequency of 2%. The baseline plasma levels were determined through normalised protein expression values. After removing individuals with familial relations and of non-caucasian ethnicity, a 1:1 age- and sex-matched cohort (n=2430) of carriers and non-carriers was created. Associations between rs72705424 and PD-L1 plasma levels at baseline were assessed. Incident CVD (arrhythmia, coronary artery disease, cardiac inflammation and heart failure) was ascertained through the associated first CVD hospital diagnoses and dates. A cox proportional hazard model was fitted to evaluate the association between the scaled plasma PD-L1 levels and incident CVD, adjusted for age, sex, body mass index and c-reactive protein levels.
Carriers of the PD-L1 rs72705424 SNP exhibited a significant increase of baseline circulating PD-L1 levels compared to age- and sex-matched non-carriers (0.15 ± 0.39 vs. 0.15 ± 0.37, p = 6.36 × 10^-12)
Additionally, among all individuals with PD-L1 plasma measurements without CVD at baseline, elevated PD-L1 levels were associated with an increased risk of incident CVD, with a hazard ratio (HR) of 1.25 (confidence interval (CI): 1.22-1.27, p = 1.03 × 10^-112). After model adjustment, we observed a HR of 1.12 per standard deviation increase in PD-L1 (95% CI: 1.10-1.15, p = 1.30 × 10^-24).
These findings indicate that the variant rs72705424 is associated with higher circulating PD-L1 levels and that elevated PD-L1 increases the risk of incident CVD. Collectively, these results highlight how genetic variation can affect circulating factors and the subsequent CVD risks, underscoring the relevance of further investigation.
The GA genotype of rs5742621 was significantly associated with elevated IGF-1 levels and increased PCa risk, promoting cell proliferation, inhibiting apoptosis, and accelerating tumor growth.
Fatima Abdul Jabbar, R. AlChalabi, Russul AlObaidi et al.· Iraqi Journal of Science· 0 citations
Background Alcohol dependence and cirrhosis are key outcomes of increased alcohol use, with genetic factors increasingly implicated. A functional promoter variant (rs361525) in the TNF-α gene may contribute to ALD pathogenesis, while a loss-of-function variant (rs58542926) in TM6SF2 modifies liver disease progression. We aimed to study these SNPs and assess DNA methylation at TM6SF2 loci in individuals with and without alcohol-related cirrhosis. Methods The study included men (N = 243) with alcohol dependence with cirrhosis (AUD-C+ve) and without cirrhosis (AUD-C-ve), based on ICD-10 criteria, recruited from SJMCH. Fibroscan and/or sonography (LSM < 14 kPa) ruled out severe fibrosis. Genotyping was performed for TNFα (rs361525) and TM6SF2 (rs58542926). Genomic DNA (N = 100) underwent bisulfite conversion followed by pyrosequencing at TM6SF2 loci. Methylation levels were calculated separately for individual CpG sites and as the mean of four CpG sites. Group differences were assessed using unpaired t-tests, and genetic models were applied based on risk allele status. Results Genotype and allele frequencies at both loci were comparable between AUD-C+ve and AUD-C–ve groups. TM6SF2 methylation was significantly reduced in the AUD-C+ve group (uncorrected p = 0.03). A trend was also noted for TNF-genotype with A-carriers having lower TM6SF2 global methylation levels (p = 0.06). We did not observe any differences in genotype and allele frequencies for both TM6SF2 and TNFα variants. Duration of alcohol consumption was significantly associated with TM6SF2 methylation (p = 0.02). Conclusion TM6SF2 hypomethylation in AUD-C+ve individuals may influence lipid metabolism and contribute to liver injury and HCC progression. Reduced methylation among TNF-α risk allele carriers suggests a potential gene–epigenetic interaction. Overall, higher alcohol exposure and genetic susceptibility may together predispose to worsening alcohol-related cirrhosis.
