title: Diversity in intrinsic strengths of the human complement system: serum C4 protein concentrations correlate with C4 gene size and polygenic variations, hemolytic activities, and body mass index.
abstract: Among the genes and proteins of the human immune system, complement component C4 is extraordinary in its frequent germline variation in the size and number of genes. Definitive genotypic and phenotypic analyses were performed on a central European population to determine the C4 polygenic and gene size variations and their relationships with serum C4A and C4B protein concentrations and hemolytic activities. In a study population of 128 healthy subjects, the number of C4 genes present in a diploid genome varied between two to five, and 77.4% of the C4 genes belonged to the long form that contains the endogenous retrovirus HERV-K(C4). Intriguingly, higher C4 serum protein levels and higher C4 hemolytic activities were often detected in subjects with short C4 genes than those with long genes only, suggesting a negative epistatic effect of HERV-K(C4) on the expression of C4 proteins. Also, the body mass index appeared to affect the C4 serum levels, particularly in the individuals with medium or high C4 gene dosages, a phenomenon that was dissimilar in several aspects from the established correlation between body mass index and serum C3. As expected, there were strong, positive correlations between total C4 gene dosage and serum C4 protein concentrations, and between serum C4 protein concentrations and C4 hemolytic activities. There were also good correlations between the number of long genes with serum levels of C4A, and the number of short genes with serum levels of C4B. Thus, the polygenic and gene size variations of C4A and C4B contribute to the quantitative traits of C4 with a wide range of serum protein levels and hemolytic activities, and consequently the power of the innate defense system.
authors.affiliation: Center for Molecular and Human Genetics, Columbus Children's Research Institute, Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Erwin K
authors.initials: EK
authors.lastname: Chung
authors.forename: Bi
authors.initials: B
authors.lastname: Zhou
authors.forename: Carol A
authors.initials: CA
authors.lastname: Blanchong
authors.forename: C Yung
authors.initials: CY
authors.lastname: Yu
authors.forename: George
authors.initials: G
authors.lastname: Füst
authors.forename: Margit
authors.initials: M
authors.lastname: Kovács
authors.forename: Agnes
authors.initials: A
authors.lastname: Vatay
authors.forename: Csaba
authors.initials: C
authors.lastname: Szalai
authors.forename: István
authors.initials: I
authors.lastname: Karádi
authors.forename: Lilian
authors.initials: L
authors.lastname: Varga
mesh_terms: D000328:Adult; D015992:Body Mass Index; D003176:Complement C3 / Q000032:analysis; D015934:Complement C4a / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D015935:Complement C4b / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D015941:Complement Hemolytic Activity Assay / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics; D005136:Eye Proteins; D005260:Female; D019204:GTP-Binding Proteins; D018628:Gene Dosage; D014644:Genetic Variation / Q000276:immunology; D005838:Genotype; D006801:Humans; D006814:Hungary; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics* / Q000276:immunology*; D005810:Multigene Family / Q000276:immunology; D011110:Polymorphism, Genetic / Q000276:immunology; D011506:Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics
chemical_list: D003176:Complement C3; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011506:Proteins; C120042:RP1 protein, human; C072178:RP2 protein, human; D015534:Trans-Activators; D015934:Complement C4a; D015935:Complement C4b; D019204:GTP-Binding Proteins