The gene encoding acyloxyacyl hydroxylase (AOAH), an enzyme that hydrolyzes secondary fatty acyl chains of LPS, is localized on chromosome 7p14-p12, where evidence for linkage to total IgE (tIgE) ...concentrations and asthma has been previously reported.
We hypothesized that variants in AOAH are associated with asthma and related phenotypes. Because both AOAH and soluble CD14 respond to LPS, we tested for gene-gene interaction.
We investigated the association between 28 single nucleotide polymorphisms throughout the AOAH gene and asthma, concentrations of tIgE, the ratio of IL-13/IFN-γ, and soluble CD14 levels among 125 African Caribbean, multiplex asthmatic pedigrees (n = 834). Real-time PCR was used to assess whether AOAH cDNA expression differed with AOAH genotype.
Significant effects were observed for all 4 phenotypes and AOAH markers in 3 distinct regions (promoter, introns 1-6, and the intron 12/exon 13 boundary/intron 13 region) by means of single-marker and haplotype analyses, with the strongest evidence for a 2-single-nucleotide-polymorphism haplotype and logtIgE (
P = .006). There was no difference in AOAH expression levels by AOAH genotype for any of the markers. Comparing genotypic distributions at both the AOAH marker rs2727831 and
CD14(−260)C>T raises the possibility of gene-gene interaction (
P = .006-.036).
Our results indicate that polymorphisms in markers within the AOAH gene are associated with risk of asthma and associated quantitative traits (IgE and cytokine levels) among asthmatic subjects and their families in Barbados, and there is an interactive effect on tIgE and asthma concentrations between an AOAH marker and the functional
CD14(−260)C>T polymorphism.
AOAH is a novel innate immunity candidate gene associated with asthma and related phenotypes in an African ancestry population.
To identify genes potentially relevant in atopic asthma, we analyzed markers in chromosome 12q15–q24.1 for linkage to asthma and total serum IgE concentration. Sib-pair analyses of 10 markers in 345 ...full- and 219 half-sib pairs from 29 multiplex Afro-Caribbean families provided evidence for linkage to this region for both asthma and total serum IgE. Certain alleles at these loci showed significant evidence of transmission disequilibrium with both asthma and high IgE. Using 6 of these markers and 11 additional markers, evidence for linkage of total IgE to 12q was also found in 12 Caucasian Amish kindreds (24 nuclear families) by both sib-pair and transmission disequilibrium analyses. These findings suggest that the 12q15–q24.1 region may contain a gene(s) controlling asthma and the associated “high total IgE” trait.
Sib-pair analysis of 170 individuals from 11 Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum immunoglobulin E (IgE) ...concentration. No linkage was found between these markers and specific IgE antibody concentrations. Analysis of total IgE within a subset of 128 IgE antibody-negative sib pairs confirmed evidence for linkage to 5q31.1, especially to the interleukin-4 gene (IL4). A combination of segregation and maximum likelihood analyses provided further evidence for this linkage. These analyses suggest that IL4 or a nearby gene in 5q31.1 regulates IgE production in a nonantigen-specific (noncognate) fashion.
Background: We have recently conducted a genome-wide screening for genes influencing
Dermatophagoides pteronyssinus–specific IgE responsiveness as a part of the Collaborative Study on the Genetics of ...Asthma (CSGA), which showed evidence for linkage in some regions, including chromosomes 5q31-q33 and 11q13 in African American families.
Objectives: To clarify relative contributions of these regions to atopy in the same African American population, we have conducted further genetic linkage studies of specific IgE responses toward common inhaled allergens.
Methods: We studied 328 individuals in 58 African American families participating in the CSGA. Specific IgE responses toward
Dermatophagoides farinae, cat, dog, American cockroach, rye grass, and Bermuda grass, as measured by skin tests, were used for multipoint linkage analysis with polymorphic markers on chromosomes 5q31-q33 and 11q13.
Results: Specific IgE response toward American cockroach showed evidence for linkage to chromosomes 5q31-q33 (
P = .0050) and 11q13 (
P = .017). Specific IgE response toward dog showed evidence for linkage with chromosome 5q31-q33 (
P = .0043). Evidence for linkage with chromosome 11q13 was obtained for specific IgE responses toward
Dermatophagoides farinae (
P = .012), cat (P = .035), and Bermuda grass (
P = .017). The presence of a positive ST response for at least 1 of 30 common allergens showed evidence for linkage to chromosomes 5q31-q33 (
P = .017) and 11q13 (
P = .00058).
