scholarly journals Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome

2018 ◽  
Vol 29 (7) ◽  
pp. 2000-2013 ◽  
Author(s):  
Hanna Debiec ◽  
Claire Dossier ◽  
Eric Letouzé ◽  
Christopher E. Gillies ◽  
Marina Vivarelli ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Untranslated Region ◽  
Meta Analysis ◽  
Conditional Analysis ◽  
Risk Haplotype ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Genome Wide ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive

Background Steroid-sensitive nephrotic syndrome (SSNS) is a childhood disease with unclear pathophysiology and genetic architecture. We investigated the genomic basis of SSNS in children recruited in Europe and the biopsy-based North American NEPTUNE cohort.Methods We performed three ancestry-matched, genome-wide association studies (GWAS) in 273 children with NS (Children Cohort Nephrosis and Virus [NEPHROVIR] cohort: 132 European, 56 African, and 85 Maghrebian) followed by independent replication in 112 European children, transethnic meta-analysis, and conditional analysis. GWAS alleles were used to perform glomerular cis-expression quantitative trait loci studies in 39 children in the NEPTUNE cohort and epidemiologic studies in GWAS and NEPTUNE (97 children) cohorts.Results Transethnic meta-analysis identified one SSNS-associated single-nucleotide polymorphism (SNP) rs1063348 in the 3′ untranslated region of HLA-DQB1 (P=9.3×10−23). Conditional analysis identified two additional independent risk alleles upstream of HLA-DRB1 (rs28366266, P=3.7×10−11) and in the 3′ untranslated region of BTNL2 (rs9348883, P=9.4×10−7) within introns of HCG23 and LOC101929163. These three risk alleles were independent of the risk haplotype DRB1*07:01-DQA1*02:01-DQB1*02:02 identified in European patients. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS, with younger age of onset across all cohorts, and with increased odds of complete remission across histologies in NEPTUNE children. rs1063348 associated with decreased glomerular expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1.Conclusions Transethnic GWAS empowered discovery of three independent risk SNPs for pediatric SSNS. Characterization of these SNPs provide an entry for understanding immune dysregulation in NS and introducing a genomically defined classification.

scholarly journals Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

2019 ◽  
Vol 30 (8) ◽  
pp. 1375-1384 ◽  
Author(s):  
Stephanie Dufek ◽  
Chris Cheshire ◽  
Adam P. Levine ◽  
Richard S. Trompeter ◽  
Naomi Issler ◽  
...  
Keyword(s):  
Immune Response ◽  
Nephrotic Syndrome ◽  
Genetic Identification ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Hla Association ◽  
Genome Wide ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive ◽  
Genome Wide Significance

BackgroundSteroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance.MethodsIn an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls.ResultsThe GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10−43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10−17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6.ConclusionsBecause CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

scholarly journals Steroid treatment for the first episode of childhood nephrotic syndrome: comparison of the 8 and 12 weeks regimen using an individual patient data meta-analysis

2021 ◽  
Author(s):  
Anne M. Schijvens ◽  
Nynke Teeninga ◽  
Eiske M. Dorresteijn ◽  
Steven Teerenstra ◽  
Nicholas J. Webb ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Steroid Treatment ◽  
First Episode ◽  
Childhood Nephrotic Syndrome ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive ◽  
First Relapse ◽  
Steroid Regimen

AbstractSteroids are the cornerstone of the treatment of childhood nephrotic syndrome. The optimal duration for the first episode remains a matter of debate. The aim of this study is to determine whether the 8 weeks International Study of Kidney Disease in Children (ISKDC) regimen is equally effective as the 12 weeks steroid regimen from the German society of pediatric nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie [APN]). An individual patient data (IPD) meta-analysis of randomized controlled trials reporting on prednisolone treatment for a first episode of childhood nephrotic syndrome was conducted. European trials aimed at investigating the ISKDC and/or APN steroid regimen were selected. The lead investigators of the selected trials were requested to provide the IPD of the specific treatment groups. Four trials included European cohorts using dosing schedules according to the regimens studied. IPD of two trials were available. A significant difference was found in time to first relapse after cessation of steroid treatment between the 8 and 12 weeks treatment group with a median time to relapse of 29 and 63 days, respectively. Moreover, relapse rate ratios during total follow-up were 51% higher for the 8 weeks regimen. Finally, younger children have a significantly lower time to first relapse and frequently relapsing nephrotic syndrome.Conclusions: The results of this IPD meta-analysis suggest that the 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen. Moreover, this study highlights the importance of using uniform definitions to enable accurate comparison and interpretation of trial results.Trial registration: Registration number: CRD42020199244, date of registration 16-08-2020 What is Known:• Steroids are the cornerstone of the treatment of childhood nephrotic syndrome, however the optimal duration for the first episode remains a matter of debate.• Currently, the 8 weeks ISKDC protocol and 12 weeks APN protocol are among the most frequently used protocols in Europe. What is New:• The 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen for the treatment of a first episode of nephrotic syndrome.• Younger children have a significantly shorter time to first relapse and time to frequent relapsing nephrotic syndrome.

