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 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 Genome-wide association studies on endometriosis and endometriosis-related infertility

2018 ◽  
Author(s):  
Geneviève Galarneau ◽  
Pierre Fontanillas ◽  
Caterina Clementi ◽  
Tina Hu-Seliger ◽  
David-Emlyn Parfitt ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Reproductive Age ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Model Organisms ◽  
Genome Wide Association Studies ◽  
Gwas Study ◽  
Genome Wide ◽  
Genome Wide Significance

AbstractEndometriosis affects ∼10% of women of reproductive age. It is characterized by the growth of endometrial-like tissue outside the uterus and is frequently associated with severe pain and infertility. We performed the largest endometriosis genome-wide association study (GWAS) to date, with 37,183 cases and 251,258 controls. All women were of European ancestry. We also performed the first GWAS of endometriosis-related infertility, including 2,969 cases and 3,770 controls. Our endometriosis GWAS study replicated, at genome-wide significance, seven loci identified in previous endometriosis GWASs (CELA3A-CDC42, SYNE1, KDR, FSHB-ARL14EP, GREB1, ID4, and CEP112) and identified seven new candidate loci with genome-wide significance (NGF, ATP1B1-F5, CD109, HEY2, OSR2-VPS13B, WT1, and TEX11-SLC7A3). No loci demonstrated genome-wide significance for endometriosis-related infertility, however, the three most strongly associated loci (MCTP1, EPS8L3-CSF1, and LPIN1) were in or near genes associated with female fertility or embryonic lethality in model organisms. These results reveal new candidate genes with potential involvement in the pathophysiology of endometriosis and endometriosis-related infertility.

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.

IL-18 is correlated with type-2 immune response in children with steroid sensitive nephrotic syndrome

Cytokine ◽  
2008 ◽  
Vol 44 (2) ◽  
pp. 262-268 ◽  
Author(s):  
Nikoleta Printza ◽  
Fotios Papachristou ◽  
Vassiliki Tzimouli ◽  
Anna Taparkou ◽  
Florence Kanakoudi-Tsakalidou
Keyword(s):  
Immune Response ◽  
Nephrotic Syndrome ◽  
Type 2 Immune Response ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive

scholarly journals Common genetic variants shared among five major psychiatric disorders: a large-scale genome-wide combined analysis

2019 ◽  
pp. 21-30 ◽  
Author(s):  
Lu Xia ◽  
Kun Xia ◽  
Daniel Weinberger ◽  
Fengyu Zhang
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Variants ◽  
Autism Spectrum ◽  
Epigenetic Mechanism ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Childhood Disorders ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Genome Wide Significance

Background. Genetic correlation and pleiotropic effects among psychiatric disorders have been reported. This study aimed to identify specific common genetic variants shared between five adult psychiatric disorders: schizophrenia, bipolar, major depressive disorder, attention deficit-hyperactivity disorder, and autism spectrum disorder. Methods. A combined p-value of about 8 million single nucleotide polymorphisms (SNPs) was calculated in an equivalent sample of 151,672 cases and 284,444 controls of European ancestry from published data based on the latest genome-wide association studies of five major psychiatric disorder. SNPs that achieved genome-wide significance (P<5x10-08) were mapped to loci and genomic regions for further investigation; gene annotation and clustering were performed to understand the biological process and molecular function of the loci identified. We also examined CNVs and performed expression quantitative trait loci analysis for SNPs by genomic region. Results. We find that 6,293 SNPs mapped to 336 loci shared by the three adult psychiatric disorders, 1,108 variants at 73 loci shared by the childhood disorders, and 713 variants at 47 genes shared by all five disorders at genome-wide significance (P<5x10-08). Of the 2,583 SNPs at the extended major histocompatibility complex identified for three adult disorders, none of them were associated with childhood disorders; and SNPs shared by all five disorders were located in regions that have been identified as containing copy number variation associated with autism and had largely neurodevelopmental functions. Conclusion. We show a number of specific SNPs associated with psychiatric disorders of childhood or adult-onset, illustrating not only genetic heterogeneity across these disorders but also developmental genes shared by them all.  These results provide a manageable list of anchors from which to investigate epigenetic mechanism or gene-gene interaction on the development of neuropsychiatric disorders and for developing a measurement matrix for disease risk to potentially develop a novel taxonomy for precision medicine.

