Populations Of European Descent Research Articles

The HLA region in ANCA-associated vasculitis: characterisation of genetic associations in a Scandinavian patient population

ObjectiveThe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci...

Genome-wide association study identifies DRAM1 associated with Tourette syndrome in Taiwan

BackgroundTourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Several susceptibility loci associated with TS have been identified previously in populations of European descent using genome-wide association studies (GWAS). However, the exact pathogenic mechanism underlying TS is unknown; additionally, the results of previous GWAS for TS were based on Western populations, which may not translate to other populations. Therefore, we conducted a GWAS in Taiwanese patients with TS and chronic tic disorders (CTDs), with an aim to elucidate the genetic basis and potential risk factors for TS in this population. MethodsGWAS was performed on a Taiwanese TS/CTDs cohort with a sample size of 1,007 patients with TS and 25,522 ancestry-matched controls. Additionally, polygenic risk score was calculated and assessed. ResultsGenome-wide significant locus, rs12313062 (p=1.43 × 10-8) and other 9 single nucleotide polymorphisms, were identified in chromosomes 12q23.2, associated with DRAM1 and was a novel susceptibility locus identified in TS/CTDs group. DRAM1, a lysosomal transmembrane protein regulated by p53, modulates autophagy and apoptosis, with potential implications for neuropsychiatric conditions associated with autophagy disruption. ConclusionsThis study conducted the first GWAS for TS in a Taiwanese population, identifying a significant locus on chromosome 12q23.2 associated with DRAM1. These findings provide novel insights into the neurobiology of TS and potential directions for future research in this area.

Vitamin D-associated genetic variants in the Brazilian population: Investigating potential instruments for Mendelian randomization

Introduction. Vitamin D is required for bone and mineral metabolism and participates in the regulation of the immune response. It is also linked to several chronic diseases and conditions, usually in populations of European descent. Brazil presents a high prevalence of vitamin D deficiency and insufficiency despite the widespread availability of sunlight in the country. Thus, it is important to investigate the role of vitamin D as a risk factor for disease and to establish causal relationships between vitamin D levels and health-related outcomes in the Brazilian population.Objective. To examine genetic variants identified as determinants of serum vitamin D in genome-wide association studies of European populations and check whether the same associations are present in Brazil. If so, these single nucleotide polymorphisms (SNPs) could be developed locally as proxies to use in genetically informed causal inference methods, such as Mendelian randomization.Materials and methods. We extracted SNPs associated with vitamin D from the genomewide association studies catalog. We did a literature search to select papers ascertaining these variants and vitamin D concentrations in Brazil.Results. GC was the gene with the strongest association with vitamin D levels, in agreement with existing findings in European populations. However, VDR was themost investigated gene, regardless of its non-existing association with vitamin D in the genomewide association studies.Conclusions. More research is needed to validate sound proxies for vitamin D levels in Brazil, for example, prioritizing GC rather than VDR.

Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights

BackgroundDystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those...

Oral microbiome research - working in partnership with Indigenous Australian communities.

Microbiome research is currently biased towards populations of European descent, with such populations providing a weak basis upon which to understand microbiome-health relationships in under-studied populations, many of whom carry the highest burdens of disease. Most oral microbiome studies to date have been undertaken in industrialized countries. Research involving marginalised populations should be shaped by a number of guiding principles. In the Indigenous Australian context, one useful framework is the Consolidated Criteria for Strengthening Reporting of Health Research involving Indigenous Peoples (CONSIDER) statement. This paper describes how the microbiome research field is having impacts in the Indigenous Australian health space, and describes a particular project involving Indigenous Australians in which the CONSIDER statement is used as the underlying framework.

Epigenetic modifications in solid tumor metastasis in people of African ancestry.

