Th17 cells increase in RRMS as well as in SPMS, whereas various other phenotypes of Th17 increase in RRMS only.

BACKGROUND: The nature and extent of inflammation seen in multiple sclerosis (MS) varies throughout the course of the disease. Changes seen in CD4+ T-helper cells in relapsing-remitting (RR) MS and secondary progressive (SP) MS might differ qualitatively and/or quantitatively. OBJECTIVE: The objective of this paper is to study the frequencies of all major CD4+ T-helper subtypes - Th17, Th22 and Th1 lineage cells - in relapse, remission and secondary progression alongside CCR6 status, a chemokine receptor involved in migration of these cells into the central nervous system. METHODS: We compared 100 patients (50 RRMS and 50 SPMS) and 50 healthy volunteers and performed flow cytometric analysis of lymphocytes in blood samples. RESULTS: We demonstrated raised frequencies of various cell types along the Th17 axis; Th17, Th17.1 (IL-17+ interferon gamma+) and dual IL-17+ IL-22+ cells in RRMS. Th22 and CCR6+ Th1 cells (nonclassical Th1) were also increased in RRMS. All these cells were CCR6+. Only Th17 frequencies were elevated in SPMS. CONCLUSIONS: Increased frequencies of Th17 cells are implicated both in RRMS and SPMS. The CCR6 pathway includes Th17, Th22 and Th1 nonclassical cells, of which Th22 and Th1 cells represent the greatest subsets in MS.

The association of sex hormone-binding globulin with mortality is mediated by age and testosterone in men with type 2 diabetes.

BACKGROUND: Serum sex hormone-binding globulin levels have been associated with mortality in adult men with type 2 diabetes (T2DM). OBJECTIVES: To confirm the association of serum sex hormone-binding globulin with mortality and then determine whether this association is mediated by age and total testosterone concentration. MATERIALS AND METHODS: We studied 364 men (median age: 66 years) with T2DM over a median follow-up of 4.3 years using the Cox regression to study associations between sex hormone-binding globulin, age, total testosterone, and mortality. RESULTS: Mortality was significantly and independently associated with sex hormone-binding globulin, age, and total testosterone. In pairwise combinations of age and sex hormone-binding globulin dichotomized by median values, the association of sex hormone-binding globulin with mortality was age-dependent. Relative to the combination of age >66 years/SHBG >35 nmol/L (mortality 22.5%), the other combinations were associated with significantly less mortality (mortality in men ≤66 years/SHBG ≤ 35 nmol/L was 3.23%). In men >66 years, SHBG ≤ 35 nmol/L was associated with decreased mortality (HR: 0.41, p = 0.037) compared with SHBG > 35 nmol/L. In men ≤66 years, there was no significant difference between those with sex hormone-binding globulin above or below the median (HR: 1.73, p = 0.56, reference: SHBG ≤ 35 nmol/L). TT < 12 nmol/L was associated with increased mortality in both age categories. Men >66 years with the reference combination of SHBG > 35 nmol/L and TT < 12 nmol/L (36.84%) nmol/L had significantly higher mortality than those with SHBG > 35 nmol/L and TT ≥ 12 (18.06%) and those with SHBG ≤ 35 nmol/L and TT < 12 nmol/L (13.79%). DISCUSSION: Our data suggest sex hormone-binding globulin and total testosterone have particular impact on mortality in men aged over 66 years. Further, in older men, the combination of high sex hormone-binding globulin levels and low total testosterone is associated with greater risk than either high sex hormone-binding globulin or low total testosterone individually. CONCLUSIONS: Our findings are compatible with data suggesting the importance of sex hormone-binding globulin lies in mediating free testosterone levels.

Testosterone replacement therapy: improved sexual desire and erectile function in men with type 2 diabetes following a 30-week randomized placebo-controlled study.

