Association analysis of common variants of STAT6, GATA3, and STAT4 to asthma and high serum IgE phenotypes.

BACKGROUND: Immune responses characterized by T H 2 type cells and IgE are important for the development of asthma and atopy. The transcription factors STAT6, GATA3, and STAT4 mediate the cytokine-induced development of naive CD4 + T cells into either T H 1 or T H 2 type. OBJECTIVE: We studied genetic variation of the STAT6, GATA3, and STAT4 genes and examined whether single nucleotide polymorphisms (SNPs) in these loci were associated with asthma or serum high IgE levels in the Finnish asthmatic families. METHODS: With denaturing high-performance liquid chromatography we screened all exons and exon-intron boundaries of the genes in 14 to 22 patients. All identified SNPs were genotyped in 120 nuclear families, and the haplotypes were analyzed by Haplotype Pattern Mining based statistical analysis. When potential association was observed, the analysis was replicated among 245 asthmatic patients and 405 population-based control subjects. RESULTS: A total of 23 SNPs were identified, of which 8 were not previously listed in the SNP database. Interestingly, a haplotype analysis of GATA3 showed 3 related haplotypes that associated with different asthma and atopy related phenotypes among both the family and case-control data sets. For STAT6 and STAT4, no significant association to asthma or serum total IgE levels was observed. CONCLUSIONS: We identified a panel of novel SNPs in genes coding for proteins important in the T H 1/T H 2 cell differentiation. SNPs of the GATA3 gene showed an initial association to asthma-related phenotypes. Elucidation of the importance of the identified panel of SNPs in other T H 1/T H 2 mediated diseases will be of great interest.

Total C4B deficiency due to gene deletion and gene conversion in a patient with severe infections.

Deficiencies of the early components of the classical complement pathway impair the actions of innate and humoral immunity and may lead to increased susceptibility to infections. We have studied the genetic basis of total C4B deficiency in a Finnish patient with recurrent meningitis, chronic fistulas and abscesses. The maternal chromosome carried a four-gene deletion including the C4B gene, and a conversion from C4B to C4A gene was found on the paternal chromosome resulting in complete deficiency of C4B. In the converted C4A gene, mutation screening did not reveal any amino acid changes or prominent mutations, yet a large number of nucleotide variations were found. Further, the patient was heterozygous for structural deficiency of mannan binding lectin (MBL) associating with medium levels of serum MBL. Our data provides new information on the genetic instability of the C4 gene region, and on the association of homozygous C4B deficiency and variant MBL genotype with increased susceptibility to recurrent and chronic infections. Importantly, plasma therapy induced a prompt clinical cure with long-term effects.