This review focuses on the critical role of epigenetic modifications in solid tumor metastasis, particularly in people of African ancestry. Epigenetic alterations, such as DNA methylation, histone modifications, alterations in non-coding RNAs, and mRNA methylation, significantly influence gene expression, contributing to cancer development and progression. Despite the primary focus on populations of European, American, and Asian descent in most cancer research, this work emphasizes the importance of studying the unique genetic and epigenetic landscapes of African populations for a more inclusive approach in understanding and treating cancer. Insights from this review have the potential to pave the way for the development of effective, tailored treatments, and provide a richer resource for understanding cancer progression and metastasis. Specific focus was placed on the role of DNA methylation, histone modifications, non-coding RNAs, and mRNA methylation in solid tumor metastasis, including how these modifications contribute to the regulation of tumor suppressor genes and oncogenes, influence cellular pathways and signaling, and interact with the immune system. Moreover, this review elaborates on the development of epigenetic-targeted therapeutic strategies and the current advances in this field, highlighting the promising applications of these therapies in improving outcomes for African ancestry populations disproportionately affected by certain types of cancer. Nevertheless, this work acknowledges the challenges that lie ahead, particularly the under-representation of African populations in cancer genomic and epigenomic studies and the technical complications associated with detecting subtle epigenetic modifications. Emphasis is placed on the necessity for more inclusive research practices, the development of more robust and sensitive methods for detecting and interpreting epigenetic changes, and the understanding of the interplay between genetic and epigenetic variations. The review concludes with an optimistic outlook on the future of epigenetic research in People of African ancestry, urging the concerted efforts of researchers, clinicians, funding agencies, and policymakers to extend the benefits of this research to all populations.

Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

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

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

Local Ancestry at the Major Histocompatibility Complex Region is Not a Major Contributor to Disease Heterogeneity in a Multiethnic Lupus Cohort.

Systemic lupus erythematosus (SLE) is an autoimmune disease resulting in debilitating clinical manifestations that vary in severity by race and ethnicity with a disproportionate burden in African American, Mestizo, and Asian populations compared with populations of European descent. Differences in global and local genetic ancestry may shed light on the underlying mechanisms contributing to these disparities, including increased prevalence of lupus nephritis, younger age of symptom onset, and presence of autoantibodies. A total of 1,139 European, African American, and Mestizos patients with SLE were genotyped using the Affymetrix LAT1 World array. Global ancestry proportions were estimated using ADMIXTURE, and local ancestry was estimated using RFMIXv2.0. We investigated associations between lupus nephritis, age at onset, and autoantibody status with both global and local ancestry proportions within the Major Histocompatibility Complex region. Our results showed small effect sizes that did not meet the threshold for statistical significance for global or local ancestry proportions in either African American or Mestizo patients with SLE who presented with the clinical manifestations of interest compared with those who did not. These findings suggest that local genetic ancestry within the Major Histocompatibility Complex region is not a major contributor to these SLE manifestations among patients with SLE from admixed populations.

Perspectives on genetic studies of type 2 diabetes from the genome-wide association studies era to precision medicine.

Genome-wide association studies (GWAS) have facilitated a substantial and rapid increase in the number of confirmed genetic susceptibility variants for complex diseases. Approximately 700 variants predisposing individuals to the risk for type 2 diabetes have been identified through GWAS until 2023. From 2018 to 2022, hundreds of type 2 diabetes susceptibility loci with smaller effect sizes were identified through large-scale GWAS with sample sizes of 200,000 to >1 million. The clinical translation of genetic information for type 2 diabetes includes the development of novel therapeutics and risk predictions. Although drug discovery based on loci identified in GWAS remains challenging owing to the difficulty of functional annotation, global efforts have been made to identify novel biological mechanisms and therapeutic targets by applying multi-omics approaches or searching for disease-associated coding variants in isolated founder populations. Polygenic risk scores (PRSs), comprising up to millions of associated variants, can identify individuals with higher disease risk than those in the general population. In populations of European descent, PRSs constructed from base GWAS data with a sample size of approximately 450,000 have predicted the onset of diseases well. However, European GWAS-derived PRSs have limited predictive performance in non-European populations. The predictive accuracy of a PRS largely depends on the sample size of the base GWAS data. The results of GWAS meta-analyses for multi-ethnic groups as base GWAS data and cross-population polygenic prediction methodology have been applied to establish a universal PRS applicable to small isolated ethnic populations.