Although testosterone replacement treatment (TRT) can improve sexual function in many hypogonadal (HG) men with type 2 diabetes (T2DM), some show either no improvement or only in a limited number of domains. Indeed, it is often difficult for the clinician to offer an indication of the likely efficacy of TRT as little data exist on the proportion of TRT-treated men who will demonstrate improvement in domains such as sexual desire (SxD) and erectile function (EF). We describe in men with T2DM: firstly, the likelihood of improved sexual desire (SxD) and erectile function (EF) following TRT at various time points, and secondly, if probability of SxD change predicted likelihood of subsequent EF change. During a 30-week randomized controlled study of testosterone undecanoate (TU), 199 T2DM men with HG (189 men completing) identified from primary care registers (placebo (P): 107, TU: 92) were stratified using baseline total testosterone (TT)/free testosterone (FT) into Mild (TT 8.1-12 nmol/L or FT 0.18-0.25 nmol/L) and Severe HG groups (TT ≤8 nmol/L and FT ≤0.18 nmol/L) and placebo (P)- and TU-treated groups. Associations between TU, SxD and EF were investigated using chi-square and logistic regression analysis. The proportion of men with improved SxD after 6 weeks and EF improvement after 30 weeks was significantly higher following TU treatment compared to P, this particularly evident in Severe HG men. Changes in SxD and EF were significantly associated in all groups. Logistic regression showed that SxD change at 6 weeks predicted of EF change after 30 weeks. Our study confirms TRT leads to changes in SxD and EF at different time points and suggests SxD and EF changes are related. SxD change after 6 weeks predicting EF change at 30 weeks is possibly a useful clinical finding.

Serum testosterone, testosterone replacement therapy and all-cause mortality in men with type 2 diabetes: retrospective consideration of the impact of PDE5 inhibitors and statins.

BACKGROUND: Low testosterone levels occur in over 40% of men with type 2 diabetes mellitus (T2DM) and have been associated with increased mortality. Testosterone replacement together with statins and phosphodiesterase 5 inhibitors (PDE5I) are widely used in men with T2DM. PURPOSE: To determine the impact of testosterone and testosterone replacement therapy (TRT) on mortality and assess the independence of this effect by adjusting statistical models for statin and PDE5I use. METHODS: We studied 857 men with T2DM screened from five primary care practices during April 2007-April 2009. Of the 857 men, 175/637 men with serum total testosterone ≤ 12 nmol/l or free testosterone (FT) ≤ 0.25 nmol/l received TU for a mean of 3.8 ± 1.2 (SD) years. PDE5I and statins were prescribed to 175/857 and 662/857 men respectively. All-cause mortality was the primary end-point. Cox regression models were used to compare survival in the three testosterone level/treatment groups, the analysis adjusted for age, statin and PDE5I use, BMI, blood pressure and lipids. RESULTS: Compared with the Low T/untreated group, mortality in the Normal T/untreated (HR: 0.62, CI: 0.41-0.94) or Low T/treated (HR: 0.38, CI: 0.16-0.90) groups was significantly reduced. PDE5I use was significantly associated with reduced mortality (HR: 0.21, CI: 0.066-0.68). After repeating the Cox regression in the 682 men not given a PDE5I, mortality in the Normal T/untreated and Low T/treated groups was significantly lower than that in the reference Low T/untreated group. Mortality in the PDE5I/treated was significantly reduced compared with the PDE5I/untreated group (OR: 0.06, CI: 0.009-0.47). CONCLUSIONS: Testosterone replacement therapy is independently associated with reduced mortality in men with T2DM. PDE5I use, included as a confounding factor, was associated with decreased mortality in all patients and, those not on TRT, suggesting independence of effect. The impact of PDE5I treatment on mortality (both HR and OR < 0.25) needs confirmation by independent studies.

X-ray crystallography and computational docking for the detection and development of protein-ligand interactions.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective dysfunction and death of the upper and lower motor neurons. Median survival rates are between 3 and 5 years after diagnosis. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been linked to a subset of familial forms of ALS (fALS). Herein, we describe a fragment- based drug discovery (FBDD) approach for the investigation of small molecule binding sites in SOD1. X-ray crystallography has been used as the primary screening method and has been shown to directly detect protein-ligand interactions which cannot be unambiguously identified using other biophysical methods. The structural requirements for effective binding at Trp32 are detailed for a series of quinazoline-containing compounds. The investigation of an additional site that binds a range of catecholamines and the use of computational modelling to assist fragment evolution is discussed. This study also highlights the importance of ligand solubility for successful Xray crystallographic campaigns in lead compound design.

