Diseases associated with the low copy number of the <i>C4B</i> gene encoding C4, the fourth component of complement

Abstract

In this review article, earlier and recent work of the research group on the copy number polymorphism of the C4B gene are summarized. In a study performed in 1991 a sharp decrease was found among healthy elderly (>60 years old) people as compared to healthy young (<45 years old) people in the frequency of the individuals with a low copy number of the C4B gene (one of the two genes (C4A and C4B) encoding the C4 complement protein). This observation indicated that subjects with a low C4B copy number are selected out from the population of healthy individuals due to their increased morbidity/mortality of some disease(s). In accordance with this assumption a marked accumulation of low C4B copy number carriers was found in patients with acute myocardial infarction (AMI) and stroke as compared to age-matched healthy subjects. In addition it was demonstrated that AMI patients who carry a low copy number of the C4B gene have a highly significantly increased risk for short-term (1 year) post-AMI mortality as compared to non-carriers. These relationships, which were first revealed more than 15 years ago by our group, have been recently supported by new data obtained using up-to-date genotyping methods worked out by our group in two Caucasian populations, Hungarian and Icelandic. In addition, we proved that this relationship concerns only recent smokers. These findings indicate that there is strong connection between low copy number of the C4B gene on one hand and cardiovascular disease morbidity and mortality on the other. Hypotheses and the results of recent studies aiming to elucidate the mechanism of this association as well as other diseases connected with the low C4B copy number are discussed.

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

“…37 Our much larger study failed to replicate either association for C4 gene CNV in the 10 years of follow-up after transplantation, at least as reflected by the recorded data on cardiovascular death and hospitalization for infection. One cannot exclude the possibility that a relatively small effect on C4 gene CNV found in the general population is overwhelmed by the much more powerful additional risks present in the renal transplant population.…”

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

“…14 Both RCCX structural variations and MHC haplotypes have long been studied for their effects on diverse physiological and pathological processes. 6,36,37 The exact relationship between disorder and RCCX is unambiguous when a defective gene is involved; 7,38 most often, however, identification of the real causative factors proves fairly challenging. RCCX disease association studies have mainly focused on C4 GCNs, [39][40][41] but forgetting about the complexity of RCCX variations and the longrange LD characteristics of the MHC hides the danger of overseeing the genuine molecular background.…”

“…4 Lower levels of C4A confer higher susceptibility to autoimmune disorders, 5 and lower levels of C4B have been associated with increased prevalence of cardiovascular disease. 6 Integration of the HERV-K(C4) sequence presumably confers protection against exogenous retroviral attacks, but also decreases serum C4 concentrations. 1 Defects of the functional CYP21A2 gene lead to congenital adrenal hyperplasia, the most common autosomal recessive disorder worldwide.…”

Association between Age and the 7 Repeat Allele of the Dopamine D4 Receptor Gene

“…Also, a potential negative effect of certain complement C4 haplotypes on health and survival was shown in a Hungarian study by Kramer and colleagues [10], which was more recently replicated by Arason and colleagues [11]. This might be due to non-specific disease susceptibility presumably acting through insufficient immune response [12]. It is also possible, that some genes exert their influence on longevity through personality traits, such as conscientiousness and some of its facets (responsibility, self-control and traditionalism) which have been shown to be significant predictors of extended life-span [13].…”