Suggestive genome-wide associations with inflammatory biomarkers in an admixed population, including a missense variant in the OR6K6 olfactory receptor gene associated with MCP-1
Aug 2026· Frontiers in Immunology· Vol 17· 0 citations· 44 references
Medicine
TL;DR
New SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population are identified, including a missense variant in an olfactory receptor gene linked to MCP-1, which may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.
Abstract
Background Chronic low-grade inflammation drives cardiometabolic diseases and has a strong genetic basis. Most genome-wide association studies (GWAS) have focused on European populations, limiting knowledge of the genetic influences on inflammation in admixed populations such as those in Brazil. Methods This study is part of the cross-sectional ISA Capital Health Survey. It uses data from the 2015 ISA Nutrition cohort, which measured biochemical, genetic, anthropometric, and lifestyle factors in a probabilistic sample of São Paulo residents. Genomic DNA was extracted from 841 individuals. Genotyping was performed using the Axiom 2.0 Precision Medicine Research Array. After quality control and missing data exclusion, 244,338 SNPs from 638 individuals remained for GWAS-based association analysis with eight inflammatory biomarkers. Models were adjusted for sex, age, age2, overweight, and the first two principal components of ancestry. Results Most participants were male (53%) and not overweight (55%). The median age was 49, and 38% were older adults. In the genome-wide analysis of TNF-α, IL-10, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and adiponectin, 12 SNPs were significantly associated, most of which were intronic. Notably, one signal mapped to the missense variant rs16841009 in the olfactory receptor gene OR6K6. This variant was associated with MCP-1, suggesting a possible involvement in inflammatory responses. Conclusions We identified new SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population, including a missense variant in an olfactory receptor gene linked to MCP-1. This association may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.
BACKGROUND
Hepatic steatosis is a highly prevalent metabolic condition and a major contributor to chronic liver disease, particularly in Asian populations. This study was conducted to identify genetic variants associated with the severity of ultrasound-defined hepatic steatosis in a Taiwanese Han population and evaluate the variants' biological relevance through cross-ancestry meta-analysis and functional validation.
METHODS
We conducted a genome-wide association study (GWAS) of 133,895 individuals with data in the Genetic Biobank of China Medical University Hospital. Hepatic steatosis severity was graded on an ordinal scale (0-3) using standardised ultrasonographic criteria. The polygenic risk score (PRS) under continuous shrinkage (CS) approach was used to construct a PRS for genetic risk stratification across severity grades.
FINDINGS
In the GWAS, we identified 1,229 single-nucleotide polymorphisms associated with hepatic steatosis severity (P < 1 × 10⁻5), with the strongest signals discovered at the PNPLA3 locus (rs738408 and rs738409). The PRS-CS model exhibited strong discriminative performance (area under the receiver operating characteristic curve = 0.875) and a clear dose-response relationship with ultrasound-defined steatosis severity, substantially outperforming the risk model based on body mass index only. In vitro assays confirmed significantly increased lipid accumulation and intracellular triglyceride content in I148M-expressing hepatocytes under lipid-loading conditions.
INTERPRETATION
This study delineates the genetic landscape of ultrasound-defined hepatic steatosis severity in a large Taiwanese Han population and demonstrates the robust ability of the PRS to predict disease stage.
The authors' study identified putative actionable proteins that could reduce the elevated T2D risk attributable to childhood adiposity in Europeans, but their relevance in Asian populations requires further investigation.
Siyu Chen, Yiwen Liang, Shan Luo et al.· International Journal of Epi...· 0 citations
Background: Interindividual variability in intestinal cholesterol absorption contributes to differences in serum lipid concentrations and cardiovascular risk. Total cholesterol (TC)-standardized campesterol and sitosterol levels are established markers of cholesterol absorption. However, genetic variants in Europeans associated with these markers remain incompletely characterized. Methods: A genome-wide association study (GWAS) was performed in 398 healthy individuals of European ancestry. Samples were genotyped using the Precision Medicine Research Array (PMRA). After quality control, 166,037 common genetic variants with a minor allele frequency (MAF) > 20% were analyzed. Associations between genetic variants and intestinal cholesterol absorption markers (campesterol/TC and sitosterol/TC) were evaluated using additive and recessive genetic models. Results: A total of 16 SNPs were identified. Eight SNPs overlapped with both campesterol/TC and sitosterol/TC, of which 2 reached genome-wide significance. Six overlapping SNPs were associated with higher concentrations of both markers: 3 SNPs in ABCG8 (rs4299376, rs6544713, and rs4245791), 1 SNP in ADAM12 (rs4962526), and 2 SNPs in non-coding regions (rs260769 and rs5011112). Additionally, two SNPs (rs2033254 and rs12708980) in CETP were associated with lower concentrations of these markers. Five of the identified SNPs have not previously been linked to markers of intestinal cholesterol absorption. Conclusions: This GWAS confirmed previously reported associations within ABCG8 and identified candidate loci in CETP and ADAM12 that may be involved in intestinal cholesterol absorption. These findings contribute to our understanding of genetic factors underlying intestinal cholesterol absorption and highlight candidate loci for future replication and functional studies.
F. A. Mokhtar, Dina Nuwaylati, J. Plat et al.· Nutrients· 0 citations
This study illustrates that GWAS with high-scale imputation may still help to unravel the biological mechanism behind circulating lipid levels and identifies more new rare and low-frequency functional variants associated with circulating lipid levels.
E. V. van Leeuwen, A. Sabo, J. Bis et al.· 0 citations
BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder resulting from a complex interplay of multiple factors. Recent hypotheses suggest a potential role of selenium and selenoproteins in AD pathogenesis. However, the causality relationship between them remains to be elucidated.ObjectiveThis study investigates the causal link between selenoproteins and AD risk.MethodsWe analyzed the data by leveraging genome-wide association studies from European cohorts (90,338 AD patients and 1,036,225 controls) and expression quantitative trait loci (eQTLs) from eQTLGen (31,684 individuals) and GTEx v8 (838 individuals). Mendelian randomization and summary data-based Mendelian randomization were applied to assess the potential causal associations between selenoproteins and AD. To further confirm these genetic associations at the clinical level, we conducted a case-control study to evaluate the levels of four differentially expressed selenoproteins in peripheral blood in individuals with AD and cognitively normal controls.ResultsOur analysis revealed that four selenoproteins, including selenoprotein S (SEPH2) and selenoprotein M (SELENOM), glutathione peroxidase 4 (GPX4) and thioredoxin reductase 2 (TXNRD2), were correlated with a decreased risk of AD. The levels of GPX4, SELENOM, and TXNRD2 were found to be significantly downregulated in AD patients compared to controls in the case-control validation study, supporting the change identified in our genetic analysis.ConclusionsThis study provides genetic and clinical evidence that specific selenoproteins are associated with a decreased risk of AD. The findings highlight the potential role of these proteins in AD pathophysiology and suggest their promise as biomarkers or therapeutic targets, warranting further investigation.
Peixin Jiang, Sibo Peng, Yanling Huang et al.· Journal of Alzheimer's Disea...· 0 citations
Genomic analysis presented convincing evidence supporting the association between genetically predicted smoking initiation and an increased susceptibility to type 2 diabetes, highlighting the role of epigenetic DNA methylation.
Wenhua Li, Yixiao Li, Pan Dong et al.· Tobacco Induced Diseases· 0 citations
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