scholarly journals Deletion Variants of CFHR1 and CFHR3 Associate with Mesangial Immune Deposits but Not with Progression of IgA Nephropathy

2017 ◽  
Vol 29 (2) ◽  
pp. 661-669 ◽  
Author(s):  
Perrine Jullien ◽  
Blandine Laurent ◽  
Guillaume Claisse ◽  
Ingrid Masson ◽  
Miriana Dinic ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Association Studies ◽  
Alternative Pathway ◽  
Factor H ◽  
Genome Wide Association Studies ◽  
Complement Factor ◽  
Gene Deletions ◽  
Immune Deposits ◽  
Gene Copies ◽  
Genome Wide

Activation of complement through the alternative pathway has a key role in the pathogenesis of IgA nephropathy (IgAN). Large, international, genome-wide association studies have shown that deletion of complement factor H–related genes 1 and 3 (CFHR3,1Δ) is associated with a reduced risk of developing IgAN, although the prognostic value of these deletions in IgAN remains unknown. Here, we compared the renal outcomes of patients with IgAN according to their CFHR3,1Δ genotype. This retrospective, monocentric cohort study included 639 white patients with biopsy-proven IgAN since 1979 (mean age at diagnosis, 40.1 years; median follow-up, 132 months). We determined the number of CFHR3 and CFHR1 gene copies by quantitative PCR and collected clinical and biologic data by reviewing the patients’ medical records. In all, 30.5% of the patients were heterozygous and 4% were homozygous for CFHR3,1Δ. We did not detect an association between CFHR3,1Δ and age, eGFR, urinary protein excretion rate, or the presence of hypertension or hematuria at the time of diagnosis. The mean intensities of immune IgA, IgG, and C3 deposits were lower in the group with heterozygous or homozygous gene deletions than in those with no deletion. However, CFHR3,1Δ did not associate with progression to stage 3 CKD or renal death. In conclusion, the CFHR3,1Δ genotype did not associate with progression toward CKD stages 3 and 5 in our white population of patients with IgAN, although it did associate with a reduced level of glomerular immune deposits.

scholarly journals Case Report: A Rare Truncating Variant of the CFHR5 Gene in IgA Nephropathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Gabriella Guzzo ◽  
Salima Sadallah ◽  
Heidi Fodstad ◽  
Jean-Pierre Venetz ◽  
Samuel Rotman ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Association Studies ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Genome Wide Association Studies ◽  
Complement Factor ◽  
Loss Of Function ◽  
Renal Disease Progression ◽  
Therapeutic Implications

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Despite appropriate therapy, 20–40% of affected-patients evolve toward end-stage kidney disease (ESKD). Mesangial IgA deposits are the hallmark of IgAN, and complement deposition (C3) seems to differentiate latent IgA mesangial deposits from active IgAN. Atypical hemolytic uremic syndrome (aHUS), another disease in which complement plays an important role, is caused by inherited or acquired deregulation of the alternative pathway (AP) of complement. A subgroup of IgAN shows thrombotic microangiopathy (TMA) lesions in kidney biopsies, the histological characteristic of aHUS. Genetic variants of complement Factor H (CFH), known to be present in aHUS, have been associated with rapidly progressive forms of IgAN and a clinical pattern of aHUS. Genome-wide association studies (GWAS) have confirmed that the 1q32 region, encoding for CFH and its related proteins, is an IgAN susceptibility locus. A 30 year-old man was admitted for seizures and malignant hypertension. The kidney biopsy showed IgAN associated with features of TMA. Despite five plasma exchanges, the patient remained dialysis-dependent, and ESKD was diagnosed. Functional and genetic complement analysis were performed. A monoallelic protein-truncating, likely loss-of-function variant was identified in the CFHR5 gene. Eculizumab is the treatment of aHUS. As it has been successfully used in a few cases of rapidly progressive IgAN, it was decided to administer eculizumab over a period of 12 months in addition to the usual immunosuppression for renal transplantation. After a follow-up of 3 years, there was no clinical disease recurrence. Systematic biologic and genetic screening of complement in individuals with IgAN might be useful to better delineate the role of the AP of complement in renal disease progression, and this may have therapeutic implications.