Electroporation-mediated gene transfer directly to the swine heart.

In vivo gene transfer to the ischemic heart via electroporation holds promise as a potential therapeutic approach for the treatment of heart disease. In the current study, we investigated the use of in vivo electroporation for gene transfer using three different penetrating electrodes and one non-penetrating electrode. The hearts of adult male swine were exposed through a sternotomy. Eight electric pulses synchronized to the rising phase of the R wave of the electrocardiogram were administered at varying pulse widths and field strengths following an injection of either a plasmid encoding luciferase or one encoding green fluorescent protein. Four sites on the anterior wall of the left ventricle were treated. Animals were killed 48 h after injection and electroporation and gene expression was determined. Results were compared with sites in the heart that received plasmid injection but no electric pulses or were not treated. Gene expression was higher in all electroporated sites when compared with injection only sites demonstrating the robustness of this approach. Our results provide evidence that in vivo electroporation can be a safe and effective non-viral method for delivering genes to the heart, in vivo.

Production of Ascochyta rabiei lacking solanapyrone A toxin production.

Ascochyta rabiei, agent of Ascochyta blight of chickpea produces three toxins, Solanapyrones A, B and C of which solanapyrone A is the most toxic. All isolates of the fungus so far examined produce at least one of the Solanapyrone toxins, usually Solanapyrone A. The universality of solanapyrone production argues strongly for the importance of the toxins in virulence or pathogenicity. However, further evidence for this awaits the development of mutants lacking toxin production. Generation and isolation of fungal mutants defective in pathogenicity has been very useful for understanding the genetic and enzymatic processes responsible for infectivity in a number of pathosystems. Numerous tools have been used to transform plants and micro-organisms but the most widely micro-organism employed is Agrobacterium tumefaciens. In the present experiments, two strains of A. tumefaciens, AGL1 and LBA1126, harbouring two different plasmids, both encoding a gene for hygromycin resistance in the T-DNA region were used to transform isolate Tk21 of A. rabiei. The transformation of Ascochyta rabiei, gave rise to 498 colonies which grew on media supplemented with the selective agent; hygromycin B. The 30 sporulated transformants produced solanapyrone A on the specific medium at different rates. Solanapyrone A production, as demonstrated by the absorption of light at 327 nm, varied from 2.11 microg/ml to 4.32 microg/ml, representing a reduction of 74.11% to 46.99% in comparison with the wild type (8.15 microg/ml).

Antifungal activity of rhizospheric bacteria.

Fluorescent Pseudomonad spp. were isolated from the rhizosphere of potato plants (Algeria) by serial dilutions of rhizosphere soils on Kings B medium and were tested for their antifungal activity. The antifungal activity of the Pseudomonas isolated from Potatoes rhizosphere was tested against Pythium ultimum, Rhizoctonia solani and Fusarium oxysporum in dual culture with bacteria on PDA. The Petri dish was divided into tow, on one the bacteria was spread and on the opposite side fungal plugs were inoculated and incubated for one week. Fourteen bacteria were isolated; only one isolate inhibited the growth of Pythium ultimum, Rhizoctonia solani, Fusarium solani; Fusarium oxysporum f.sp. albedinis and Fusarium oxysporum f. sp. Lycopersici with inhibition zones of 39.9, 33.7, 30.8, 19.9 and 22.5 mm respectively.

The effect of essential oil of Ammoides pusilla (brot.) breistr on the growth and the production of solanapyrone a by Ascochyta rabiei.

Biological control such as the use of plant extracts has emerged as promising option to the phenomena of fungi resistance to chemical. Several constituent of essential oil have been studied for their biological activity including antibacterial and antifungal activity. In this study the effect of Ammoides pusilla essential oil with different concentrations was test against the growth of Ascochyta rabiei and the production of solanapyrone A by the fungus. After 14 days the mycelium was collected and the dry weight measured. A. rabiei did not grow at a final concentration of 6 and 3 mg/ml, at 1.5 mg/ml and 0.625ml there was little growth of the fungus with a dry weight of 55 mg and 99 mg respectively compared to the control with 519 mg dry weight, but there was no solanapyrone A produced. However a new compound appeared at the HPLC at 10 min. 30 sec. compared with the solanapyrone A which elutes at nearly 14 minutes.

