The genetics and immunobiology of IgA nephropathy

Kiryluk, Krzysztof; Novák, Jan

doi:10.1172/jci74475

Cited by 194 publications

(156 citation statements)

References 123 publications

(140 reference statements)

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“…IgAN recurs in approximately 50%-60% of transplanted patients, indicating an important contribution of extrarenal factors to pathogenesis. [2][3][4][5] A great deal of evidence exists to support a significant genetic contribution to IgAN. [5][6][7][8][9] The incidence of IgAN varies geographically, being most prevalent in East Asian populations and less prevalent in European and African populations.…”

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confidence: 99%

“…[2][3][4][5] A great deal of evidence exists to support a significant genetic contribution to IgAN. [5][6][7][8][9] The incidence of IgAN varies geographically, being most prevalent in East Asian populations and less prevalent in European and African populations. 10,11 Six genomewide association studies have collectively identified 20 distinct loci associated with IgAN.…”

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confidence: 99%

“…In IgAN patients an increased proportion of IgA1 glycans terminate in N-acetylgalactosamine or sialylated Nacetylgalactosamine. 5,18 This type of IgA1 is termed galactose-deficient IgA1 (gd-IgA1). gd-IgA1 has an established role in the development of IgAN.…”

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confidence: 99%

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IgA1 Glycosylation Is Heritable in Healthy Twins

Lomax-Browne

Visconti

Pusey

et al. 2016

JASN

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IgA nephropathy (IgAN) is the most common form of primary GN and an important cause of kidney failure. Characteristically, patients with IgAN have increased serum levels of undergalactosylated IgA1 (gd-IgA1). To assess the degree to which serum gd-IgA1 levels are genetically determined in healthy individuals, we determined serum IgA and gd-IgA1 levels by ELISA in a sample of 148 healthy female twins, including 27 monozygotic and 47 dizygotic pairs. Using the classic twin model, we found the heritability of serum gd-IgA1 and IgA levels to be 80% (95% confidence interval, 66% to 89%) and 46% (95% confidence interval, 15% to 69%), respectively. These data indicate that serum gd-IgA1 levels are highly heritable. Elucidating the genetic basis of this heritability will be important in understanding the pathogenesis of IgAN.

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IgA1 Glycosylation Is Heritable in Healthy Twins

Lomax-Browne

Visconti

Pusey

et al. 2016

JASN

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“…The currently available modern antiinflammatory therapies will result in a substantial reduction of renal amyloidosis, a severe consequence of prolonged and poorly controlled chronic inflammatory states like RA. The occurrence of mesangial IgA nephropathy suggests probably a dysregulated immune response with increased production or decreased clearance of immune complexes in this subset of patients (22).…”

Section: Discussionmentioning

confidence: 92%

Respiratory Distress and Nephropathy in a Young Male With Small‐Joint Polyarthritis

Korsten

Konig

Müller

et al. 2016

Arthritis Care & Research

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History of the present illness. A 27-year-old man presented to our department with a 4-week history of worsening fatigue, malaise, and painful swelling of his wrists and finger joints. He further complained of new-onset progressive dyspnea with nonproductive cough, subfebrile temperatures, and proximal muscle weakness in his lower extremities in the last 10 days. Except for the arthritis, he had not experienced these symptoms in the past. Two months prior to admission, he was seen for the first time by a rheumatologist. At that time, he reported severe pain and stiffness in his hands, particularly at night, but no breathing or muscle difficulties. Laboratory tests at the rheumatologist's office showed increased C-reactive protein (CRP) levels and high-titer anti-cyclic citrullinated peptide (CCP) antibodies. Plain radiographs demonstrated an erosion at the fifth metatarsal head of his right foot. He was diagnosed with rheumatoid arthritis (RA) and started on oral methotrexate (MTX) and prednisone. Medical historyThe patient reported having intermittent arthralgias in his hands, elbows, and hips for the past 3 years. He had been treated with nonsteroidal antiinflammatory drugs and oral glucocorticoids as needed by his primary care provider. In the last couple of months, he increasingly experienced painful arthritis in his hands. After being diagnosed with RA, oral treatment with MTX 15 mg weekly and prednisone 50 mg daily (followed by slow tapering) was initiated, along with prophylactic pantoprazole (40 mg daily) and folic acid (5 mg weekly). He was adherent to the therapy and denied taking over-the-counter drugs or supplements. There were no other medical or surgical illnesses.Social and family history. He used to work as a gardener. His social history was negative for smoking and alcohol abuse. He denied recent travel or contact with someone with similar symptoms. His grandmother had a diagnosis of RA, but his family history was otherwise negative for autoimmune or pulmonary disorders. Review of systems.There was no history of photosensitivity, rash, sicca symptoms, Raynaud's phenomenon, back pain, hemoptysis, dysphagia, or diarrhea.Physical examination. On admission, his temperature was 37.08C, blood pressure 130/80 mm Hg, pulse 105 beats per minute, respiratory rate 24 breaths per minute, and oxygen saturation of 95% while breathing ambient air. There was no lymphadenopathy, jaundice, or cyanosis. Auscultation of the lung revealed fine bibasilar crackles. Cardiac (except tachycardia), abdominal, and neurologic examinations were unremarkable. His wrists, metacarpophalangeal, and proximal interphalangeal joints of both hands were swollen and tender with limited range of motion. There was isolated weakness of the thigh muscles (4/5), but no muscle wasting or fasciculations.Laboratory tests and imaging. Initial workup showed a hemoglobin level of 14.5 gm/dl (normal range [NR] 13.5-17.5), white blood cell count of 13.3 3 10 3 /ml (NR 4-11 3 10 3 ), and platelets of 273 3 10 3 /ml (NR 150-350 3 10 3 ). The differe...