scholarly journals Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis

2021 ◽  
Vol 17 (10) ◽  
pp. e1009992
Author(s):  
Sarah G. Earle ◽  
Mariya Lobanovska ◽  
Hayley Lavender ◽  
Changyan Tang ◽  
Rachel M. Exley ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Binding Protein ◽  
Association Studies ◽  
Bacterial Genome ◽  
Factor H ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Complement Factor ◽  
Genome Wide ◽  
Bacterial Genetic

Many invasive bacterial diseases are caused by organisms that are ordinarily harmless components of the human microbiome. Effective interventions against these microbes require an understanding of the processes whereby symbiotic or commensal relationships transition into pathology. Here, we describe bacterial genome-wide association studies (GWAS) of Neisseria meningitidis, a common commensal of the human respiratory tract that is nevertheless a leading cause of meningitis and sepsis. An initial GWAS discovered bacterial genetic variants, including single nucleotide polymorphisms (SNPs), associated with invasive meningococcal disease (IMD) versus carriage in several loci across the meningococcal genome, encoding antigens and other extracellular components, confirming the polygenic nature of the invasive phenotype. In particular, there was a significant peak of association around the fHbp locus, encoding factor H binding protein (fHbp), which promotes bacterial immune evasion of human complement by recruiting complement factor H (CFH) to the meningococcal surface. The association around fHbp with IMD was confirmed by a validation GWAS, and we found that the SNPs identified in the validation affected the 5’ region of fHbp mRNA, altering secondary RNA structures, thereby increasing fHbp expression and enhancing bacterial escape from complement-mediated killing. This finding is consistent with the known link between complement deficiencies and CFH variation with human susceptibility to IMD. These observations demonstrate the importance of human and bacterial genetic variation across the fHbp:CFH interface in determining IMD susceptibility, the transition from carriage to disease.

scholarly journals Competition between antagonistic complement factors for a single protein on N. meningitidis rules disease susceptibility

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Joseph JE Caesar ◽  
Hayley Lavender ◽  
Philip N Ward ◽  
Rachel M Exley ◽  
Jack Eaton ◽  
...  
Keyword(s):  
Meningococcal Disease ◽  
Serum Proteins ◽  
Association Studies ◽  
Factor H ◽  
Complement Factor H ◽  
Host Susceptibility ◽  
Genome Wide Association Studies ◽  
Complement Factor ◽  
Bacterial Surface ◽  
Related Proteins

Genome-wide association studies have found variation within the complement factor H gene family links to host susceptibility to meningococcal disease caused by infection with Neisseria meningitidis (<xref ref-type="bibr" rid="bib4">Davila et al., 2010</xref>). Mechanistic insights have been challenging since variation within this locus is complex and biological roles of the factor H-related proteins, unlike factor H, are incompletely understood. N. meningitidis subverts immune responses by hijacking a host-immune regulator, complement factor H (CFH), to the bacterial surface (<xref ref-type="bibr" rid="bib25">Schneider et al., 2006</xref>; <xref ref-type="bibr" rid="bib17">Madico et al., 2007</xref>; <xref ref-type="bibr" rid="bib27">Schneider et al., 2009</xref>). We demonstrate that complement factor-H related 3 (CFHR3) promotes immune activation by acting as an antagonist of CFH. Conserved sequences between CFH and CFHR3 mean that the bacterium cannot sufficiently distinguish between these two serum proteins to allow it to hijack the regulator alone. The level of protection from complement attack achieved by circulating N. meningitidis therefore depends on the relative levels of CFH and CFHR3 in serum. These data may explain the association between genetic variation in both CFH and CFHR3 and susceptibility to meningococcal disease.

scholarly journals Cumulative Effects of Variants Identified by Genome-wide Association Studies in IgA Nephropathy

2014 ◽  
Vol 4 (1) ◽  
Author(s):  
Xu-Jie Zhou ◽  
Yuan-Yuan Qi ◽  
Ping Hou ◽  
Ji-Cheng Lv ◽  
Su-Fang Shi ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Association Studies ◽  
Cumulative Effects ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Tale of two nephropathies; co-occurring Alport syndrome and IgA nephropathy, a case report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Aniruddha Bhattacharyya ◽  
Yuting Huang ◽  
Sarah Hussain Khan ◽  
Cinthia Beskow Drachenberg ◽  
Laura C. Malone
Keyword(s):  
Iga Nephropathy ◽  
Alport Syndrome ◽  
Interstitial Fibrosis ◽  
Association Studies ◽  
Genome Wide Association ◽  
Immunofluorescent Staining ◽  
Renal Ultrasound ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Nephrotic Range Proteinuria