scholarly journals An updated view of the pathogenesis of steroid-sensitive nephrotic syndrome

2022 ◽  
Author(s):  
Tomoko Horinouchi ◽  
Kandai Nozu ◽  
Kazumoto Iijima
Keyword(s):  
Nephrotic Syndrome ◽  
Genome Wide Association Study ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Genome Wide ◽  
A Genome ◽  
Immunological Mechanisms ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive ◽  
Genetic Techniques

Abstract Idiopathic nephrotic syndrome is the most common childhood glomerular disease. Most forms of this syndrome respond to corticosteroids at standard doses and are, therefore, defined as steroid-sensitive nephrotic syndrome (SSNS). Immunological mechanisms and subsequent podocyte disorders play a pivotal role in SSNS and have been studied for years; however, the precise pathogenesis remains unclear. With recent advances in genetic techniques, an exhaustive hypothesis-free approach called a genome-wide association study (GWAS) has been conducted in various populations. GWASs in pediatric SSNS peaked in the human leukocyte antigen class II region in various populations. Additionally, an association of immune-related CALHM6/FAM26F, PARM1, BTNL2, and TNFSF15 genes, as well as NPHS1, which encodes nephrin expressed in podocytes, has been identified as a locus that achieves genome-wide significance in pediatric SSNS. However, the specific mechanism of SSNS development requires elucidation. This review describes an updated view of SSNS pathogenesis from immunological and genetic aspects, including interactions with infections or allergies, production of circulating factors, and an autoantibody hypothesis.

scholarly journals The Role of 39 Psoriasis Risk Variants on Age of Psoriasis Onset

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Yingchang Lu ◽  
Sinae Kane ◽  
Haoyan Chen ◽  
Argentina Leon ◽  
Ethan Levin ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
False Discovery ◽  
Risk Variants ◽  
Genome Wide ◽  
Independent Cohort

Recent genome-wide association studies (GWAS) have identified multiple genetic risk factors for psoriasis, but data on their association with age of onset have been marginally explored. The goal of this study was to evaluate known risk alleles of psoriasis for association with age of psoriasis onset in three well-defined case-only cohorts totaling 1,498 psoriasis patients. We selected 39 genetic variants from psoriasis GWAS and tested these variants for association with age of psoriasis onset in a meta-analysis. We found that rs10484554 and rs12191877 near HLA-C and rs17716942 near IFIH1 were associated with age of psoriasis onset with false discovery rate < 0.05. The association between rs17716942 and age of onset was not replicated in a fourth independent cohort of 489 patients (). The imputed HLA-C*06:02 allele demonstrated a much stronger association with age of psoriasis onset than rs10484554 and rs12191877. We conclude that despite the discovery of numerous psoriasis risk alleles, HLA-C*06:02 still plays the most important role in determining the age of onset of psoriasis. Larger studies are needed to evaluate the contribution of other risk alleles, including IFIH1, to age of psoriasis onset.

scholarly journals A meta-analysis of the association between angiotensin-converting enzyme insertion/deletion gene polymorphism and steroid-sensitive nephrotic syndrome in children

2011 ◽  
Vol 13 (1) ◽  
pp. 175-183 ◽  
Author(s):  
Tian-Biao Zhou ◽  
Yuan-Han Qin ◽  
Chao Ou ◽  
Li-Na Su ◽  
Feng-Ying Lei ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Gene Polymorphism ◽  
Angiotensin Converting Enzyme ◽  
Meta Analysis ◽  
Positive Association ◽  
Protective Role ◽  
Cochrane Library ◽  
Converting Enzyme ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive

