Low C4 gene copy numbers are associated with superior graft survival in patients transplanted with a deceased donor kidney

Bay, Jakob Thaning; Schejbel, Lone; Madsen, Hans O.; Sørensen, Søren Schwartz; Hansen, Jesper Melchior; Garred, Peter

doi:10.1038/ki.2013.195

Cited by 18 publications

(7 citation statements)

References 28 publications

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“…Our finding that increased copy number of C4A is associated with protection in AMD may have direct implications for therapy, as targeted approaches to molecular constituents of the complement pathway have the potential for early intervention before vision is compromised. This is especially true, in very contrast to most associated single nucleotide variants, as we can directly implicate the relevant gene ( C4A ) and the orientation of the protective effect with increased copy numbers and thus with increased C4A protein levels in serum [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD)

Graßmann

Cantsilieris

Schulz-Kuhnt

et al. 2016

J Neuroinflammation

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BackgroundAge-related macular degeneration (AMD) is the leading cause of vision loss in Western societies with a strong genetic component. Candidate gene studies as well as genome-wide association studies strongly implicated genetic variations in complement genes to be involved in disease risk. So far, no association of AMD with complement component 4 (C4) was reported probably due to the complex nature of the C4 locus on chromosome 6.MethodsWe used multiplex ligation-dependent probe amplification (MLPA) to determine the copy number of the C4 gene as well as of both relevant isoforms, C4A and C4B, and assessed their association with AMD using logistic regression models.ResultsHere, we report on the analysis of 2645 individuals (1536 probands and 1109 unaffected controls), across three different centers, for multiallelic copy number variation (CNV) at the C4 locus. We find strong statistical significance for association of increased copy number of C4A (OR 0.81 (0.73; 0.89);P = 4.4 × 10−5), with the effect most pronounced in individuals over 78 years (OR 0.67 (0.55; 0.81)) and females (OR 0.77 (0.68; 0.87)). Furthermore, this association is independent of known AMD-associated risk variants in the nearby CFB/C2 locus, particularly in females and in individuals over 78 years.ConclusionsOur data strengthen the notion that complement dysregulation plays a crucial role in AMD etiology, an important finding for early intervention strategies and future therapeutics. In addition, for the first time, we provide evidence that multiallelic CNVs are associated with AMD pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0548-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD)

Graßmann

Cantsilieris

Schulz-Kuhnt

et al. 2016

J Neuroinflammation

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“…It was also reported that the deficiency of either C4A or C4B has been associated with the increased susceptibility of infections (18,64,65). Interestingly, it was reported by Bay et al that low C4 gene copy numbers (< 4 total copies of C4 genes) are associated with superior graft survival in patients transplanted with a deceased donor kidney (66). A comprehensive review on the variations of C4 genetic structures and proteins was presented by Blanchong CA et al (36).…”

Section: Diversity Of Complement C4 Genes and Proteinsmentioning

confidence: 99%

Complement C4, Infections, and Autoimmune Diseases

Wang

Liu

2021

Front. Immunol.

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Complement C4, a key molecule in the complement system that is one of chief constituents of innate immunity for immediate recognition and elimination of invading microbes, plays an essential role for the functions of both classical (CP) and lectin (LP) complement pathways. Complement C4 is the most polymorphic protein in complement system. A plethora of research data demonstrated that individuals with C4 deficiency are prone to microbial infections and autoimmune disorders. In this review, we will discuss the diversity of complement C4 proteins and its genetic structures. In addition, the current development of the regulation of complement C4 activation and its activation derivatives will be reviewed. Moreover, the review will provide the updates on the molecule interactions of complement C4 under the circumstances of bacterial and viral infections, as well as autoimmune diseases. Lastly, more evidence will be presented to support the paradigm that links microbial infections and autoimmune disorders under the condition of the deficiency of complement C4. We provide such an updated overview that would shed light on current research of complement C4. The newly identified targets of molecular interaction will not only lead to novel hypotheses on the study of complement C4 but also assist to propose new strategies for targeting microbial infections, as well as autoimmune disorders.

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“…Some complement proteins are located in the MHC locus (C2, C4), and are also polymorphic [57]. Genetic predisposition to specific polymorphisms may be useful for risk stratifying patients, and indeed polymorphisms in complement C4 [58] but not C3 [59] have been shown to influence renal allograft outcome. In addition, complement concentration is potentiated in response to local inflammation.…”

Section: Factors Which Dictate Complement Activationmentioning

confidence: 99%

The perfect storm: HLA antibodies, complement, FcγRs, and endothelium in transplant rejection

Thomas

Valenzuela

Reed

2015

Trends in Molecular Medicine

105

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The pathophysiology of antibody-mediated rejection (AMR) in solid organ transplants is multi-faceted and predominantly caused by antibodies directed against polymorphic donor human leukocyte antigens (HLA). Despite the clearly detrimental impact of HLA antibodies (HLA-Ab) on graft function and survival, the prevention, diagnosis and treatment of AMR remain a challenge. Histological manifestations of AMR reflect signatures of HLA-Ab-triggered injury, specifically endothelial changes, recipient leukocytic infiltrate, and complement deposition. We review the interconnected mechanisms of HLA-Ab-mediated injury that might synergize in a “perfect storm” of inflammation. Characterization of antibody features that are critical for effector functions may help identify HLA-Ab more likely to cause rejection. We also highlight recent advancements that may pave the way for new, more effective therapeutics.

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Low C4 gene copy numbers are associated with superior graft survival in patients transplanted with a deceased donor kidney

Cited by 18 publications

References 28 publications

Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD)

Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD)

Complement C4, Infections, and Autoimmune Diseases

The perfect storm: HLA antibodies, complement, FcγRs, and endothelium in transplant rejection

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