The polymorphisms of protein-tyrosine phosphatase receptor-type delta gene and its association with pediatric asthma in the Taiwanese population.

We previously reported an association between genetic differences of pediatric asthma subtypes and a short tandem repeat (STR) marker, D9S286. It has been known that the protein-tyrosine phosphatase receptor-type delta (PTPRD) gene is located downstream of D9S286 and that the physical distance between them is about 0.25 Mb. We selected and conducted genotyping on 76 single-nucleotide polymorphisms (SNPs) that encircle the genomic region of PTPRD in Taiwanese children with or without asthma. A total of 996 subjects were divided into testing group (674 subjects) and validation group (322 subjects). The results were further validated with the third subject group (611 subjects) recruited from different geographical regions. After Bonferroni correction, 3 out of 80 SNPs were found to be strongly significant (P < 0.05/76 = 0.000658) in the allele frequency test. This association was confirmed by validation groups. The results indicate that polymorphisms of PTPRD are strongly associated with pediatric bronchial asthma in the Taiwanese population.

Genetic structural differences between responders and non-responders to interferon therapy for chronic hepatitis-B patients.

Interferon-alpha therapy has become a main stay of treatment for hepatitis-B patients. The sustained remission rates are around 30%, and the factors determining response are poorly defined. Our study aimed to search for the genetic differences between responder and non-responder patients. We have found 13 short tandem repeat markers (STR) that display different allele and/or genotype frequency between the two patient groups. Eleven out of 13 STR markers were selected to perform principal component analysis and hierarchical clustering. The study subjects could be further divided into six groups based on their genetic similarity, which correlated with the drug response rate. In conclusion, this pilot study has developed a new approach to identify genetic markers that allows us to predict the drug response in hepatitis B patients. Our study utilizing STR markers may provide an alternative approach to the utilized SNP markers in pharmacogenetic study.

Variant in promoter region of platelet-derived growth factor receptor-alpha (PDGFRalpha) gene is associated with the severity and allergic status of childhood asthma.

BACKGROUND: Upregulation of the platelet-derived growth factor receptor-alpha (PDGFRalpha) in airway myofibroblast cells is one of the mechanisms of airway remodeling. The genetic association between PDGFRalpha promoter polymorphism and severity of childhood asthma was examined. METHODS: Five single nucleotide polymorphisms (SNPs) at the promoter regions of the PDGFRalpha gene were genotyped in 277 unrelated allergic and nonallergic asthmatic children and 93 age-matched controls. Promoter haplotypes were constructed using SNP genotyping data. The serum level of PDGF-AA, the ligand for PDGFRalpha, was assayed by ELISA kits. RESULTS: The genotype distribution of SNP rs1800810 (-1171G/C) in nonallergic asthma was significantly different from controls (p=0.038), as well as its allele distribution (p=0.028). Using haplotype analysis, the combination frequency of the low expression of H1 homozygous and heterozygous genotype (H1/H1+H1/H2) was significantly higher in nonallergic asthma as compared to controls (OR=1.94, CI=1.11-3.39, p<0.02). The frequency of H2/H2 homozygous was higher in persistent asthma than in intermittent asthma (p=0.008, OR=2.625). In addition, the PDGF-AA serum level in H2/H2 homozygous haplotype was significantly lower as compared to non-H2/H2 homozygous haplotype both in asthmatic (138.1+/-62.9 vs. 249.7+/-97.1 ng/ml, p<0.05) and nonallergic asthmatic children (113.8+/-38.0 vs. 256.6+/-58.3 ng/ml, p<0.05). CONCLUSIONS: The developmental deficiency due to the low expression of PDGFRalpha may be one of the susceptible factors for nonallergic asthmatic children. There was also an autocrine effect of lower PDGF-AA and higher PDGFRalpha expression that might lead to airway remodeling causing the severity of asthma.

Discovery of genetic difference between asthmatic children with high IgE level and normal IgE level by whole genome linkage disequilibrium mapping using 763 autosomal STR markers.

The genome-wide linkage disequilibrium screen for loci associated with genetic difference between allergic and nonallergic asthma was conducted with 763 autosomal STR markers and included 190 asthmatic children. Evidence for association with differences between the two forms of asthma was observed for 36 STR markers. Marker-to-marker synergetic effect and by simulation resampling tests revealed D5S2011, D6S305, and D9S286 were important loci in allergic asthma while D6S1574, D8S1769, and D19S226 were important in nonallergic asthma. Our results show strong genetic evidence that these markers play an important role in defining allergic and nonallergic asthma and provides important candidates of susceptible genes in these two categories of asthma. This study further shows that asthma is, indeed, a heterogeneous group of underlying diseases and, although with similar clinical phenotypes, may have different clinical severities, outcomes, and need more tailor-made management.

Association study using combination analysis of SNP and STRP markers: CD14 promoter polymorphism and IgE level in Taiwanese asthma children.

Chromosome 5, especially the 5q31-33 region, may contain one or more loci to control total serum IgE as well as asthma and bronchial hyperresponsiveness. To investigate the regions related with IgE level in chromosome 5, we performed a case-control association study on 105 high-IgE-level and 85 normal-IgE-level asthmatic children using 43 microsatellite markers that span the whole chromosome 5 with 5 cM intervals. One of microsatellite marker, D5S2011, had significantly different allele frequency between the two asthmatic groups. E allele (143 bp) of the D5S2011 marker was more frequent in high-IgE asthmatics. CD14 is the candidate gene of atopy and asthma and is distant from D5S2011 by about 1 Mb. We analyzed the SNP genotypes in the CD14 gene region alone and in combination with microsatellite marker D5S2011. The CD14/-2984 polymorphism but not the CD14/-159 is associated with IgE level in Taiwanese asthmatic children. The CD14/-159 allele was observed only to be associated with IgE level when -159T was part of a haplotype containing a D5S2011 E allele. The combination analysis using SNP and STRP markers provided a novel method for increasing detection power in candidate gene association studies.

Heterozygosities and allelic frequencies of 811 dinucleotide-repeat marker loci in the Taiwanese population.

To evaluate basic informativeness of commercially available microsatellite markers in theTaiwanese population, 190 unrelated Taiwanese children were genotyped using ABI PRISM Linkage Mapping Set-HD5. The average heterozygosity in Taiwanese was slightly lower than that in Caucasians among these 811 microsatellite markers. There were 50 marker loci with heterozygosities lower than 50%. Moreover, allelic distributions at many of the loci were significantly different in two ethnic groups. The results reported here represent a valuable database for disease genes mapping in the Taiwanese population. This database can be easily accessed at the Web site of Vita Genomics, Inc. (http://www.vitagenomics.com/str.html).