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The association of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers was assessed through a meta-analysis of published case-control studies and a pooled analysis of both published and unpublished case-control studies from the Genetic Susceptibility to Environmental Carcinogens database (http://www.upci.upmc.edu/research/ccps/ccontrol/index.html ). Thirty publications used in the meta-analysis included a total of 7783 subjects (3177 cases and 4606 controls); 21 datasets, 9397 subjects (3130 cases and 6267 controls) were included in the pooled analysis. The GSTM1 deletion was 2-fold more likely to occur in African American and African cases than controls (odds ratio: 1.7, 95% confidence interval: 0.9-3.3), although this was not observed among whites (odds ratio: 1.0, 95% confidence interval: 0.9-1.1). The meta-analysis and pooled analysis showed a significant association between oral and pharyngeal cancer and the CYP1A1 MspI homozygous variant (meta-ORm2/m2: 1.9, 95% confidence interval: 1.4-2.7; Pooled ORm2m2: 2.0, 95% confidence interval: 1.3-3.1; ORm1m2 or [infi]m2m2: 1.3, 95% confidence interval: 1.1-1.6). The association was present for the CYP1A1 (exon 7) polymorphism (ORVal/Val: 2.2, 95% confidence interval: 1.1-4.5) in ever smokers. A joint effect was observed for GSTM1 homozygous deletion and the CYP1A1 m1m2 variant on cancer risk. Our findings suggest that tobacco use and genetic factors play a significant role in oral and pharyngeal cancer.

Background: Exposure to ultraviolet radiation (UVR) has been inversely associated with prostate cancer risk. We determined if skin type and UVR exposure are linked with parameters of prostate cancer outcome., Methods: We used a questionnaire to determine UVR exposure parameters and skin type in 553 men with prostate cancer and, using logistic regression and survival analysis, studied their association with T-stage, Gleason score, and survival after starting hormone manipulation therapy., Results: UVR exposures 10, 20, and 30 years before diagnosis were inversely associated with T-stage. The odds ratio (OR) for UVR exposure 10 years before diagnosis was lowest (OR=0.69, 95% CI=0.56-0.86). ORs were lower in men with skin types I/II than III/IV. Skin types I/II were associated with longer survival after commencing hormone therapy (hazard ratio=0.62, 95% CI=0.40-0.95)., Conclusions: Our finding that UVR exposure is beneficial is compatible with accumulating data showing sunlight has a protective effect on disease phenotype.

Families with asthmatic children were recruited to take part in a multi-centre collaborative study into the genetics of asthma. Detailed phenotypic information was collected on all family members including: lung function, anthropomorphic measurements, response to methacholine challenge, skin prick testing, serum IgE measurements and a detailed nurse-administered questionnaire. Families were eligible for entry into the study if they had two children with a doctor-diagnosis of asthma. Bennett/Twin nebulisers were supplied to each centre from a single source and these were calibrated to determine gravimetric nebuliser output prior to use. Asthmatic probands from each centre had similar degrees of asthma severity and atopy. There was no significant difference in the sex ratios or ages of the probands or numbers of parents with a history of smoking in the families recruited at each centre. However, there was a significant difference in the number of children with airway hyperresponsiveness, with 90% of the North Staffordshire group but only 60% of the Sheffield group having a PC20 of <8 mg/ml for methacholine. This difference highlights the difficulty of using families from different centres in genetic and epidemiological studies.