B. Shankarappa, J. Mahadevan, Pratima Murthy et al.· Frontiers in Medicine· 0 citations
An important role of neuroinflammation in the pathogenesis of Parkinson’s disease (PD) has been proposed. Since some microRNAs (miRNAs), and miR-155 in particular, are involved in neuroinflammatory processes, a previous study reported an association between one of the most common single nucleotide variants (SNVs), rs767649, in the MIR155 gene, and risk for PD. The aim of the current study was to replicate this finding in a larger Spanish population case–control series. We analyzed genotype and allele frequencies of the MIR155 rs767649 SNV in a Spanish Caucasian cohort consisting of 459 PD patients and 460 age- and sex-matched healthy controls, using a TaqMan allelic discrimination assay specifically designed for rs767649. The genotype frequencies of the MIR155 rs767649, under codominant, dominant, recessive, and overdominant inheritance models, as well as allelic frequencies, showed no significant differences between PD patients and healthy controls. Likewise, the age at PD onset did not differ among the three MIR-155 rs767649 genotypes. These data did not identify a statistically significant association between MIR155 rs767649 variants and PD risk. However, the low frequency of the variant allele resulted in limited statistical power, and modest genetic effects cannot be excluded.
H. Alonso-Navarro, S. Ladera-Navarro, P. Ayuso et al.· International Journal of Mol...· 0 citations
Transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI), encoded by TNFRSF13B, plays a central role in B cell maturation and antibody responses through its interactions with BAFF and APRIL, with variants being linked to common variable immunodeficiency (CVID) and selective IgA deficiency. To characterise the clinical, immunological and genetic spectrum of these individuals, we recruited 30 participants (21 patients and nine family members) and classified patients into Group 1 (n = 16), carrying only TACI variants and Group 2 (n = 5), carrying both an IEI-related variant and an additional TACI variant. With a male/female ratio of 12/9, the median age was 2 years at symptom onset and 14 years at genetic diagnosis. Common clinical manifestations included recurrent infections (90%), autoimmune/inflammatory features (62%) and lymphoproliferation (57%). Twelve distinct TNFRSF13B mutations were identified, predominantly clustering in the cysteine-rich domain 2 (CRD2), with Cys104Arg being the most frequent (57%) variant. Immunophenotyping revealed decreased switched-memory and marginal zone B cells, reduced naïve CD4+ T cells and increased effector memory subsets. Notably, clinical and laboratory features overlapped between Groups 1 and 2, as well as between monoallelic and biallelic TNFRSF13B variant carriers. Patients with TNFRSF13B variants display broad phenotypic heterogeneity ranging from asymptomatic carriage to CVID and combined immunodeficiency phenotypes. Given the high polymorphism ratio and incomplete penetrance observed, TACI acts as both a genetic modifier and a monogenic disease-causing gene in this cohort, suggesting that coexisting genetic variants and exposomal factors likely determine the clinical expression and disease severity.
Begum Cicek, Deniz Ilgun Gurel, Ismail Yaz et al.· Immunology· 0 citations
The COVID-19 caused by SARS-CoV-2 has resulted in widely variable clinical outcomes. The virus relies on host metabolic pathways particularly the PI3K/AKT/mTOR axis, which regulate cell survival, metabolism, and viral replication. Genetic variants whitin this pathway may influence disease severity. This study evaluated variants in PI3K genes among 216 mild and 291 severe COVID-19 patients, focusing on rs3730089 (PIK3R1), rs785468 (PIK3R3), and rs11121484 (PIK3CD). Genotypes were evaluted in peripheral blood samples, inflammatory cytokines (IL-6 and TNF) were measured in plasma samples and immune cell profiles were assessed in peripheral blood mononuclear cells. The C allele of rs11121484 was associated with susceptibility to severe COVID-19, while rs785468 and rs3730089 were correlated with higher mortality risk. The presence of multiple risk alleles showed a cumulative effect on disease outcome. Patients with the GG genotype of rs3730089 had increased IL-6 levels, and carriers of risk alleles displayed reduced non-classic monocytes and CD4 + memory T cells. These findings indicate that PI3K single-nucleotide variants (SNVs) may exacerbate inflammation and immune dysregulation in COVID-19, contributing to severe outcomes. Overall, these results highlight a potential pathological role for PI3K SNVs in driving hyperinflammation in COVID-19 patients and may contributes to predicting the severe outcome of COVID-19 and better disease prognosis.
B. R. Tosta, João Victor Andrade Cruz, Ingrid Marins de Almeida et al.· Scientific Reports· 0 citations
