Alireza Sadeghnejad

IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study.

BackgroundTobacco smoke and genetic susceptibility are risk factors for asthma and wheezing. The aim of this study was to investigate whether there is a combined effect of interleukin-13 gene (IL13) polymorphisms and tobacco smoke on persistent childhood wheezing and asthma.MethodsIn the Isle of Wight birth cohort (UK, 1989–1999), five IL13 single nucleotide polymorphisms (SNPs): rs1800925 (-1112C/T), rs2066960, rs1295686, rs20541 (R130Q) and rs1295685 were genotyped. Parents were asked whether their children had wheezed in the last 12 months at ages 1, 2, 4 and 10 years. Children who reported wheeze in the first 4 years of life and also had wheezing at age 10 were classified as early-onset persistent wheeze phenotype; non-wheezers never wheezed up to age 10. Persistent asthma was defined as having a diagnosis of asthma both during the first four years of life and at age 10. Logistic regression methods were used to analyze data on 791 children with complete information. Potential confounders were gender, birth weight, duration of breast feeding, and household cat or dog present during pregnancy.ResultsMaternal smoking during pregnancy was associated with early-onset persistent wheeze (OR 2.93, p < 0.0001); polymorphisms in IL13 were not (OR 1.15, p = 0.60 for the common haplotype pair). However, the effect of maternal smoking during pregnancy was stronger in children with the common IL13 haplotype pair compared to those without it (OR 5.58 and OR 1.29, respectively; p for interaction = 0.014). Single SNP analysis revealed a similar statistical significance for rs20541 (p for interaction = 0.02). Comparable results were observed for persistent childhood asthma (p for interaction = 0.03).ConclusionThis is the first report that shows a combined effect of in utero exposure to smoking and IL13 on asthma phenotypes in childhood. The results emphasize that genetic studies need to take environmental exposures into account, since they may explain contradictory findings.

Polymorphisms in the interleukin 13 and GATA binding protein 3 genes and the development of eczema during childhood.

Background  Atopic eczema is characterized by Th2‐dominant immunity with the cytokine interleukin 13 and the transcription factor GATA binding protein 3 playing a critical role.

Do Symptoms Predict COPD in Smokers

BACKGROUND The US Preventive Services Task Force recommends against spirometry in the absence of symptoms. However, as much as 50% of COPD cases in the United States remain undiagnosed. METHODS Report of symptoms, smoking history, and spirometric data were collected from subjects screened for a work-related medical evaluation (N = 3,955). Prevalence of airflow obstruction and respiratory symptoms were assessed. Sensitivity, specificity, positive and negative predictive values, and relative risks of predicting symptoms and smoking history for COPD were calculated. RESULTS Forty-four percent of smokers in our sample had airways obstruction (AO). Of these, 36% reported a diagnosis of or treatment for COPD. Odds ratio (95% CI) for AO with smoking (> or = 20 pack-years) was 3.73 (3.12- 4.45), 1.98 (1.73-2.27) for cough, 1.79 (1.55-2.08) for dyspnea, 1.95 (1.70-2.34) for sputum, and 2.59 (2.26-2.97) for wheeze. Respiratory symptoms were reported by 92% of smokers with AO, 86% smokers with restriction, 76% smokers with normal spirometry, and 73% of nonsmokers. Sensitivity (92% vs 90%), specificity (19% vs 22%), positive (47% vs 40%) and negative (75% vs 80%) predictive values for the presence of one or more symptoms were similar between smokers and all subjects. CONCLUSIONS COPD is underdiagnosed in the United States. Symptoms are frequent in subjects with AO and increase their risk for COPD, but add little beyond age and smoking history to the predictive value of spirometry. In view of the high prevalence of symptoms and their poor predictive value, a simpler and more effective approach would be to screen older smokers.

COPD Is Associated With a Macrophage Scavenger Receptor-1 Gene Sequence Variation

BACKGROUND Macrophages play an important role in COPD. We genotyped at-risk smokers to evaluate the role of polymorphisms in the macrophage scavenger receptor-1 gene (MSR1) in COPD susceptibility and related measures of lung function. Then, in macrophages from donors with specific MSR1 genotypes, we determined the effect of MSR1 single nucleotide polymorphisms (SNPs) on macrophage function by examining in vitro adhesion, receptor expression, and cell number in culture as an index of increased survival/reduced apoptosis. METHODS Smokers (> or = 20 pack-years) who were > 40 years (n = 714) were genotyped for seven SNPs; one nonsense change (ex6R293x_C/T), four missense changes (ex4V113A_T/C, ex4P174Y_G/T, ex11H441R_A/G, and in the ligand binding site ex6P275A_C/G), -176511_A/G in the promoter region, and IVS5-59_C/A in the intron. Nonsmoking healthy volunteers (n = 85) were genotyped, and peripheral blood monocytes were isolated from seven P275A_CG/GG and eight P275A_CC controls and cultured to generate monocyte-derived macrophages (MDM). The effectiveness of trypsin and scraping to dislodge MDM was scored on a four-point subjective scale. MDM were counted on a Z1 particle counter and surface expression of MSR1 was determined by fluorescence-activated cell sorting analysis using secondary staining of antibodies against human macrophage scavenger receptor (MSR1). RESULTS The MSR1-coding SNP P275A was associated with susceptibility to COPD in smokers (P < .005) and a lower percent predicted (pp) FEV(1), FEV(1)/FVC, and pp forced expiratory flow (FEF)(25-75) (P = .03). P275A_CG/GG was also associated with increases in maintenance of cell number in culture (increased survival/reduced apoptosis), MSR1 expression, and adhesion of macrophages to plastic in vitro (P < .05). CONCLUSIONS The MSR1 association with COPD susceptibility, COPD-related measures of lung function, and abnormalities of macrophage function may account for significant COPD morbidity.