Rare Variants in the Complement Factor H–Related Protein 5 Gene Contribute to Genetic Susceptibility to IgA Nephropathy

Zhai, Yunkai; Meng, Sijun; Zhu, Li; Shi, Sufang; Wang, Suxia; Liu, Lijun; Lv, Jicheng; Yu, Feng; Zhao, Ming‐Hui; Zhang, Hong

doi:10.1681/asn.2015010012

Cited by 60 publications

(53 citation statements)

References 42 publications

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“…23,24 In summary, although CFHR5 represents a biologically plausible candidate, more evidence is still needed before unequivocally declaring CFHR5 as a new IgAN susceptibility gene. As noted by Zhai et al, 17 independent replication is needed to confirm that these findings are not caused by chance or an artifact because of uncontrolled biases. Moreover, validation studies in non-Asian cohorts would also help to solidify the evidence and provide more information on the generalizability of these intriguing findings to other populations.…”

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confidence: 70%

“…The study by Zhai et al 17 in this issue of the Journal of the American Society of Nephrology illustrates some of the challenges in the execution and interpretation of sequence-based rare variant associations. The study is motivated by the initial GWAS findings for IgAN, which established a disease association within the complement factor H (CFH) locus on chromosome 1q32 encompassing the CFH gene and five CFH-related genes (complement factor H-related protein 1 [CFHR1] through CFHR5).…”

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confidence: 99%

“…20 CFHR5 is a universal component of complement deposits in vivo, suggesting its function in complement regulation. 21 Indeed, recent studies show that CFHR5, CFHR2, and CFHR1 share a dimerization motif that enables the formation of homo-and heterodimers enhancing the avidity of these proteins for C3b, allowing them to function as competitive antagonists of factor H. 22 Given these findings, Zhai et al 17 hypothesized that rare genetic variation in CFHR5 may also be contributing to the risk of IgAN. By applying SKAT to CFHR5 sequence data from 500 patients with IgAN and 576 controls, Zhai et al 17 observed a difference in rare variant distributions with P52310…”

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confidence: 99%

“…Careful analysis of the 28 detected rare variants identified nine as potentially functional, including three variants altering protein length and three variants increasing C3b binding to recombinant CFHR5 by in vitro assays. On the basis of these promising data, Zhai et al 17 conclude that these rare variants contribute to the genetic risk of IgAN and suggest CFHR5 as a new "IgAN susceptibility gene. "…”

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confidence: 99%

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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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confidence: 70%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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

Krzemieniecki

2016

JASN

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“…Not surprisingly, there is extensive clinical evidence of glomerular C activation in patients with this disease (68). Unbiased genome wide association studies have also identified variants in CFH and the CFHRs that strongly associate with the risk of developing IgA nephropathy (69,70). Thus, the disease may be caused by the formation of IgA 1 containing ICs, but injury of the glomerulus may also be determined by an individual's ability to regulate amplification through the AP.…”

Section: Mesangiummentioning

confidence: 99%

All Things Complement

Thurman

Nester

2016

CJASN

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The complement (C) cascade is an ancient system of proteins whose primary role is to initiate and modulate immune responses. During C activation, circulating proteins are cleaved and nascent cleavage fragments participate in a broad range of downstream innate and adaptive immune functions. Although the majority of these functions are either homeostatic or protective, a large body of experimental and clinical evidence also highlights a central role for the C system in the pathogenesis of many types of glomerular disease. From classic pathway activation in lupus nephritis to alternative pathway dysregulation in C3 glomerulopathy, our understanding of the spectrum of C involvement in kidney disease has expanded greatly in recent years. However, the characteristics that make the glomerulus so uniquely susceptible to C-mediated injury are not fully understood, and this remains an area of ongoing investigation. Several C inhibitors have been approved for clinical use, and additional C inhibitory drugs are in development. The use of these drugs in patients with kidney disease will expand our understanding of the benefits and limitations of C inhibition.

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Atypical hemolytic uremic syndrome: Unique clinical presentation linked to rare CFHR5 mutation

Menotti

Donini

Pessolano

et al. 2021

eJHaem

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Rare Variants in the Complement Factor H–Related Protein 5 Gene Contribute to Genetic Susceptibility to IgA Nephropathy

Cited by 60 publications

References 42 publications

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

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

All Things Complement

Atypical hemolytic uremic syndrome: Unique clinical presentation linked to rare CFHR5 mutation

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