Identification of a Locus on the X Chromosome Linked to Familial Membranous Nephropathy

Downie, Mallory L.; Gupta, Sanjana; Tekman, Mehmet; Cheshire, Chris; Arora, Sourabh; Licht, Christoph; Robinson, Lisa A.; Muñoz, Marina; Aris, Álvaro Madrid; Attrach, Ibrahim Al; Brenchley, Paul; Gale, Daniel P.; Stanescu, Horia; Böckenhauer, Detlef; Kleta, Robert

doi:10.1016/j.ekir.2021.02.025

Cited by 3 publications

(2 citation statements)

References 35 publications

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“…The effect for the added epistatic interaction between PLA2R1 and HLA-DRB1 was accounted for – if all 4 risk alleles were present in these 2 SNVs, then the interaction effect was added to the previous sum. The overall result was divided by 6 (to correct for the total number of loci) [34] .

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Section: Genotypingmentioning

confidence: 99%

A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy

Gupta¹,

Downie²,

Cheshire³

et al. 2023

Glomerular Dis

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=Introduction: Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults and is characterized by detectable autoantibodies against glomerular antigens, most commonly phospholipase A2 receptor-1 (PLA2R1) and thrombospondin type-1 domain containing 7A (THSD7A). In Europeans genetic variation in at least five loci, PLA2R1, HLA-DRB1, HLA-DQA1, IRF4 and NFKB1 affect the risk of disease. Here, we investigated the genetic risk differences between different autoantibody states. Methods: 1409 MN individuals were genotyped genome-wide with a dense SNV array. The genetic risk score (GRS) was calculated utilising the previously identified European MN loci and results were compared with 4929 healthy controls and 422 individuals with steroid sensitive nephrotic syndrome. Results: GRS was calculated in the 759 MN individuals in whom antibody status was known. The GRS for MN was elevated in the anti-PLA2R1 antibody positive (N=372) compared with both the unaffected control (N=4929) and anti-THSD7A positive (N=31) groups (p<0.0001 for both comparisons), suggesting that this GRS reflects anti-PLA2R1 MN. Among PLA2R1 positive patients, GRS was inversely correlated with age of disease onset (p=0.009). Further, the GRS in the dual antibody negative group (N=355) was intermediate between controls and the PLA2R1 positive group (p<0.0001). Conclusion: We demonstrate that the genetic risk factors for PLA2R1- and THSD7A-antibody associated MN are different. A higher GRS is associated with younger age of onset of disease. Further, a proportion of antibody negative MN cases have an elevated GRS similar to PLA2R1-positive disease. This suggests that in some individuals with negative serology the disease is driven by autoimmunity against PLA2R1.

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Section: Genotypingmentioning

confidence: 99%

A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy

Gupta¹,

Downie²,

Cheshire³

et al. 2023

Glomerular Dis

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“…1A. SSNS-GRS was determined by the sum of the natural logarithm (ln) of the odds ratio multiplied by the number of risk alleles at each locus (0, 1, or 2), divided by the total number of possible alleles [35,36]. At protective loci, values were computed using the natural logarithm of the inverse odds multiplied by the number of non-protective alleles.…”

Section: Calculation Of the Genetic Risk Scorementioning

confidence: 99%

Shared genetic risk across different presentations of gene test–negative idiopathic nephrotic syndrome

et al. 2022

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Background Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways. Methods We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls. Results The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS. Conclusions The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. Graphical abstract

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Association between PLA2R gene polymorphism and idiopathic membranous nephropathy in Heilongjiang Chinese

Tian¹,

Zheng²,

Li³

et al. 2023

Ann Transl Med

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Background: The aim of this study was to investigate the correlation between the phospholipase A2 receptor (PLA2R) gene polymorphism and idiopathic membranous nephropathy (IMN) in Heilongjiang Chinese. Methods: Thirty-five patients with IMN confirmed by renal biopsy attending the Heilongjiang Hospital of Traditional Chinese Medicine between June 2021 and December of 2021 were selected as the IMN group, and a group of 25 healthy participants from the Physical Examination Center of Heilongjiang Hospital of Traditional Chinese Medicine were enrolled as healthy controls. Polymerase chain reaction (PCR) was used to identify and genotype 8 single-nucleotide polymorphism (SNP) loci (rs16844715, rs2715918, rs2715928, rs35771982, rs3749119, rs3828323, rs4665143, and rs6757188) of PLA2R and to analyze the PLA2R gene polymorphisms that correlated with IMN. SPSS 26.0 statistical software was used for data analysis, and the chi-squared (χ 2 ) goodness-of-fit test was used to determine whether each SNP genotype and allele in the PLA2R gene complied with the Hardy-Weinberg equilibrium. The qualitative data were analyzed via χ 2 or Fisher exact probability method. Logistic regression was used to analyze risk factors, and the odds ratios (ORs)values and 95% confidence intervals (CIs) were calculated. α=0.05 was taken as the test level, and P<0.05 was considered statistically significant.Results: Statistically significant differences were found in the genotype and allele frequencies of rs35771982 and rs3749119 between the IMN and control groups (P<0.05). Logistic regression analysis showed that the genotypes rs35771982 GG and rs3749119 CC were associated with IMN susceptibility. Statistically significant differences in uric acid level were found between the rs35771982 GG and CG + CC genotypes (P<0.05), while statistically significant differences in serum albumin were detected between rs3749119 CC and the CT + TT genotypes (P<0.05). Multivariate logistic regression analysis showed that gender, age, and triglyceride levels affected the occurrence of IMN (P<0.05). Conclusions:The PLA2R gene polymorphisms rs35771982 and rs3749119 in Heilongjiang Chinese may be related to IMN susceptibility and correlated with clinical indicators of IMN. Gender, age, and triglyceride levels may influence the occurrence of IMN.

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Identification of a Locus on the X Chromosome Linked to Familial Membranous Nephropathy

Cited by 3 publications

References 35 publications

A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy

A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy

Shared genetic risk across different presentations of gene test–negative idiopathic nephrotic syndrome

Association between PLA2R gene polymorphism and idiopathic membranous nephropathy in Heilongjiang Chinese

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