Figure 12.13 Gene dosage for C4 observed in Caucasians. Redrawn from Blanchong et al. (2000), copyright Blanchong et al, 2000 (originally published in the Journal of Experimental Medicine).
functional CYP21B gene, while RP2 and TNXA are fragments and non-functional. Most work has been done on Caucasian populations with between one and three copies of the module found on a given haplotype (Fig. 12.14). A 1-2-3-locus concept has been proposed with over 22 haplotypes of RCCX described comprising different combinations of long and short genes for C4A, C4B, CYP21A, CYP21B, TNXA, and TNXB (Blanchong et al. 2000).
The bimodular state is most commonly seen, with most people having a combination of C4A and C4B. There are, however, ethnic differences (Yu and Whitacre 2004). The bimodular long-long (LL) state is the most common seen in Caucasians and is associated with equal expression of C4A and C4B but at relatively low levels when C4 protein is measured in the plasma. Among blacks and orientals, long-short (LS) is the most common with higher plasma levels of C4B than C4A. Monomodular short RCCX with C4B alone is found at a relatively high frequency in Caucasians of 10%, but at only 1% in Asians: this variant of the RCCX module is found as part of the 8.1 ancestral haplotype associated with susceptibility to systemic lupus erythematosus (SLE) and type 1 diabetes. In contrast, the bimodular LL RCCX module associated with low expression of C4A and C4B is found on the 7.2 ancestral haplotype associated with susceptibility to SLE and multiple sclerosis but with protection from type 1 diabetes.
While this diversity has advantages for our immune response, the fact that 69.4% of the population have heterozygous haplotypic combinations in terms of number of modules and gene size promotes misalignment of chromosomes during meiosis, with risk of non-allelic homologous recombination and unequal crossover. This in turn poses a risk of gene deletions and duplications and disease.
The complex possible haplotypic combinations of C4A and C4B are the major determinants of levels of protein expression. C4 gene dosage, gene size, and body mass index have all been found to be associated with quantitative variation in plasma levels of C4 protein (Yu and Whitacre 2004). Thus people with four copies of the long C4 gene (LL/LL) have 40% lower C4 levels than those having four copies of the gene if they comprise two long and two short versions (LS/LS). This apparent association with the possession of the HERV-K(C4) insertion may be a direct consequence as experiments have shown that sequences from the 3' LTR of HERV-K(C4) have promoter activity and can direct synthesis of antisense transcripts complementary to human C4 (Mack et al. 2004). Serum C4B levels are 40% higher in African Americans than those Americans of European descent (Moulds et al. 1991): the former have a high frequency of the short form of C4 lacking the HERV-K(C4) insertion.
There is strong evidence to link deficiencies of C4 proteins with the autoimmune disease SLE. It is striking that in the extremely rare instances where individuals with complete C4A and C4B deficiency have been identified, almost all had SLE or the associated renal or skin symptoms found in lupus (Yang et al. 2004b). Among SLE patients in general, low serum C4 protein levels are often seen with two- to five-fold greater rates of homozygous or partial deficiency of C4A than matched control individuals without SLE (Yang et al. 2004a). There are, however, ethnic differences reported: among patients with SLE of Spanish, Mexican, or Australian aboriginal origin, a high frequency of C4B deficiency is found. A diverse range of other autoimmune diseases have been associated with polymorphism of C4, including type 1 diabetes, IgA deficiency, common variable immunodeficiency, IgA nephropathy, vitiligo, and pemphigus vulgaris. Elsewhere in the RCCX module, mutations or deletions of CYP21B cause congenital adrenal hyperplasia (Miller and Morel 1989).
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