Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement &lt;i&gt;C4&lt;/i&gt; CNVs in European American healthy subjects and those with systemic lupus erythematosus

Wu, Yee Ling; Yang, Yan; Chung, Erwin K.; Zhou, Bi; Kitzmiller, Kathryn; Savelli, Stephanie; Nagaraja, H. N.; Birmingham, Dan; Tsao, Betty P.; Rovin, Brad H.; Hebert, Lee A.; Yu, Chack‐Yung

doi:10.1159/000184700

Cited by 63 publications

(48 citation statements)

References 111 publications

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“…Our negative result contrasts with other immune-mediated inflammatory settings, such as susceptibility to autoimmune disease and the response to infection, both of which have been associated with C4 gene CNV. [15][16][17][18] The large sample size is a major strength of our study and gives it sufficient statistical power to justify our conclusions. However, it did require the use of archived samples and retrospective database analyses with all their inherent limitations.…”

Section: Discussionmentioning

confidence: 91%

“…12 Importantly, the number of copies inherited correlates closely with plasma C4 concentrations and functional complement activity 13,14 and may contribute to susceptibility to infection and autoimmune disease. [15][16][17][18] Consequently, genetic analysis in kidney transplant donor recipient pairs provides an unusual human model system to study the influence of C4 in immunemediated injury that uniquely is able to distinguish between local and systemic origin.…”

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confidence: 99%

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Genotypic Diversity of Complement Component C4 Does Not Predict Kidney Transplant Outcome

Wahrmann¹,

Döhler²,

Ruhenstroth³

et al. 2011

Journal of the American Society of Nephrology

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Gene copy number of complement component C4, which varies among individuals, may determine the intrinsic strength of the classical complement pathway. Presuming a major role of complement as an effector in transplant rejection, we hypothesized that C4 genetic diversity may partially explain the variation in allograft outcomes. This retrospective study included 1969 deceased-donor kidney transplants randomly selected from the Collaborative Transplant Study DNA bank. We determined recipient and donor gene copy number of total C4, C4 isotypes (C4A and C4B), and C4 gene length variants (C4L and C4S) by quantitative real-time PCR analysis. Groups defined according to recipient C4 gene copy number (low, intermediate, and high) had similar 10-year allograft survival. Genotypic groups showed comparable rates of graft dysfunction, treatment for rejection, immunological graft loss, hospitalization for infection, malignant disease, and death. Similarly, separate analyses of C4A, C4B, C4L, and C4S; combined evaluation of donor and recipient C4 genotype; or analysis of recipients with higher risk for rejection did not reveal considerable outcome effects. In conclusion, we did not demonstrate that C4 gene copy number associates with transplant outcome, and we found no evidence that the resulting variation in the strength of classical complement activation influences susceptibility to rejection.

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

Genotypic Diversity of Complement Component C4 Does Not Predict Kidney Transplant Outcome

Wahrmann¹,

Döhler²,

Ruhenstroth³

et al. 2011

Journal of the American Society of Nephrology

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“…20 Here we also give evidence of the assumption that C4A genes are almost always long and that there is an approximately equal chance that a C4B gene belongs to the short or the long variant. 21 Former RCCX-related studies sometimes also detected dosage ratios of TNX and CYP21 active genes and pseudogenes. 10,11 Our group did not examine the TNX genes, but CYP21A2 and CYP21A1P…”

Section: (L)-b(s)-b(s) and B(l)-a(s)-b(s)mentioning

confidence: 99%

Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes

et al. 2012

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The human RCCX is a common multiallelic copy number variation locus whose number of segments varies between one and four in a chromosome. The monomodular form normally comprises four functional genes, but in duplicated RCCX segments generally only the gene-encoding complement component C4 produces a protein. C4 genes can code either for a C4A or a C4B isotype protein and exhibit dichotomous size variation. Distinct RCCX variants show association with numerous diseases; however, identification of the basis of these associations is often challenging, not least because the RCCX is localized in the major histocompatibility complex (MHC) region, a genomic area characterized by exceedingly long-range linkage disequilibrium. Here we present a detailed analysis on RCCX variants and their relationship with so-called 'ancestral' or 'conserved extended' MHC haplotypes in healthy Caucasians. In addition to former investigations, precise order and size of all C4A and C4B genes were determined even in trimodular RCCX structures. Considering C4 copy numbers, length, isotype specificity and CYP21A2 copy numbers, we have identified 15 distinct RCCX variants and described the RCCX structures involved in 29 repeatedly occurring MHC haplotypes. The findings should become a useful tool for future RCCX-and MHC-related disease association studies.

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“…Based on our interesting preliminary results such a study is underway. While the two C4 proteins, C4A and C4B, have mainly overlapping functions, some differences may also be observed (27). C4A deficiencies are often associated with susceptibility to autoimmune diseases (28).…”

Section: Discussionmentioning

confidence: 99%

Complement activation and regulation in preeclamptic placenta

et al. 2014

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† Anna Inkeri Lokki and Jenni Heikkinen-Eloranta have contributed equally to this work.Preeclampsia (PE) is a common disorder of pregnancy originating in the placenta. We examined whether excessive activation or poor regulation of the complement system at the maternal-fetal interface could contribute to the development of PE. Location and occurrence of complement components and regulators in placentae were analyzed. Cryostat sections of placentae were processed from 7 early-onset PE (diagnosis <34 weeks of gestation), 5 late-onset PE, 10 control pregnancies, and immunostained for 6 complement activators and 6 inhibitors. Fluorescence was quantified and compared between PE and control placentae. Gene copy numbers of complement components C4A and C4B were assessed by a quantitative PCR method. Maternal C4 deficiencies (≥1 missing or nonfunctional C4) were most common in the early-onset PE group (71%), and more frequent in late-onset PE compared to healthy controls (60 vs. 38%). Complement C1q deposition differed significantly between control and patient groups: controls and early-onset PE patients had more C1q than late-onset PE patients (mean p = 0.01 and p = 0.005, respectively). C3 activation was analyzed by staining for C3b/iC3b and C3d. C3d was mostly specific to the basal syncytium and C3b/iC3b diffuse in other structures, but there were no clear differences between the study groups. Activated C4 and membrane-bound regulators CD55, CD46, and CD59 were observed abundantly in the syncytiotrophoblast. Syncytial knots, structures enriched in PE, stained specifically for the classical pathway inhibitor C4bp, whereas the key regulator alternative pathway, factor H (FH) showed a wider distribution in the placenta. Differences in C1q deposition between late-and early-onset PE groups may be indicative of the different etiology of PE symptoms in these patients. Irregular distribution of the complement regulators C4bp and FH in the PE placenta and a higher frequency of C4A deficiencies suggest a disturbed balance between complement activation and regulation in PE.

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Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement <i>C4</i> CNVs in European American healthy subjects and those with systemic lupus erythematosus

Cited by 63 publications

References 111 publications

Genotypic Diversity of Complement Component C4 Does Not Predict Kidney Transplant Outcome

Genotypic Diversity of Complement Component C4 Does Not Predict Kidney Transplant Outcome

Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes

Complement activation and regulation in preeclamptic placenta

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