title: Relationship between complement components C4A and C4B diversities and two TNFA promoter polymorphisms in two healthy Caucasian populations.
abstract: The RP-C4-CYP21-TNX (RCCX) modules and the tumor necrosis factor (TNF) gene cluster are probably the most polymorphic genomic regions in the human central major histocompatibility complex (MHC). Using definitive methods for genotypic and phenotypic analyses of complement components C4A and C4B, determination of the RCCX length variants, and SSP-PCR/RFLP analyses of TNFA promoter polymorphisms at positions -308 and -238, we studied the complex relationships between the C4 and TNFA polymorphisms in two normal Caucasian populations. The patterns of the RCCX modular structures and the allelic frequency of -308A TNFA (TNF2) were similar between the Budapest (n = 125) and the Ohio (n = 80) Caucasians. However, the frequency of the -238A allele was significantly higher in the Ohio (11.3%) than in the Budapest (1.6%) study population (p < 0.0001). Marked features were found in the RCCX length variants in the TNF2 carriers and noncarriers. Strong associations were found between the C4AQ0 B1 haplotype from the monomodular short (mono-S) RCCX structure and the TNF2 allele, and between the C4A6 B1 haplotype from the bimodular long-short (LS) structure of the RCCX and the TNFA -238A allele. However, 36%-46% of the TNF2 carriers did not associate with a mono-S in both study cohorts, and 57.1% of the TNFA -238A carriers in Ohio did not associate with C4A6, which has a defective complement C5 convertase activity. The carriers of TNF2 allele had significantly lower C4A serum concentration (0.17 +/- 0.08 g/l) than noncarriers (0.23 +/- 0.09 g/l) (p < 0.001). The lowest C4A serum levels were found in TNF2 carriers with mono-S structures (0.14 +/- 0.06 g/l). In essence, our results demonstrated the heterogeneities of the TNFA promoter polymorphisms, and the linkage disequilibrium of TNFA -308A and -238A alleles with complement C4A deficiency and impaired C4A protein function, respectively.
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Agnes
authors.initials: A
authors.lastname: Vatay
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Erwin K
authors.initials: EK
authors.lastname: Chung
authors.forename: B i
authors.initials: Bi
authors.lastname: Zhou
authors.forename: Carol A
authors.initials: CA
authors.lastname: Blanchong
authors.forename: Margit
authors.initials: M
authors.lastname: Kovács
authors.forename: István
authors.initials: I
authors.lastname: Karádi
authors.forename: George
authors.initials: G
authors.lastname: Füst
authors.forename: László
authors.initials: L
authors.lastname: Romics L
authors.forename: Lilian
authors.initials: L
authors.lastname: Varga
authors.forename: C Yung
authors.initials: CY
authors.lastname: Yu
authors.forename: Csaba
authors.initials: C
authors.lastname: Szalai
mesh_terms: D015139:Blotting, Southern; D015934:Complement C4a / Q000032:analysis / Q000235:genetics*; D015935:Complement C4b / Q000032:analysis / Q000235:genetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D014409:Tumor Necrosis Factor-alpha; D015934:Complement C4a; D015935:Complement C4b