Conclusions: These data support that genes on both chromosomes 5q31-q33 and 11q13 confer susceptibility to upregulated IgE-mediated immune responses in this African American population. The putative genes on chromosomes 5q31-q33 and 11q13, however, showed contrasting effects on atopy, which may result from strong gene–environmental interactions. (J Allergy Clin Immunol 1998;102:449-53.)
Mite sensitivity has been reported to be a major risk factor for asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), a genome scan using mite reactivity (Dermatophagoides ...Pteronyssinus (Der p) and Dermatophagoides farinae (Der f)) as the phenotype was conducted. In 287 CSGA families, 122 were informative for linkage. Evidence supporting linkage was observed for regions on chromosome 19 (D19S591, lod=2.43, P=0.0008; D19S1037, lod=1.57, P=0.007) and chromosome 20 (D20S473/D20S604, lod=1.41, P=0.01). All three ethnic groups appeared to contribute to the evidence for linkage on chromosome 20. African-American families gave strongest support for linkage on chromosomes 3 (D3S2409, lod=1.33, P=0.01), 12 (D12S373, lod=1.51, P=0.008) and 18 (ATA82B02, lod=1.32, P=0.01). Caucasian families showed strong evidence for linkage on chromosome 19 (D19S591, lod=3.51, P=0.00006). Hispanic families supported linkage on chromosomes 11 (D11S1984, lod=1.56, P=0.007), 13 (D13S787, lod=1.30, P=0.01) and 20 (D20S470, lod=1.71, P=0.005). These results suggest that multiple genes may be involved in controlling skin reactivity to Dermatophoigoies.
An overview of the methods and the philosophy of privatization in the V4 (the Czech Republic, Hungary, Poland, and Slovakia). If economic growth resumes and proves lasting so that domestic demand ...begins to expand, the process of privatizing the remaining large state-owned companies may well accelerate. On the other hand, it seems likely that the state sector in the V4 economies will remain larger than is usual in developed market economies, where it has been formed by a historical process of integral development. The management and privatization of the state's business assets should be farmed out and controlled by private concerns, not a state agency.
Background: Recently, we have obtained evidence for linkage between Der p 1–specific IgE antibodies and markers on chromosome 6p21 (
HLA-D region) in a genome-wide screening in Caucasian families ...recruited as a part of the Collaborative Study on the Genetics of Asthma (CSGA).
Objective: Specific IgE antibodies toward different
Dermatophagoides pteronyssinus (Der p) polypeptides were detected by immunoblotting analysis, and the transmission/disequilibrium test (TDT) was performed between specific IgE responsiveness toward each different Der p polypeptide and markers on chromosome 6p21 to better clarify the genetic contribution of
HLA-D genes.
Methods: We studied 299 individuals in 45 Caucasian families participating in the CSGA. Serum samples from 137 individuals that showed elevated specific IgE antibodies toward the Der p crude allergen (> –0.5 log IU/mL) by ACCESS immunoassay were subjected to immunoblotting analysis. TDT was conducted between the presence of specific IgE antibodies toward each of 12 different Der p polypeptides and 4 polymorphic markers on chromosome 6p21.
Results: The 196-bp allele of
D6S1281 and the 104-bp allele of
DQCAR showed significant excess transmission to specific IgE responders toward a particular Der p polypeptide (120 kd, 55 kd, 45 kd, or 37 kd). In contrast, the 200-bp allele of
D6S1281 and the 204-bp allele of
D6S291 showed significantly decreased transmission to specific IgE responders toward a particular Der p polypeptide (120 kd, 90 kd, 52 kd, or 45 kd). Deviation from the expected 50% transmission in heterozygous parents was statistically significant after correcting for multiple comparisons.
Conclusion: This study supported our previous findings that genes on chromosome 6p21 (
HLA-D region) may influence the expression of Der p–specific IgE responsiveness in this Caucasian population. Our results, however, reveal the complexity of genetic regulations of Der p–specific IgE responsiveness by
HLA-D genes, suggesting the strong influence of non-
HLA loci and perhaps environmental factors for the development of Der p–specific IgE responsiveness. (J Allergy Clin Immunol 1998;102:443-8.)
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