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 Distribution of serum adiponectin isoforms in pediatric patients with steroid-sensitive nephrotic syndrome

2021 ◽  
Author(s):  
Tetsuro Tamai ◽  
Kaori Kamijo ◽  
Yoshifusa Abe ◽  
Satoshi Hibino ◽  
Shunsuke Sakurai ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Nephrotic Syndrome ◽  
Pediatric Patients ◽  
Serum Adiponectin ◽  
Total Serum ◽  
Control Subjects ◽  
Remission Period ◽  
Total Adiponectin ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive

Abstract Background Serum adiponectin circulates in three multimeric isoforms: high-molecular-weight (HMW), middle-molecular-weight (MMW), and low-molecular-weight (LMW) isoforms. Potential change in the circulating adiponectin levels in patients with nephrotic syndrome (NS) remain unknown. This study aimed to assess the levels of total adiponectin and the distribution of its isoforms in pediatric patients with NS. Methods We sequentially measured total adiponectin and each adiponectin isoform levels at the onset of NS, initial remission, and during the remission period of the disease in 31 NS patients. We also calculated the ratios of HMW (%HMW), MMW (%MMW), and LMW (%LMW) to total adiponectin incuding 51 control subjects. Results The median of total serum adiponectin levels in patients were 36.7, 36.7, and 20.2 μg/mL at the onset, at initial remission, and during the remission period of NS, respectively. These values were significantly higher than those in control subjects. The median values of %HMW, %MMW, and %LMW values were 56.9/27.0/14.1 at the onset, 62.0/21.8/13.4 at the initial remission, and 58.1/21.7/17.5 at during the remission period of NS, respectively. Compared with control subjects, %HMW at initial remission and %MMW at the onset were high, and the %LMW values at the onset and at initial remission were low. Conclusions In patients with NS, total serum adiponectin levels increase at the onset of the disease, and the ratio of adiponectin isoforms changes during the course of the disease. Further studies are needed to delineate the mechanisms between proteinuria and adiponectin isoforms change.

Abstract P359: A Sickle Cell Variant Associates With Urine Albumin Excretion in Genome Wide Association Study of Hispanics: The HCHS/SOL Study

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Nora Franceschini ◽  
Adrienne Stilp ◽  
Christina L Wassel ◽  
Holly J Mattix-Kramer ◽  
Michael F Flessner ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Sickle Cell ◽  
Missense Variant ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Minority Population ◽  
Genome Wide Association Studies ◽  
Urine Albumin ◽  
Genome Wide ◽  
A Genome

Introduction: Genome wide association studies have identified genetic variants in the Cubillin gene ( CUBN ) that explain inter-individual variation in urine albumin-to-creatinine excretion (UACR) in populations. These studies have not included Hispanics/Latinos, the fast growing minority population in the U.S., who has also high prevalence of chronic kidney disease and its risk factors. Hypothesis: By leveraging on population admixture of Hispanics and using a genome wide association approach, we hypothesized that novel loci associated with UACR would be identified. Methods: We used data from 12,212 self-identified Hispanic individuals recruited in a community-based study, aged 18-74 years at screening (2008-2011), and randomly selected from households in four U.S. field centers (Chicago, IL; Miami, FL; Bronx, NY; San Diego, CA). Urine albumin (mg/dl) and creatinine (g/dl) were measured at the baseline exam. UACR was log-transformed for analysis. Individuals were excluded if reporting to have end-stage renal disease. Genotyping was performed using a custom Illumina Omni2.5M array. Imputation of variants was performed using 1000 Genome Project data from cosmopolitan HapMap samples. After quality control of imputed data, we performed mixed linear regression analyses that accounted for the sampling strategy and family relatedness, for variants with minor allele frequency (MAF) > 0.01 and imputation quality > 0.3. We used additive genetic models and adjusted for age, sex, and principal components which were estimated from the data. In a secondary analysis, we also examine the association of significant variants with kidney function using estimated glomerular filtration rate (eGFR) equations. Results: Among 12,212 participants, 41% were men, and mean age was 46 (SD =13). There was little evidence for genome wide inflation (lambda =1.024). We identified significant associations of single nucleotide polymorphisms (SNPs) with UACR at two loci: CUBN and HBB . The CUBN SNP (chr10:16966414, p=2.1x10-8) is an indel variant with MAF of 0.14, which was not in linkage disequilibrium with previously reported SNP rs1801239 (rsq=0.38, p=1.3x10-4) identified in individuals of European ancestry. The HBB SNP is a missense variant which results in an E [Glu] ⇒ A [Ala] substitution in the beta-globin chain of hemoglobin and a cause of the Mendelian disorder sickle cell anemia (rs334, T allele frequency =0.01, beta=0.44, SE=0.06, p=7.6x10-12). rs344 was not associated with eGFR in our data (p>0.05). Conclusion: This study identified a novel association of a sickle cell missense variant with UACR in Hispanics, and provided evidence for allelic heterogeneity at the CUBN locus. Our findings suggest a role for Mendelian gene variants in increased albuminuria in Hispanic populations with admixture.

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