title: Great genotypic and phenotypic diversities associated with copy-number variations of complement C4 and RP-C4-CYP21-TNX (RCCX) modules: a comparison of Asian-Indian and European American populations.
abstract: Inter-individual gene copy-number variations (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 component C4 and steroid 21-hydroxylase from the RP-C4-CYP21-TNX (RCCX) modules located in the major histocompatibility complex 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 monomodular-short haplotype with a single 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 protein concentrations. Parallel variations in copy-numbers of CYP21A (CYP21A1P) and TNXA with total C4 were also observed. Notably, 13.1% of AIA-subjects had three copies of the functional CYP21B, which were likely generated by recombinations between monomodular and bimodular RCCX haplotypes. The high copy-numbers of C4 and the high frequency of RCCX recombinants offer important insights to the prevalence of autoimmune and genetic diseases.
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, United States.
authors.forename: Kapil
authors.initials: K
authors.lastname: Saxena
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Kitzmiller
authors.forename: Yee Ling
authors.initials: YL
authors.lastname: Wu
authors.forename: Bi
authors.initials: B
authors.lastname: Zhou
authors.forename: Nazreen
authors.initials: N
authors.lastname: Esack
authors.forename: Leena
authors.initials: L
authors.lastname: Hiremath
authors.forename: Erwin K
authors.initials: EK
authors.lastname: Chung
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: C Yung
authors.initials: CY
authors.lastname: Yu
mesh_terms: D001213:Asian / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics; D003181:Complement C4 / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D019204:GTP-Binding Proteins; D018628:Gene Dosage / Q000502:physiology*; D005787:Gene Frequency; D030342:Genetic Diseases, Inborn / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D015798:HLA-DR1 Antigen / Q000235:genetics; D006801:Humans; D007194:India / Q000208:ethnology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium; D008565:Membrane Proteins / Q000235:genetics*; D008869:Microtubule-Associated Proteins; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D019063:Tenascin / Q000235:genetics*; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: D003181:Complement C4; D005136:Eye Proteins; D015798:HLA-DR1 Antigen; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C120042:RP1 protein, human; C072178:RP2 protein, human; D019063:Tenascin; D013255:Steroid 21-Hydroxylase; D019204:GTP-Binding Proteins