Abstract Background Alport Syndrome and IgA Nephropathy (IgAN) are both disorders that can cause hematuria. Alport syndrome is most commonly an X-linked disease, caused by COL4A5 mutation. Mutations of COL4A3 and COL4A4 on chromosome two are also common causes of Alport syndrome. IgAN is the most common glomerulonephritis worldwide. Though IgAN is usually sporadic, an estimated 15% of cases have an inheritable component. These cases of Familal IgA Nephropathy (FIgAN) can have mutations on genes which are known to cause Alport Syndrome. Case presentation We report a case of a 27-year-old man with strong family history of renal disease, who presented with hematuria and new non-nephrotic range proteinuria. Physical exam showed no abnormalities. His creatinine remained persistently elevated, and renal ultrasound exhibited bilaterally increased echogenicity consistent with Chronic Kidney Disease. Twenty-four-hour urinary collection revealed non-nephrotic range proteinuria of 1.4 g, with otherwise negative workup. On biopsy, he had IgA positive immunofluorescent staining as well as moderate interstitial fibrosis and tubular atrophy. Electron microscopy showed a basket-weave pattern of thickening and splitting of the lamina densa-consistent with Alport Syndrome, as well as mesangial expansion with electron-dense deposits -consistent with IgAN. Conclusions Mutations of COL4A5 on the X chromosome, as well as mutations of COL4A3 and COL4A4 on chromosome 2, can cause both Alport Syndrome and FIgAN. Genome wide association studies identified certain Angiotensin Converting Enzyme gene polymorphisms as independent risk factors for progression of IgAN. Our Presentation with this co-occurring pathology suggests a new paradigm where Alport Syndrome and FIgAN may represent manifestations of a single disease spectrum rather than two disparate pathologies. Appreciating hematuria through this framework has implications for treatments and genetic counseling. Further genome wide association studies will likely increase our understanding of Alport Syndrome, FIgAN, and other causes of hematuria.

scholarly journals Genome-wide association studies for production, respiratory disease, and immune-related traits in Landrace pigs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yoshinobu Uemoto ◽  
Kasumi Ichinoseki ◽  
Toshimi Matsumoto ◽  
Nozomi Oka ◽  
Hironori Takamori ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Association Studies ◽  
Alternative Pathway ◽  
Chronic Respiratory Disease ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Complement Alternative Pathway ◽  
Genome Wide ◽  
Pleiotropic Qtl ◽  
Trait Locus

AbstractIdentification of a quantitative trait locus (QTL) related to a chronic respiratory disease such as Mycoplasmal pneumonia of swine (MPS) and immune-related traits is important for the genetic improvement of disease resistance in pigs. The objective of this study was to detect a novel QTL for a total of 22 production, respiratory disease, and immune-related traits in Landrace pigs. A total of 874 Landrace purebred pigs, which were selected based on MPS resistance, were genotyped using the Illumina PorcineSNP60 BeadChip. We performed single nucleotide polymorphism (SNP)-based and haplotype-based genome-wide association studies (GWAS) to detect a novel QTL and to evaluate the possibility of a pleiotropic QTL for these traits. SNP-based GWAS detected a total of six significant regions in backfat thickness, ratio of granular leucocytes to lymphatic cells, plasma concentration of cortisol at different ages, and complement alternative pathway activity in serum. The significant region detected by haplotype-based GWAS was overlapped across the region detected by SNP-based GWAS. Most of these detected QTL regions were novel regions with some candidate genes located in them. With regard to a pleiotropic QTL among traits, only three of these detected QTL regions overlapped among traits, and many detected regions independently affected the traits.

scholarly journals A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes

2020 ◽  
Vol 117 (18) ◽  
pp. 9942-9951 ◽  
Author(s):  
Lejla Alic ◽  
Nikolina Papac-Milicevic ◽  
Darina Czamara ◽  
Ramona B. Rudnick ◽  
Maria Ozsvar-Kozma ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Alternative Pathway ◽  
Critical Role ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor H ◽  
Complement Factor ◽  
Genome Wide ◽  
A Genome ◽  
Modified Surfaces