Crystal structure of human prion protein bound to a therapeutic antibody.

Prion infection is characterized by the conversion of host cellular prion protein (PrP(C)) into disease-related conformers (PrP(Sc)) and can be arrested in vivo by passive immunization with anti-PrP monoclonal antibodies. Here, we show that the ability of an antibody to cure prion-infected cells correlates with its binding affinity for PrP(C) rather than PrP(Sc). We have visualized this interaction at the molecular level by determining the crystal structure of human PrP bound to the Fab fragment of monoclonal antibody ICSM 18, which has the highest affinity for PrP(C) and the highest therapeutic potency in vitro and in vivo. In this crystal structure, human PrP is observed in its native PrP(C) conformation. Interactions between neighboring PrP molecules in the crystal structure are mediated by close homotypic contacts between residues at position 129 that lead to the formation of a 4-strand intermolecular beta-sheet. The importance of this residue in mediating protein-protein contact could explain the genetic susceptibility and prion strain selection determined by polymorphic residue 129 in human prion disease, one of the strongest common susceptibility polymorphisms known in any human disease.

Prepubertal physical activity up-regulates estrogen receptor beta, BRCA1 and p53 mRNA expression in the rat mammary gland.

Findings in BRCA1 mutation carriers suggest that physical activity, particularly during childhood, may be linked to a reduced risk of developing breast cancer. We investigated whether physical activity at puberty alters the expression of BRCA1 and two other tumor suppressor genes--p53 and estrogen receptor (ER)-beta--in rats. In addition, the effects on ER-alpha expression, mammary proliferation and functional epithelial differentiation were investigated as markers of altered mammary cancer risk in rats exposed to regular physical activity at puberty. Female Sprague Dawley rat pups were randomized to voluntary exercise, sham-exercise control and non-manipulated control groups. Treadmill training (20-25 m/min, 15% grade, 30 min/day, 5 days/week) started on postnatal day 14 and continued through day 32. Third thoracic mammary glands (n = 5 per group and age) were obtained at days 32, 48 and 100 and assessed for changes in morphology through wholemounts, and at 100 days cell proliferation by using Ki67 staining, protein levels of ER-alpha and ER-beta by immunohistochemistry, and mRNA expression levels of BRCA1, p53, ER-alpha and ER-beta by real-time PCR. Mammary glands of rats exposed to exercise during puberty contained fewer terminal end buds (TEBs) and a higher number of differentiated alveolar buds and lobules than the sham controls. However, cell proliferation was not significantly altered among the groups. ER-alpha protein levels were significantly reduced, while ER-beta levels were increased in the mammary ducts and lobular epithelial structures of 100-day old rays which were voluntarily exercised at puberty, compared to sham controls. ER-beta, BRCA1 and p53 mRNA levels were significantly higher in the mammary glands of 100-day-old exercised versus sham control rats. Pubertal physical activity reduced mammary epithelial targets for neoplastic transformation through epithelial differentiation and it also up-regulated tumor suppressor genes BRCA1, p53 and ER-beta, and reduced ER-alpha/ER-beta ratio in the mammary gland. It remains to be determined whether the up-regulation of BRCA1, and perhaps p53, explains the protective effect of childhood physical activity against breast cancer in women who carry a germline mutation in one of the BRCA1 alleles.

Vitamin D receptor gene polymorphism is associated with reduced disability in multiple sclerosis.

Ultraviolet radiation (UVR) may contribute to multiple sclerosis (MS) outcome by a mechanism involving vitamin D and the vitamin D receptor (VDR). In 512 patients with MS duration of 10 or more years, we studied the association of VDR single nucleotide polymorphisms (A/G(1229), C/G(3444), G/A(3944), CC(20965), CC(30056), F/f(30875), C/T(48200), T/t(65013)) with outcome or disability. ff(30875) frequency was lower in cases with EDSS > or = 6.0 than with scores < 6.0 (odds ratio = 0.38, 95% CI = 0.20-0.70). The association of ff(30875) with outcome was not mediated by cumulative exposure to UVR as assessed by questionnaire; low exposure (odds ratio = 0.42, 95% CI = 0.14-1.34) and high exposure (odds ratio = 0.34, 95% CI = 0.16-0.73).