Acquisition of cadavers for anatomy education and research in Malawi

BackgroundThe use of human cadaveric dissection forms an essential part of teaching anatomy to health sciences students in Malawi. Despite worldwide struggles in acquiring sufficient human cadavers for anatomy education, the current recommendations on the best anatomy practices require the use of cadavers exclusively from the body donation programs. The current study aims to describe the sources of cadaveric bodies used for anatomy education in the Malawian context and reflect on the feasibility of using cadavers from the body donation program only. MethodsA retrospective audit of the cadaveric records for the 2006–2022 academic years at the Kamuzu University of Health Sciences was done. The perceived challenges when sourcing the cadavers were identified and described based on the authors experiences in Malawi. ResultsThe majority (97.3%) of the cadavers used between 2006 and 2022 were unclaimed bodies. The mean age of the cadavers was 45 years. Most (95.6%) of the unclaimed bodies were males. All the unclaimed bodies were sourced from hospitals. The body donation program in Malawi was patronized by populations of European descent only. Strongly held sociocultural and religious beliefs as well as economic reasons were perceived as significant barriers to acquiring cadavers of the indigenous Malawians through the body donation program. ConclusionCadavers for anatomy education in Malawi are mainly from unclaimed bodies, similar to other African countries. The authors support the transition from using “mostly unclaimed bodies (and, less often, body donation)” to using “mostly body donation (and, less often, unclaimed bodies)” through awareness campaigns that are targeted to address the prevailing challenges.

A blood-based multi-pathway biomarker assay for early detection and staging of Alzheimer's disease across ethnic groups.

Existing blood-based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood-based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. We developed a blood-based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD-related endophenotypes in three independent cohorts from Chinese or European-descent populations. The 21-protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC]=0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC=0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic-specific dysregulations of biological processes upon AD progression. This study demonstrated the utility of a blood-based, multi-pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. The authors developed a blood-based biomarker assay for Alzheimer's disease. The 21-protein assay classifies AD/MCI and indicates brain amyloid pathology. The 21-protein assay can simultaneously assess activities of five biological processes. Ethnic-specific dysregulations of biological processes in AD were revealed.

Associations of general and central adiposity with hypertension and cardiovascular disease among South Asian populations: a systematic review and meta-analysis

BackgroundThe relevance of measures of general and central adiposity for cardiovascular disease (CVD) risks in populations of European descent is well established. However, it is less well characterised in South...

The generalizability of proposed reference values for plasma neurofilament light chain in cognitively healthy adults in Thailand

AbstractBackgroundDespite being an established biomarker for quantifying neuroaxonal injury in research, the clinical utility of neurofilament light chain (NFL) for assessing individual patients is limited, primarily due to the confounding effect of aging on its levels. Although many studies reported age‐specific cutoff values in neurologically healthy population of European descent in high‐income countries, evidence suggests that the value of neurodegenerative biomarkers may differ in ethnically and socioeconomically underrepresented populations. In this study, we aimed to evaluate the acceptability of the reported NFL cutoff values for local clinical use by examining specimens from healthy Thai cohorts.MethodThis study enrolled participants without neurological disorder and normal cognitive examination from two distinct cohorts in Bangkok, Thailand, ranging in age from 40 to 90 years old. Plasma levels of NFL were quantified using the single molecule array. By utilizing reference data from previous studies (Simrén et al., 2022; Bornhorst et al., 2022), the proportion of participants exceeding the proposed cutoff values were estimated and compared to the expected values. Furthermore, the cohort was stratified by age group and methods similar to prior studies were employed to determine age‐specific cutoff values.ResultOne hundred and three participants were included, comprising of 69 females (67%), with a median age of 65.4 years (interquartile range (IQR): 56.7, 70.3) and a cognitive z‐score of 0.11 (IQR: ‐0.44, 0.63). Using the reference threshold from prior studies, plasma NFL were elevated in 4 participants (3.9%, 95% confidence interval: 1.0‐9.6%) which is consistent with the expected prevalence of 5% (as 95th percentile cutoffs were used). Subsequently, we determined age‐specific plasma NFL cut‐off values for each decade through quantile regression, values ranging from 7.2 pg/mL for 40‐50 years to 58.2 pg/mL for >80 years.ConclusionOur initial findings suggest that the previously established cutoffs for plasma NFL may be applicable in Thailand. Nonetheless, further studies with a larger and more diverse sample size may be necessary in order to fully validate the generalizability of these cutoffs and potentially establish more specific thresholds for local use.

