The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis Jingyuan Xie et al. # Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1

General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. We propose that the promoter mutation alters tissue-specific chromatin loop formation with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic 5 causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.6

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.

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Oesophageal Carcinoma presenting as symptoms of acute respiratory distress is extremely rare. Hence diagnosis may be difficult as all the initial investigations are focused towards finding a respiratory cause. In this paper the authors report a 62 year old Caucasian male who presented with acute dyspnoea with no respiratory history but was subsequently discovered to have an oesophageal carcinoma as the likely underlying cause. Subsequent investigations revealed it to be a stage IB squamous cell midoesophageal carcinoma that was treated by radiotherapy. It is important when evaluating a patient with acute respiratory symptoms but no previous respiratory history to consider alternative pathologies related to surrounding anatomical structures also.

=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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