Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

Jia, Xiaoyuan; Horinouchi, Tomoko; Hitomi, Yuki; Shono, Atsuko; Khor, Seik‐Soon; Omae, Yosuke; Kojima, Kazuyuki; Kawai, Yosuke; Nagasaki, Masao; Kaku, Yoshitsugu; Okamoto, Takayuki; Ohwada, Yoko; Ohta, Kazuhide; Okuda, Yusuke; Fujimaru, Rika; Hatae, Ken; Kumagai, Naoya; Sawanobori, Emi; Nakazato, Hitoshi; Ohtsuka, Yasufumi; Nakanishi, Koichi; Shima, Yuko; Tanaka, Ryojiro; Ashida, Akira; Kamei, Koichi; Ishikura, Kenji; Nozu, Kandai; Tokunaga, Katsushi; Iijima, Kazumoto

doi:10.1681/asn.2017080859

Cited by 59 publications

(59 citation statements)

References 52 publications

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“…Shown is the LD data for the lead HLA SNPs identified in previous GWAS of SSNS and this analysis, based on European reference data from the 1000 genome dataset. Note that the SNPs rs9273542 and rs2858317, identified in this analysis are in strong LD with rs4642516, identified by Jia et al 23 and with two markers, rs1063348 and rs28366266, identified by Debiec et al. 24 In contrast, the third, most telomeric marker identified by Debiec et al rs9348883 is only in weak LD with the other markers.…”

Section: Supplementary Figure 5 Manhattan Plot With Genotyped Markersupporting

confidence: 45%

Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

Dufek¹,

Cheshire²,

Levine³

et al. 2019

JASN

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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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Section: Supplementary Figure 5 Manhattan Plot With Genotyped Markersupporting

confidence: 45%

Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

Dufek¹,

Cheshire²,

Levine³

et al. 2019

JASN

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“…Additionally, HLA-DRB1*04:05-DQB1*04:01, HLA-DRB1*08:02-DQB1*03:02, and HLA-DRB1*09:01-DQB1*03:03 haplotypes are associated with susceptibility to T1DM [ 29 ]. Recently, it has been reported that the HLA-DRB1*08:02, HLA-DQB1*03:02 alleles, and the HLA-DRB1*08:02-DQB1*03:02 haplotype is highly associated with steroid-sensitive nephrotic syndrome in Japanese children [ 30 ]. Although we had speculated that our patient would have HLA-DRB1*08:02-DQB1*03:02, she had HLA-DRB1*09:01/09:01 and DQB1*03:03/03:03.…”

Section: Discussionmentioning

confidence: 99%

“…Both the patient and her mother had specific HLA haplotypes that are highly associated with T1DM, but only the daughter developed MCNS. HLA-DRB1*09:01-DQB1*03:03-DPB1*02:01 and HLA-A*02:06-C*08:01-B*40:06-DRB1*09:01-DQB1*03:03 haplotypes have been reported to be associated with childhood steroid-sensitive nephrotic syndrome in Japan, so our patient might have either one of the two haplotypes [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Concurrent minimal change nephrotic syndrome and type 1 diabetes mellitus in an adult Japanese woman: a case report

et al. 2020

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Background Concurrent type 1 diabetes mellitus (T1DM) and idiopathic nephrotic syndrome is rare, and most previously reported cases were in children. We report the case of an adult woman who developed T1DM and minimal change nephrotic syndrome (MCNS) nearly simultaneously. Case presentation A 24-year-old woman had first presented to another hospital with nausea, vomiting, and fatigue. She was diagnosed with diabetic ketoacidosis and T1DM on the basis of her hyperglycemia, ketoacidosis, and positive anti-glutamic acid decarboxylase antibody test result. Rapid infusion of normal saline and insulin administration alleviated hyperglycemia and ketoacidosis. Two weeks after admission, however, she developed nephrotic syndrome (NS) with rapidly decreasing urine volume. She was referred to our hospital with a diagnosis of acute kidney injury. Although she temporarily required dialysis and high doses of insulin, within 1 month NS and acute kidney injury had been alleviated by oral prednisolone and low-density lipoprotein apheresis. Renal biopsy showed minor glomerular abnormalities without diabetic nephropathy, so we diagnosed her with MCNS. Seven weeks after the discharge, NS relapsed, and cyclosporine was added to prednisolone. However, NS relapsed twice within the next 4 months, so we started her on rituximab. At 6 months after initiating rituximab therapy, she remained in complete remission. Her mother also had T1DM but not MCNS. The patient had HLA-DRB1*09:01/09:01, DQB1*03:03/03:03, and her mother had HLA-DRB1*04:05/09:01, DQB1*03:03/04:01. Conclusions Concurrent T1DM and MCNS is rare and their coexistence might be coincidental. Alternatively, they might have been caused by an underlying, unidentified genetic predisposition. Previous reports and our patient’s findings suggest that specific HLA alleles and haplotypes or a Th1/Th2 imbalance might be associated with T1DM and MCNS that occurred nearly simultaneously.

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“…In addition, recent genetic studies implicate variants in major histocompatibility complex, class II, DQ alpha 1 (HLA-DQA1), other major histocompatibility class II loci, and phospholipase C gamma 2 (PLCG2) as important risk factors for NS and further support the importance of defective B-cell functions in the pathogenesis of the disease. 1,3,4 Corticosteroid is the mainstay of treatment for NS, and the disease is classified as steroid-sensitive nephrotic syndrome (SSNS), frequent relapsing (FR), steroid dependent (SD), and steroid-resistant NS based on response to corticosteroid therapy. The reasons for variability in response to corticosteroid therapy in a disease in which dysregulation of immune cells is central to pathogenesis is largely unknown.…”

Section: See Clinical Investigation On Page 971mentioning

confidence: 99%

Aberrant IgM on T cells: biomarker or pathogenic factor in childhood nephrotic syndrome?

Chambers

Gbadegesin

2019

Kidney International

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Although the pathogenesis of steroid-sensitive nephrotic syndrome (SSNS) remains elusive, multiple epidemiologic, clinical, and experimental studies converge on the common theme of immune dysregulation. Initially, T-cell adaptive immunity was solely emphasized; however, the role of humoral immunity in nephrotic syndrome has gained recognition. The study by Colucci and colleagues provides preliminary evidence that production of deglycosylated IgM that is unable to regulate T-cell function in the presence or absence of corticosteroid may be responsible for a steroid-dependence course in SSNS. This study provides invaluable insights into the mechanistic roles of both T-cell and B-cell responses in the pathogenesis and clinical course of SSNS.

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Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

Cited by 59 publications

References 52 publications

Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

Concurrent minimal change nephrotic syndrome and type 1 diabetes mellitus in an adult Japanese woman: a case report

Aberrant IgM on T cells: biomarker or pathogenic factor in childhood nephrotic syndrome?

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