Assessment of Bidirectional Relationships between Frailty and Mental Disorders: A Bidirectional Mendelian Randomization Study

ObjectivesAlthough observational studies have reported the association between frailty and mental disorders, the causality remains unclear. We aimed to evaluate the bidirectional causal association between frailty levels and mental disorders using a 2-sample Mendelian randomization (MR) analysis. DesignA bidirectional, 2-sample Mendelian randomization (MR) analysis. Setting and ParticipantsInstrumental variables were obtained from large-scale genome-wide association study (GWAS) of a European-descent population for frailty index (FI, n = 175,226), Fried Frailty Score (FFS, n = 386,565), major depressive disorder (MDD, n = 674,452), bipolar disorder (n = 353,899), anxiety and stress-related disorder (ASRD, n = 31,880), and schizophrenia (n = 127,906). MethodsTwo-sample MR analyses were conducted using inverse variance-weighted method, with sensitivity analyses using MR-Egger, weighted median, and simple median methods. ResultsPer SD increase in genetically predicted FI and FFS increased the risk of MDD [odds ratio (OR) 1.56, 95% CI 1.27-1.94, P = 3.65 × 10−5, and OR 1.67, 95% CI 1.26-2.20, P = 3.02 × 10−4, respectively]. Per-SD increase in genetically predicted FI also increased the risk of ASRD (OR 2.76, 95% CI 1.36-5.60, P = .005). No significant effect was observed for frailty levels on the risk of bipolar disorder and schizophrenia. In the reverse direction, genetically predicted MDD was associated with higher FI (β 0.182, 95% CI 0.087-0.277, P = 1.79 × 10−4) and FFS (β 0.121, 95% CI 0.087-0.155, P = 4.43 × 10−12). No reliable evidence supported the effects of genetically predicted bipolar disorder, ASRD, or schizophrenia on frailty levels. Conclusions and ImplicationsA bidirectionally causal association exists between frailty levels and MDD, and higher FI is associated with a higher risk of ASRD. No reliable evidence suggested the causal associations of other mental disorders with frailty. Our findings provided evidence for introduction of psychological-related strategies in management of frailty.

Characterizing causal relationships of visceral fat and body shape on multiple sclerosis risk.

Epidemiologic studies have established obesity as a risk factor for multiple sclerosis (MS). These studies relied on body-mass index (BMI) and body size silhouettes as the primary measures of obesity. Unfortunately, the causal mechanisms through which obesity confers MS risk are not yet known. To investigate the causal effects of multiple specific measures of body fat on MS risk in populations of European descent, using Mendelian randomization (MR). MR is a genetic instrumental variable analysis utilizing genome-wide association (GWA) summary statistics to infer causality between phenotypes. MR analyses were performed to investigate the relationships between seven measures of body fat (BMI, waist-hip ratio, visceral adipose tissue [VAT], subcutaneous adipose tissue, and arm-, leg-, and trunk-fat to total body fat ratio) and MS risk. Only BMI and VAT were significantly associated with MS risk in separate MR analyses (βBMI=0.27, pBMI<0.001; βVAT=0.28, pVAT=0.006). High correlation between BMI and VAT instruments suggest that two-sample MR associations for BMI and VAT likely capture the same causal mechanisms. BMI and VAT were causally associated with MS risk in European populations, though their effects do not appear independent, suggesting overlap in the role of overall body mass and visceral obesity in MS pathogenesis.

Validation of the Fatty Liver Index for identifying non-alcoholic fatty liver disease in a Kenyan population.

Fatty Liver Index (FLI) is a simple clinical scoring system estimating non-alcoholic fatty liver disease (NAFLD). It is validated in European-descent and Asian populations, but not in sub-Saharan Africans. The aim of this study is to evaluate the validity of the FLI for predicting NAFLD in a population from Kenya. Participants were recruited from a community-based study conducted in Kenya. NAFLD was diagnosed using hepatic ultrasonography. Clinical, anthropometrical, biochemical and lifestyle data were obtained. The accuracy and cut-off point of the FLI to detect NAFLD were evaluated by area under the receiver operator characteristic curve and the maximum Youden index analysis. A total of 640 participants (94 with NAFLD) were included. Mean age was 37.4 ± 0.4 years and 58.7% were women. Mean body mass index (BMI) was 22.3 ± 0.2 kg/m2 and waist circumference (WC) 79.1 ± 0.4 cm. A total of 15 (2.3%) participants were diagnosed with type 2 diabetes and 65 (10.2%) with obesity (BMI ≥ 30 kg/m2 ). AUROC of FLI for predicting NAFLD was 0.80 (95% CI 0.74-0.85), which was significantly higher compared to individual components gamma-glutamyl transferase and triglycerides (p < 0.05), but not compared to anthropometric parameters BMI (AUROC of 0.83, 95% CI 0.79-0.88) and WC (AUROC of 0.81, 95% CI 0.76-0.87). FLI is a simple valid scoring system to use in rural and urban Kenyan adults. However, this index might not be superior to BMI or WC to predict NAFLD, and those measurements might therefore be more appropriate in limited settings.