Proliferation and apoptosis in mammary epithelium during the rat oestrous cycle.

AIM: During each oestrous cycle, the mammary gland is subject to changes in ovarian hormone levels. It responds with limited proliferation, differentiation and regression. To understand the processes resulting in these changes, particularly the regulation of cell death, we examined protein levels in mammary epithelium during the oestrous cycle of the Sprague-Dawley rat. METHODS: Studies of serum hormone levels, vaginal smears, uterine weight and morphology, mammary gland morphology, proliferation and apoptotic indices, and protein levels during the stages of the Sprague-Dawley rat oestrous cycle were used to examine the response of mammary epithelium to the oestrous cycle. RESULTS: Proliferation of mammary epithelium was greater in diestrus and proestrus, while apoptosis was increased in metestrus and diestrus. Growth factor-, hormone- and anchorage-mediated cell survival signalling, indicated by activation of Stat5A, FAK and Akt 1 and expression of anti-apoptotic Bcl-2 family members, was greater in proestrus and reduced in metestrus. In contrast, the levels of pro-apoptotic Bcl-2 family members and proteins associated with apoptosis in mammary epithelium (TGFbeta3, pStat3) were increased during metestrus and diestrus. CONCLUSION: Decreases in growth factor, hormone and cell attachment survival signals corresponded with increased apoptosis during the second half of the oestrous cycle. The protein levels detected during oestrus suggest parallels to apoptosis in mammary involution.

Studies of associations between disability in multiple sclerosis, skin type, gender and ultraviolet radiation.

Recent studies suggest ultraviolet radiation (UVR)/vitamin D is protective against the development of multiple sclerosis (MS). We determined if outcome in MS is associated with the surrogate for host pigmentation, skin type, and parameters of UVR exposure. We used a validated questionnaire to determine skin type and UVR exposure during childhood (0-16 years), and early adult life (17-40 years), in 448 Caucasians with MS. Outcome was assessed using the Kurtzke Expanded Disability Status Score (EDSS) and Multiple Sclerosis Severity Scale (MSSS). We studied the association of skin type and exposure with dichotomized values of EDSS (< and >or=6) and MSSS (continuous variable) using logistic and linear regression analyses, respectively. Sex, onset age and MS duration were significantly associated with outcome in all patients. In 169 females with established disease (>or=10 years), sun sensitive skin types 1 and 2 were associated with reduced risk of EDSS >or=6 (odds ratio =0.50; 95% CI = 0.26-0.97), and higher MSSS values (coefficient = -0.86; 95% CI = -1.67 to -0.05). Parameters of UVR exposure were not significantly associated with outcome. These preliminary data show an association between skin type and disability in female MS patients. They are compatible with independent studies suggesting that exposure mediates MS pathogenesis via vitamin D. Further studies are required to properly assess these potentially important findings.

A comparison of sunlight exposure in men with prostate cancer and basal cell carcinoma.

Ultraviolet radiation exposure increases basal cell carcinoma (BCC) risk, but may be protective against prostate cancer. We attempted to identify exposure patterns that confer reduced prostate cancer risk without increasing that of BCC. We used a questionnaire to assess exposure in 528 prostate cancer patients and 442 men with basal cell carcinoma, using 365 benign prostatic hypertrophy patients as controls. Skin type 1 (odds ratio (OR)=0.47, 95% CI=0.26-0.86), childhood sunburning (OR=0.38, 95% CI=0.26-0.57), occasional/frequent sunbathing (OR=0.21, 95% CI=0.14-0.31), lifetime weekday (OR=0.85, 95% CI=0.80-0.91) and weekend exposure (OR=0.79, 95% CI=0.73-0.86) were associated with reduced prostate cancer risk. Skin type 1 (OR=4.00, 95% CI=2.16-7.41), childhood sunburning (OR=1.91, 95% CI=1.36-2.68), regular foreign holidays (OR=6.91, 95% CI=5.00-9.55) and weekend (OR=1.17, 95% CI=1.08-1.27) but not weekday exposure were linked with increased BCC risk. Combinations of one or two parameters were associated with a progressive decrease in the ORs for prostate cancer risk (OR=0.54-0.25) with correspondingly increased BCC risk (OR=1.60-2.54). Our data do not define exposure patterns that reduce prostate cancer risk without increasing BCC risk.