Genetic variants within complement factor H (CFH), a major alternative complement pathway regulator, are associated with the development of age-related macular degeneration (AMD) and other complementopathies. This is explained with the reduced binding of CFH or its splice variant factor H-like protein 1 (FHL-1) to self-ligands or altered self-ligands (e.g., malondialdehyde [MDA]-modified molecules) involved in homeostasis, thereby causing impaired complement regulation. Considering the critical role of CFH in inhibiting alternative pathway activation on MDA-modified surfaces, we performed an unbiased genome-wide search for genetic variants that modify the ability of plasma CFH to bind MDA in 1,830 individuals and characterized the mechanistic basis and the functional consequences of this. In a cohort of healthy individuals, we identified rs1061170 in CFH and the deletion of CFHR3 and CFHR1 as dominant genetic variants that modify CFH/FHL-1 binding to MDA. We further demonstrated that FHR1 and FHR3 compete with CFH for binding to MDA-epitopes and that FHR1 displays the highest affinity toward MDA-epitopes compared to CFH and FHR3. Moreover, FHR1 bound to MDA-rich areas on necrotic cells and prevented CFH from mediating its cofactor activity on MDA-modified surfaces, resulting in enhanced complement activation. These findings provide a mechanistic explanation as to why the deletion of CFHR3 and CFHR1 is protective in AMD and highlight the importance of genetic variants within the CFH/CFHR3/CFHR1 locus in the recognition of altered-self in tissue homeostasis.

scholarly journals Immunoglobulin A Nephropathy: Advances in Understanding of Pathogenesis and Treatment

2018 ◽  
Vol 47 (Suppl. 1) ◽  
pp. 43-52 ◽  
Author(s):  
Richard A. Lafayette ◽  
Ellie Kelepouris
Keyword(s):  
Iga Nephropathy ◽  
Association Studies ◽  
Treatment Options ◽  
Immunoglobulin A ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Wide Range ◽  
New Treatment ◽  
Stage Renal Disease ◽  
End Stage

Background: Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis and has clinical associations with a wide range of inflammatory and infectious diseases. There is a substantial variation in clinical course and outcomes, with many patients not diagnosed until they present with sequelae, which may include gross hematuria, hypertension, renal insufficiency, and/or significant proteinuria. Treatment options are currently limited and directed mainly toward control of these sequelae and have limited ability to reduce the incidence of end-stage renal disease or treat the primary IgA defect. Summary: Growing knowledge about the pathogenesis of IgA nephropathy and research into its genetic basis are helping to elucidate the course of this widely variable disease. IgA accumulation in the kidneys is thought to be the result of a number of different pathways in a “multi-hit” process that includes an initial traumatic trigger (often infection related) and subsequent memory responses that are amplified in those with a genetic predisposition to the disease and lead to an inflammatory response in susceptible individuals. Genome-wide association studies are providing new insights into the genetic variance of this autoimmune disease and are yielding information that may address both its causes and consequences. Key Messages: New treatment approaches are urgently required for the management of patients with IgA nephropathy. Novel interventions based around its inflammatory nature and “multi-hit” pathogenesis are being investigated to potentially limit disease progression.

scholarly journals A Proteogenomic Signature of Age-related Macular Degeneration in Blood

2021 ◽  
Author(s):  
Valur Emilsson ◽  
Elias F Gudmundsson ◽  
Thorarinn Jonmundsson ◽  
Michael Twarog ◽  
Valborg Gudmundsdottir ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Serum Proteins ◽  
Association Studies ◽  
The Elderly ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Complement Factor ◽  
Age Related ◽  
Common Genetic Variants

Age-related macular degeneration (AMD) is one of the most frequent causes of visual impairment in the elderly population. The overall etiology of AMD is complex and still poorly understood, though age, obesity, smoking, and high-density lipoprotein are known risk factors. In one of the first successful reported genome-wide association studies (GWAS), common genetic variants were strongly associated with AMD, including variants within the complement factor H (CFH) gene. To date, 34 genomic regions have been linked to AMD; however, the genes that mediate the risk remain largely unknown, indicating that novel approaches to identifying causal candidates are needed. Recent advances in proteomic technology have exposed the serum proteome's depth and complexity. In the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), a broad population-based study of the elderly (N = 5764), levels of 4137 human serum proteins and associated networks were integrated with established genetic risk loci for AMD, revealing many predicted as well as novel proteins and pathways, linked to the disease. Serum proteins were also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study of five proteins associated with AMD found CFHR1, CFHR5, and FUT5 to be causally related to the disease, all of which were directionally consistent with the observational estimates. This study provides a robust and unique framework for elucidating the pathobiology of AMD.

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