Background: Because asthma has been associated with exercise and ozone exposure, an association likely mediated by oxidative stress, we hypothesised that glutathione-S-transferase ( GST ) P1 , GSTM1 , exercise and ozone exposure have interrelated effects on the pathogenesis of asthma. Methods: Associations of the well characterised null variant of GSTM1 and four single nucleotide polymorphisms (SNPs) that characterised common variation in the GSTP1 locus with new onset asthma in a cohort of 1610 school children were examined. Children’s exercise and ozone exposure were classified using participation in team sports and community annual average ozone levels, respectively. Results: A two SNP model involving putatively functional variants (rs6591255, rs1695 (Ile105Va)) best captured the association between GSTP1 and asthma. The risk of asthma was lower for those with the Val allele of Ile105Val (hazard ratio (HR) 0.60, 95% CI 0.4 to 0.8) and higher for the variant allele of rs6591255 (HR 1.40, 95% CI 1.1 to 1.9). The risk of asthma increased with level of exercise among ile 105 homozygotes but not among those with at least one val 105 allele (interaction p value = 0.02). The risk was highest among ile 105 homozygotes who participated in ⩾3 sports in the high ozone communities (HR 6.15, 95% CI 2.2 to 7.4). GSTM1 null was independently associated with an increased risk of asthma and showed little variation with air pollution or GSTP1 genotype. These results were consistent in two independent fourth grade cohorts recruited in 1993 and 1996. Conclusion: Children who inherit a val 105 variant allele may be protected from the increased risk of asthma associated with exercise, especially in high ozone communities. GSTM1 null genotype was associated with an increased risk of asthma.

https://thorax.bmj.com/content/thoraxjnl/64/3/197.full.pdf

Glutathione-S-transferase (GST) P1, GSTM1, exercise, ozone and asthma incidence in school children

Oxidative stress is thought to be involved in the pathogenesis of
asthma. Glutathione-S-transferase (GST) enzymes, which play an
important role in antioxidant defences, may therefore influence
asthma risk. Two common deletion polymorphisms of GSTM1 and
GSTT1 genes and the GSTP1 Ile105Val polymorphism have been
associated with asthma in children and adults, but results are
inconsistent across studies.
Methods Systematic review and meta-analysis of the effects of GST
genes on asthma, wheezing and bronchial hyper-responsiveness
(BHR), with inclusion of unpublished data from three studies,
including the large Avon Longitudinal Study of Parents and
Children (ALSPAC). Random effect or fixed effect models were
used as appropriate, and sensitivity analyses were performed
to assess the impact of study characteristics and quality on
pooled results.
Results The meta-analyses of GSTM1 (n¼22 studies) and GSTT1 (n¼19)
showed increased asthma risk associated with the null genotype,
but there was extreme between-study heterogeneity and publication
bias and the association disappeared when meta-analysis was
restricted to the largest studies. Meta-analysis of GSTP1 Ile105Val
(n¼17) and asthma suggested a possible protective effect of the Val
allele, but heterogeneity was extreme. Few studies evaluated
wheezing and BHR and most reported no associations, although
weak evidence was found for positive associations of GSTM1 null and GSTP1 Val allele with wheezing and a negative association of
GSTP1 Val allele with BHR.
Conclusions Our findings do not support a substantial role of GST genes alone
in the development of asthma. Future studies of large size should
focus on interactions of GST genes with environmental oxidative
exposures and with other genes involved in antioxidant pathways.
Quality of study conduct and reporting needs to be improved to
increase credibility of the evidence accumulating over time.
Keywords Meta-analysis, systematic review, glutathione-S-transferase genes,
GSTM1 gene, GSTT1 gene, GSTP1 gene, asthma, wheezing, bronchial
responsiveness, The Avon Longitudinal Study of Parents and
Children (ALSPAC)

/pdf/glutathione-s-transferase-genes-and-asthma-phenotypes-a-54et72tyk9.pdf

Glutathione-S-transferase genes and asthma phenotypes: a Human Genome Epidemiology (HuGE) systematic review and meta-analysis including unpublished data

Rationale: Association studies have implicated many genes in asthma pathogenesis, with replicated associations between single-nucleotide polymorphisms (SNPs) and asthma reported for more than 30 genes. Genome-wide genotyping enables simultaneous evaluation of most of this variation, and facilitates more comprehensive analysis of other common genetic variation around these candidate genes for association with asthma.

Objectives: To use available genome-wide genotypic data to assess the reproducibility of previously reported associations with asthma and to evaluate the contribution of additional common genetic variation surrounding these loci to asthma susceptibility.

Methods: Illumina Human Hap 550Kv3 BeadChip (Illumina, San Diego, CA) SNP arrays were genotyped in 422 nuclear families participating in the Childhood Asthma Management Program. Genes with at least one SNP demonstrating prior association with asthma in two or more populations were tested for evidence of association with asthma, using family-based association testing.