Meta- and pooled analysis of GSTT1 and lung cancer: a HuGE-GSEC review.

Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.

Genetics and risk factors for basal cell carcinoma.

Nonmelanoma skin cancer (NMSC) is the commonest cancer in whites and its incidence is increasing worldwide. The prevalence of this cancer is predicted to equal that of all others combined and it was estimated that there were over 2 million cases diagnosed in the U.S.A. in 2004. Patients exhibit marked differences in clinical phenotype with variations in tumour numbers, rate of tumour accrual, site and histological subtype. Furthermore, patients are at increased risk of other cutaneous and noncutaneous cancers. The factors accounting for this variation are complex and still not completely understood. Clearly, ultraviolet light (UV) exposure is a major influence but its relationship to clinical phenotype is not yet clear. In addition, immunosuppression is a significant risk factor. Our group has identified high-risk groups for the development of further basal cell carcinoma (BCC), namely patients with truncal BCC and those presenting with tumour clusters. This presentation will concentrate on these clinical subgroups as well as immunosuppressed patients. These groups represent significant management challenges and are areas where novel, nonsurgical treatment options may make a significant clinical impact in patient care. The risk factors predisposing to these clinical phenotypes will be discussed, including genetic factors and UV exposure. Potential clinical applications, including predictive indices, will be considered.

Asthma severity and atopy: how clear is the relationship?

BACKGROUND: The relationship between asthma severity and atopy is complex. Many studies have failed to show significant relationships between clinical severity or lung function and markers of atopic sensitisation. AIM: To determine whether increasing asthma severity is related to atopic sensitisation in a population of children with asthma. METHODS: A total of 400 children (7-18 years) with asthma were recruited as part of a multicentre study of the genetics of asthma. Detailed phenotypic data were collected on all participants. Associations between measures of asthma severity and atopic sensitisation were sought using multilevel models allowing variation at the individual and family level. RESULTS: Children recruited to the study had a range of asthma severities, with just over a third having mild persistent asthma. The logarithm of total serum IgE was associated with increased asthma severity score, decreased FEV1, increased airways obstruction, risk of hospital admission, and inhaled steroid use. Increasing skin prick test reactivity to a panel of seven aeroallergens was associated with increased risk of hospital admission, use of an inhaled steroid, and airways obstruction. The results remained highly significant after corrections for age, gender, and birth order. CONCLUSIONS: In children with asthma, increasing atopy is associated with increasing asthma severity. However, the relationships between asthma severity and skin prick tests, and asthma severity and total serum IgE values, appear subtly different.

Effects of glutathione S-transferase M1, T1 and P1 on lung function in asthmatic families.

RATIONALE: Previous data have suggested that glutathione-S-transferase (GST) genotypes are important in determining the rate of lung function growth in childhood. This effect was most marked in Caucasian children with asthma. OBJECTIVES: We investigated the association of lung function with GSTM1, GSTP1 and GSTT1 genotypes in Caucasian families with asthma. METHODS: Four hundred and eighteen children and 316 parents from 224 Caucasian families were recruited via a child with asthma, the proband. Associations between lung function and GST genotype were determined using multilevel models. RESULTS: There were no observed associations between lung function and GST genotype in parents. However, in the children, the GSTP1 val(105)/val(105) and GSTM1 null genotypes were associated with significantly higher forced expiratory volume in 1 s (FEV(1)) and FVC values as percentage of predicted. This effect was not statistically significant in the probands but was marked in their siblings in whom GSTP1 val(105)/val(105) was associated with 9.4% higher FEV(1) and 10.7% higher FVC (P=0.005 and 0.001, respectively). The GSTM1 null genotype was associated with a 6.7% higher FEV(1) and 4.1% higher FVC (P=0.003 and 0.063, respectively). These effects remained significant after correcting for the confounders of individual atopic status, tobacco smoke exposure and familial aggregation of lung function values. CONCLUSIONS: GSTM1 and GSTP1 genotypes are important determinants of lung function in childhood. The smaller differences seen in probands are predicted by a simple model in which more rapid decline in lung function is seen in these individuals.