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“…[7][8][9] These findings led to a significant refinement of the disease pathogenesis model and provided novel clues about the disease geoepidemiology. [10][11][12] Similarly, the genetic interaction between variants in PLA2R1 and HLA arising from GWAS solidified the pathogenesis model for membranous nephropathy, highlighting the antigen-HLA interplay as central to the disease process. 13 Despite this progress, however, a large portion of the genetic contribution to many complex traits remains unexplained, including traits for which very large GWAS meta-analyses have already been performed.…”

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confidence: 94%

Challenges in Rare Variant Association Studies for Complex Kidney Traits: CFHR5 and IgA Nephropathy

Krzemieniecki

2016

JASN

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4. Cheema BS, Chan D, Fahey P, Atlantis E: Effect of progressive resistance training on measures of skeletal muscle hypertrophy, muscular strength and health-related quality of life in patients with chronic kidney disease: A systematic review and meta-analysis. These findings led to a significant refinement of the disease pathogenesis model and provided novel clues about the disease geoepidemiology. [10][11][12] Similarly, the genetic interaction between variants in PLA2R1 and HLA arising from GWAS solidified the pathogenesis model for membranous nephropathy, highlighting the antigen-HLA interplay as central to the disease process. 13 Despite this progress, however, a large portion of the genetic contribution to many complex traits remains unexplained, including traits for which very large GWAS meta-analyses have already been performed. This issue has been identified as the missing heritability problem. The missing heritability has many potential explanations, including the possibility that low-frequency variants substantially contribute to the inherited risk of disease. Such rare alleles are not well captured on popular microarray genotyping platforms and thus, have been www.jasn.org EDITORIALS largely ignored by traditional GWASs. However, rare alleles can be accurately detected by direct DNA sequencing. Rapid progress in sequencing technology now enables investigations of the role of rare genetic variants in complex traits through sequence-based association studies. Although the jury is still out on whether such studies can account for the missing heritability, this design has already been deployed for several complex disorders, and we can certainly expect its broader application to kidney traits in the near future. Sequence-based association studies present substantial challenges that relate to the detection, analysis, and interpretation of rare variants. Unless sample sizes or variant effect sizes are very large, these studies are usually limited by low statistical power. Moreover, the requisite multiple test corrections are poorly understood, creating difficulties in the interpretation of findings. In GWASs, the standard approach involves a single-variant test with the significance threshold of 531028 that accounts for the estimated number of common haplotype blocks in the genome. 14 Given sufficient sample size, a similar approach can also be applied to rare variants, but its power is inversely related to allelic frequency. For example, to achieve 80% power to detect a disease association for a rare variant with a frequency of 1:1000 (0.1%) and an odds ratio of 2.0, one would require .60,000 patients (and an equal number of controls) to detect a statistically significant association for a disease with a population prevalence of 5%. In addition, single-variant tests on the basis of standard regression methods might not be accurate if the number of subjects with the variant is very small. Numerous alternative strategies have, therefore, been proposed to circumvent these issues. Most strategies aggregate var...

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The genetics and immunobiology of IgA nephropathy

Cited by 194 publications

References 123 publications

IgA1 Glycosylation Is Heritable in Healthy Twins

IgA1 Glycosylation Is Heritable in Healthy Twins

Respiratory Distress and Nephropathy in a Young Male With Small‐Joint Polyarthritis

Challenges in Rare Variant Association Studies for Complex Kidney Traits: CFHR5 and IgA Nephropathy

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