Replication of genome‐wide association study identified seven susceptibility genes, affirming the effect of rs2856717 on renal function and poor outcome of IgA nephropathy

Wang, Wei; Li, Guisen; Hong, Daqing; Zou, Yurong; Deng, Fei; Wang, Li

doi:10.1111/nep.12860

Cited by 11 publications

(10 citation statements)

References 23 publications

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“…In this study, we determined patients carrying rs2856717-T had an increased risk for disease progression. The result replicated a recent study (21) from southwest China showing associations between rs2856717/TT or TC and increased risk for IgA nephropathy progression. To further dissect the HLA region, we next phased four SNPs (rs7763262, rs9275224, rs2856717, and rs9275596) in the HLA-DQ/DR region and tested their Genetic risk score for each SNP was calculated based on its genotype, i.e.…”

Section: Discussionsupporting

confidence: 87%

“…It is possible that incorporating genetic risk factors such as susceptibility loci identified in GWAS to current risk models could enhance their performance because the multihit pathogenesis model suggests these loci may potentially influence the pathogenesis and severity of IgA nephropathy (3). A post-GWAS revealed that △CFHR3,1 (a deletion variant encompassing CFHR1 and CFHR3) underlining the top signal on chromosome 1 might reduce tubulointerstitial injury (20), and tag single nucleotide polymorphisms (SNPs) in HLA-DQ/DR region might accelerate IgA nephropathy progression (10,21). Further, a genetic risk score including nine susceptibility loci identified in GWAS could predict ESKD in IgA nephropathy (22).…”

Section: Introductionmentioning

confidence: 99%

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IgA Nephropathy Susceptibility Loci and Disease Progression

Shi

Yang

et al. 2018

CJASN

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

IgA Nephropathy Susceptibility Loci and Disease Progression

Shi

Yang

et al. 2018

CJASN

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“…This polymorphism was previously discovered in association with increased susceptibility to immunoglobulin A nephropathy (IgA) in Chinese patients [22] (Figure 4). It was significantly associated with macroscopic hematuria of IgA patients from the Western Chinese Han population [40]; this polymorphism's minor variation had the exact opposite effect on the pathogenesis of IMN and IgAN, indicating a completely different role for this SNP for two types of primary glomerulonephritis [41] (Figure 4). rs9275596 was identified as a Peanut Allergy (PA)-specific locus in a GWAS in participants of European ancestry; the result obtained was confirmed in a replication study of independent samples from the same cohort [42] (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

An Intergenic rs9275596 Polymorphism on Chr. 6p21 Is Associated with Multiple Sclerosis in Latvians

Paramonova¹,

Trapiņa²,

Dokane³

et al. 2020

Medicina

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Background and objectives: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, leading to demyelination of neurons and potentially debilitating physical and mental symptoms. The disease is more prevalent in women than in men. The major histocompatibility complex (MHC) region has been identified as a major genetic determinant for autoimmune diseases, and its role in some neurological disorders including MS was evaluated. An intergenic single-nucleotide polymorphism (SNP), rs9275596, located between the HLA-DQB1 and HLA-DQA2 genes, is in significant association with various autoimmune diseases according to genome-wide association studies (GWASs). A cumulative effect of this SNP with other polymorphisms from this region was revealed. The aim of the study was to verify the data on rs9275596 association in multiple sclerosis in a case/control study of the Latvian population and to evaluate eventual functional significance of allele substitutions. Materials and Methods: rs9275596 (chr6:32713854; GRCh38.p12) was genotyped in 273 MS patients and 208 controls on main and sex-specific associations. Eventual functional significance of allele substitutions was evaluated in silico using publicly available tools. Results: The rs9275596 rare alleles were identified as a disease susceptibility factor in association with the MS main group and in affected females (p < 0.001 and p < 0.01, respectively). Risk factor genotypes with rare alleles included were associated with the MS common cohort (p < 0.002) and female cohort (odds ratio, OR = 2.24) and were identified as disease susceptible in males (OR = 2.41). It was shown that structural changes of rs9275596 affect the secondary structure of DNA. Functional significance of allele substitutions was evaluated on the eventual sequence affinity to transcription factors (TFs) and splicing signals similarity. A possible impact of the particular polymorphisms on the transcription and splicing efficiency is discussed. Conclusions: Our results suggest susceptibility of rs9275596 to multiple sclerosis in Latvians.

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“…Previous studies have reported cases of IgAN and C1q nephropathy associated with TRPC6 mutations (7,22), but there is no further explanation for the deposition of immune complexes in the kidney. It has been reported that several candidate genes relating to IgAN are involved in cytokine pathways, immunoregulation, and glycosylation (23,24). Cox et al identified 23 genes with candidate pathogenic variants functionally related to a large network of immune-related pathways.…”

Section: Discussionmentioning

confidence: 99%

Two Children With Novel TRPC6 Spontaneous Missense Mutations and Atypical Phenotype: A Case Report and Literature Review

Wang

Ren

et al. 2020

Front. Pediatr.

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Background: The phenotypes of TRPC6 mutations have been reported mainly in familial and sporadic focal segmental glomerulosclerosis (FSGS), which can occur in both adults and children. Herein, we report on two children with novel TRPC6 spontaneous missense mutations associated with immune complex-mediated glomerulonephritis and minor glomerular abnormality (MGA) that showed to be resistant to corticosteroids and other immunosuppressants. Case Presentation: A 9-year-old girl presented with steroid-resistant nephrotic syndrome (SRNS), while another 11-year-old boy developed proteinuria at 7 years old. Treatment with a variety of immunosuppressants had no effect, and the renal biopsy showed immune complex-mediated glomerulonephritis and MGA. No members of their family were clinically affected. Genetic testing was performed in the two patients, revealing two novel spontaneous missense mutations in TRPC6-N110S and P112R. The girl developed end-stage renal disease (ESRD) 5 months after onset while the boy continued to have sub-nephrotic range proteinuria and normal creatinine. Conclusions: Two novel TRPC6 mutations were associated with the atypical phenotype-immune complex-mediated glomerulonephritis and MGA, rather than FSGS as previously reported. Their rates of disease progression are different. Genetic testing is helpful to identify the etiology and avoid the side effects brought on by immunosuppressants.

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Replication of genome‐wide association study identified seven susceptibility genes, affirming the effect of rs2856717 on renal function and poor outcome of IgA nephropathy

Abstract: rs2856717 may influence the clinical characteristics and poor outcome of IgAN. Further studies are warranted to explore the mechanisms for such genotype-disease phenotype association.

Cited by 11 publications

References 23 publications

IgA Nephropathy Susceptibility Loci and Disease Progression

IgA Nephropathy Susceptibility Loci and Disease Progression

An Intergenic rs9275596 Polymorphism on Chr. 6p21 Is Associated with Multiple Sclerosis in Latvians

Two Children With Novel TRPC6 Spontaneous Missense Mutations and Atypical Phenotype: A Case Report and Literature Review

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