Great genotypic and phenotypic diversities associated with copy-number variations (CNVs) of complement C4 and RP-C4-CYP21-TNX (RCCX) modules in Asian-Indian and European Americans (136.29)

Abstract

Abstract Inter-individual CNVs probably afford human populations the flexibility to respond to a variety of environmental challenges, but also lead to differential disease predispositions. We investigated gene CNVs for complement C4 and steroid 21-hydroxylase from the RCCX modules located in the MHC among healthy Asian-Indian Americans (AIA) and compared them to European Americans. A combination of definitive techniques that yielded cross-confirmatory results was used. The medium gene copy-numbers for C4 and its isotypes, acidic C4A and basic C4B, were 4, 2 and 2, respectively, but their frequencies were only 53-56%. The distribution patterns for total C4 and C4A are skewed towards the high copy-number side. For example, the frequency of AIA-subjects with three copies of C4A (30.7%) was 3.92-fold of those with a single copy (7.83%). The haplotype with a single short C4B gene and the absence of C4A, which is in linkage- disequilibrium with HLA DRB1*0301 in Europeans and a strong risk factor for autoimmune diseases, has a frequency of 0.012 in AIA but 0.106 among healthy European Americans (p=6.6x10-8). The copy-number and the size of C4 genes strongly determine the plasma C4 concentrations. Parallel variations in copy-numbers of CYP21A and TNXA with total C4 were observed. The high copy-numbers of C4 and the high frequency of RCCX recombinants offer important insights to the prevalence of autoimmune and genetic diseases.