No genetic causal association between dental caries and Alzheimer's disease: a bidirectional two-sample Mendelian randomization analysis.

An increasing number of observational studies have suggested an association between dental caries and Alzheimer's disease (AD). The association between dental caries and Alzheimer's disease may be mediated by confounders or reverse causality. In this study, we conducted bidirectional two-sample Mendelian randomization (MR) to estimate the bidirectional causality between dental caries and AD. Genome-wide association study (GWAS) summary statistics of dental caries were extracted from a published meta-analysis which included a total of 487,823 participants. GWAS datasets of AD and AD onset age were obtained from the FinnGen bank. A bidirectional two-sample analysis was performed to explore the causality between dental caries and AD. For the dental caries-AD causality estimation, there was no significant association between dental caries and AD, neither with the AD GWASs from the FinnGen database (OR: 1.041, p = 0.874) nor with those from the International Genomics of Alzheimer's Project (OR: 1.162, p = 0.409). In addition, the genetic susceptibility to dental caries was not related to the onset age of AD. No causality existed between dental caries and early-onset AD (OR: 0.515, p = 0.302) or late-onset AD (OR: 1.329, p = 0.347). For the AD-dental caries relationship, no causality was detected by the IVW method (OR: 1.000, p = 0.717). Findings from other MR methods were consistent. The pleiotropy test and sensitivity analysis confirmed the validity of these MR results. In this bidirectional MR study, robust evidence to support a bidirectional causal effect between dental caries and AD from the GWAS results within large-scale European-descent populations was absent. Having dental caries would not alter the onset age of AD.

Application of facial analysis Technology in Clinical Genetics: Considerations for diverse populations.

Facial analysis technology in rare diseases has the potential to shorten the diagnostic odyssey by providing physicians with a valuable diagnostic tool. Given that most clinical genetic resources focus on populations of European descent, we compare craniofacial features in genetic syndromes across different populations and review how machine learning algorithms perform on diagnosing genetic syndromes in geographically and ethnically diverse populations. We also discuss the value of populations from ancestrally diverse backgrounds in the training set of machine learning algorithms. Finally, this review demonstrates that across diverse population groups, machine learning models have outstanding accuracy as supported by the area under the curve values greater than 0.9. Artificial intelligence is only in its infancy in the diagnosis of rare disease in diverse populations and will become more accurate as larger and more diverse training sets, including a wider spectrum of ages, particularly infants, are studied.

Tumor Necrosis Factor-α G-308A Polymorphism and Sporadic IgA Nephropathy: A Meta-Analysis Using a Genetic Model-Free Approach.

Tumor necrosis factor-α (TNF-α) is a potent pro-inflammatory cytokine, involved in the pathogenesis and progression of immunoglobulin A nephropathy (IgAN). A bi-allelic polymorphism in the promoter region, at position -308 (G/A) of the TNF-α gene (rs1800629) is associated with an increased TNF-a production. However, several previous association studies of TNF-α G-308A polymorphism and IgAN rendered contradictory findings. The objective of the present study is to shed light on these inconclusive results and clarify the role of TNF-α and any possible contribution of this factor in the development and progression of sporadic IgAN. Therefore, a meta-analysis of all available genetic association studies relating the TNF-α G-308A polymorphism to the risk for development and/or progression of IgAN was conducted. Seven studies were included in the meta-analysis. Three of them included populations of European descent (Caucasians) and four involved Asians. The generalized odds ratio (ORG) was used to estimate the risk for the development and/or progression of the disease. Overall, the meta-analysis did not detect any significant association between the G-308A variant and both the risk of developing IgAN and the risk for progression of IgAN. In conclusion, these results suggest that TNF-α does not constitute a key component in the genetic architecture of sporadic IgAN. However, further evidence deciphering the influence of TNF-α on IgAN is still needed.