Measurements and Main Results: We identified 39 candidate genes from the literature, using prespecified criteria. Of the 160 SNPs previously genotyped in these 39 genes, 10 SNPs in 6 genes were significantly associated with asthma (including the first independent replication for asthma-associated integrin β3 [ITGB3]). Evaluation of 619 additional common variants included in the Illumina 550K array revealed additional evidence of asthma association for 15 genes, although none were significant after adjustment for multiple comparisons.

Conclusions: We replicated asthma associations for a minority of candidate genes. Pooling genome-wide association study results from multiple studies will increase the power to appreciate marginal effects of genes and further clarify which candidates are true “asthma genes.”

/pdf/assessing-the-reproducibility-of-asthma-candidate-gene-34e1lj0y51.pdf

Assessing the Reproducibility of Asthma Candidate Gene Associations, Using Genome-wide Data

Kikuchi's disease, also known as histiocytic necrotizing lymphadenitis, is a systemic illness with classic clinical findings of cervical lymphadenopathy and fever. Diagnosis is confirmed by lymph node histology, which reveals paracortical foci of necrosis and a histiocytic infiltrate. Kikuchi's disease has been associated with a number of infections, but no single source has been identified. Diverse, often nonspecific, cutaneous findings have been described in up to 40% of cases. Description of the histopathologic findings of skin lesions is limited to single case reports and one case series. We describe a 24-year-old woman with fevers, lymphadenopathy, hepatic and hematologic abnormalities, and a skin eruption involving the face, neck, trunk, and extremities with characteristic lymph node and cutaneous histopathologic findings. We completed a systematic review of the clinical presentations and histopathology of Kikuchi's disease.

Kikuchi's disease: Case report and systematic review of cutaneous and histopathologic presentations

BACKGROUND/PURPOSE: Kikuchi’s disease (KD), also known as histiocytic necrotizing lymphadenitis, is a benign and self-limiting disease of unknown etiology that mainly affects young women. There is limited data on the long-term prognosis of patients with KD. METHODS: We describe the clinical manifestations and outcomes of 195 patients, diagnosed as having KD at National Taiwan University Hospital from March 1989 to September 2006. RESULTS: All together, 53.3% of our patients presented with tender lymphadenopathy, 37.9% with fever and 16.9% with headache. The most common laboratory findings were elevated erythrocyte sedimentation rate (78.9%), elevated serum lactate dehydrogenase (52.5%), elevated C-reactive protein (38.3%), monocytosis (26.9%), elevated serum alanine aminotransferase (23.3%) and leukopenia (18.9%). A total of 183 patients followed a benign course, with spontaneous resolution of fever and lymphadenopathy. However, 14 patients (14.6%) with follow-up of more than 6 months had clinical recurrence of KD; hence, long-term follow-up is suggested. Five of these patients developed an autoimmune disease, namely, systemic lupus erythematosus (n = 2), Graves’ disease (n = 2), or mixed connective tissue disease (n = 1). One patient with recurrent KD died of intracranial hemorrhage due to thrombocytopenia. CONCLUSION: The prognosis for KD patients is generally optimistic; however, a concurrent autoimmune disease or the risk of developing an autoimmune disease requires careful monitoring.

Clinical Presentations, Laboratory Results and Outcomes of Patients with Kikuchi's Disease: Emphasis on the Association Between Recurrent Kikuchi's Disease and Autoimmune Diseases

Background. A positive association between genetic polymorphism and asthma may not be extrapolated from one ethnic group to another based on intra- and interethnic allelic and genotype frequencies differences. Objective. We assessed whether polymorphisms of GST genes (GSTM1, GSTT1, and GSTP1) are associated with asthma and atopy among Tunisian children. Methods. 112 unrelated healthy individuals and 105 asthmatic (73 atopic and 32 nonatopic) children were studied. Genotyping the polymorphisms in the GSTT1 and GSTM1 genes was performed using the multiplex PCR. The GSTP1 ILe105Val polymorphism was determined using PCR-RFLP. Results. GSTM1 null genotype was significantly associated with the increased risk of asthma (P = .002). Asthmatic children had a higher prevalence of the GSTP1Ile105 allele than the control group (43.8% and 33.5%, respectively; P = .002). Also, the presence of the GSTP1 homozygote Val/Val was less common in subjects with asthma than in control group. We have found that GSTT1 null genotype (GSTT1 *0/*0) was significantly associated with atopy (P = .008). Conclusion. Polymorphisms within genes of the GST superfamily were associated with risk of asthma and atopy in Tunisia.

/pdf/association-of-gst-genes-polymorphisms-with-asthma-in-30a1a4qnz7.pdf

Ammar Jamel

Papers

Association of GST genes polymorphisms with asthma in Tunisian children.

Kikuchi-Fujimoto disease associated with systemic lupus erythematosus.