Background and objective: Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism correlates with circulating and cellular ACE concentration. Association between ACE I/D gene polymorphism and steroid-sensitive nephrotic syndrome (SSNS) risk in children is still controversial. This meta-analysis was performed to evaluate the relation between ACE I/D gene polymorphism and SSNS susceptibility in children. Methods: The relevant investigations were screened from the search engines of PubMed, Cochrane Library and CBM-disc (China Biological Medicine Database) as of 1 March 2011, and eligible studies were synthesized using meta-analysis methods. Results: Ten studies were identified for the analysis of association between ACE I/D gene polymorphism and SSNS risk in children, including seven in Asians, one for Caucasians and two in Africans. There was no markedly positive association between D allele or DD genotype and SSNS susceptibility in Asians, Caucasians and Africans (D: Asians OR = 1.24, p = 0.28; Caucasians OR = 1.61, p = 0.15; Africans OR = 1.61, p = 0.53; DD: Asians OR = 1.72, p = 0.15; Caucasians OR = 1.39, p = 0.48; Africans OR = 1.80, p = 0.56). Furthermore, II homozygous seemed not to play a protective role against SSNS onset for Asians, Caucasians and Africans (Asians OR = 0.95, p = 0.85; Caucasians OR = 0.30, p = 0.11; Africans OR = 0.60, p = 0.65). Conclusions: There was no association between ACE I/D gene polymorphism and SSNS susceptibility in Asians, Caucasians and Africans. However, the conclusions for Caucasians and Africans were less powerful.

scholarly journals A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry

2020 ◽  
Vol 4 (1) ◽  
pp. 181-190 ◽  
Author(s):  
Zhaohui Du ◽  
Niels Weinhold ◽  
Gregory Chi Song ◽  
Kristin A. Rand ◽  
David J. Van Den Berg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Association Studies ◽  
Meta Analysis ◽  
African Ancestry ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Admixture Mapping ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Genome Wide

Abstract Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P &lt; 1 × 10−6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P &lt; .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10−12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Genome-Wide Association Studies Identify Two Novel Loci Conferring Susceptibility to Diabetic Retinopathy in Japanese Patients with Type 2 Diabetes

2021 ◽  
Author(s):  
Minako Imamura ◽  
Atsushi Takahashi ◽  
Masatoshi Matsunami ◽  
Momoko Horikoshi ◽  
Minoru Iwata ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Association Studies ◽  
Meta Analysis ◽  
Japanese Patients ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Stage 1

Abstract Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases, and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (p &lt; 1.0 × 10−4) in an independent case–control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stage-1 and -2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, p = 1.62 × 10−9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11–1.23, and rs140508424 within PALM2 on chromosome 9, p = 4.19 × 10−8, OR = 1.61, 95% CI 1.36–1.91. However, the association of these two loci were not replicated in Korean, European, or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (p = 2.17 × 10−6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.

scholarly journals Genetic factors influencing a neurobiological substrate for psychiatric disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Till F. M. Andlauer ◽  
Thomas W. Mühleisen ◽  
Felix Hoffstaedter ◽  
Alexander Teumer ◽  
Katharina Wittfeld ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Risk ◽  
Meta Analysis ◽  
Anterior Cingulate ◽  
Psychiatric Disease ◽  
Salience Network ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Common Substrate ◽  
The Common

AbstractA retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex—areas that constitute hub nodes of the salience network—represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n = 2271), followed by meta-analysis and replication in a fifth cohort (n = 865). After correction for covariates, the heritability of the common substrate was estimated at 0.50 (standard error 0.18). The top single-nucleotide polymorphism (SNP) rs17076061 was associated with the common substrate at genome-wide significance and replicated, explaining 1.2% of the common substrate variance. This SNP mapped to a locus on chromosome 5q35.2 harboring genes involved in neuronal development and regeneration. In follow-up analyses, rs17076061 was not robustly associated with psychiatric disease, and no overlap was found between the broader genetic architecture of the common substrate and genetic risk for major depressive disorder, bipolar disorder, or schizophrenia. In conclusion, our study identified that common genetic variation indeed influences the common substrate, but that these variants do not directly translate to increased disease risk. Future studies should investigate gene-by-environment interactions and employ functional imaging to understand how salience network structure translates to psychiatric disorder risk.

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