Governmental and research agencies worldwide have strongly advocated sun avoidance strategies in an attempt to counter marked increases in skin cancer incidence. Concurrently, there are reports describing widespread Vitamin D3 deficiency. Because 1,25-dihydroxyvitamin D3, through interaction with the Vitamin D receptor, exerts pleiotrophic effects, such deficiency might be expected to have clinical consequences. Indeed, various reports indicate that exposure to ultraviolet radiation (UVR) exerts a protective effect on development of some common diseases including internal cancers and multiple sclerosis. We describe studies indicating that modest exposure reduces risk of prostate cancer. The effect of UVR is mediated by skin type; at lower levels of exposure a relative inability to effect skin pigmentation is protective presumably because it allows more efficient Vitamin D3 synthesis. Polymorphic variants in genes associated with pigmentation including melanocyte stimulating hormone receptor and tyrosinase are also associated with prostate cancer risk. Overall, though preliminary and requiring cautious interpretation, these data indicate that moderate UVR exposure together with characteristics linked with less effective tanning confer reduced prostate cancer risk. Clearly, it is important to define safe levels of UVR that do not result in increased risk of skin cancers such as malignant melanoma.

We have examined the association of the CCND1 A/G870 polymorphism with susceptibility and outcome in 174 German patients with oral SCC (OSCC). The CCND1 G870 allele frequency was increased in cases (G870=0.65) when compared to controls (n=155, G870=0.54) and the distribution of CCND1 genotypes were significantly different (p=0.014). Using logistic regression, correcting for age, gender and tobacco consumption, an increased frequency of the CCND1 GG870 genotype was observed in the OSCC cases (p=0.025, OR 3.37, 95% CI 1.61-9.80). No significant associations were observed between CCND1 A/G870 and tumour histological factors. Our data suggests that the CCND1 GG870 genotype is associated with increased susceptibility to OSCC. The involvement of cyclin D1 polymorphism in mechanisms of SCC development may differ in the different sub-sites of the head and neck.

Maternal factors including atopy and smoking during pregnancy are associated with asthma risk during childhood. Suggested mechanisms include transmission of specific maternal alleles and maternal influences on the intrauterine environment. We have previously shown that polymorphism in glutathione S-transferase, GSTP1 is associated with airway hyperresponsiveness (AHR) and atopy in adults. We now hypothesise that GSTP1 genotypes in the mother and child, but not the father, mediate asthma phenotypes in the child. One hundred and forty-five Caucasian families were recruited via an asthmatic proband aged 7-18 years. Atopy and asthma were assessed using a questionnaire, skin prick testing, serum IgE, spirometry and methacholine challenge (PC20, dose-response slope--DRS). GSTP1 genotyping was determined using PCR. GSTP1 Val105/Val105 genotype in the child was associated with a reduced risk of atopy (P = 0.038) and AHR (PC20, P = 0.046; DRS, P = 0.032). In mothers (P = 0.014) but not fathers (P = 0.623), Val105/Val105 was associated with a reduced risk of AHR in the child. We have identified, for the first time, an association between maternal genotype and the child's asthma phenotype that appears not to be due to transmission of specific maternal alleles. This preliminary data supports the view of in utero effects of maternal genotype and adds new insights into the possible mechanisms by which maternal factors may influence development of childhood asthma.

Background: Malignant melanoma, the most serious cutaneous malignancy, has attracted substantial attention because of its rapidly increasing incidence and the poor prognosis of some tumours. Little is known of the genetic factors that mediate susceptibility to, and outcome of, sporadic malignant melanoma. Because of its role in mitogenesis, which is especially relevant to wound healing, tumorigenesis, and proliferation of epidermal tissues, epidermal growth factor (EGF) is an attractive candidate in which to look for genetic polymorphisms., Methods: We enrolled 135 white European patients with malignant melanoma and 99 healthy white European controls, and screened a selection of DNA samples for polymorphisms in the promoter and 5' untranslated region of the EGF gene by analysis. We then screened DNA samples from all participants for the identified polymorphism by restriction-fragment-length polymorphism (RFLP) analysis. In-vitro EGF production was measured in peripheral-blood mononuclear cells from 34 controls, and the results were compared with the individuals' EGF genotypes., Findings: We identified a single nucleotide substitution (G to A) at position 61 of the EGF gene. Allele frequencies in the controls were 56% EGF 61*A and 44% EGF 61*G. Cells from individuals homozygous for the 61*A allele produced significantly less EGF than cells from 61*G homozygotes (p=0.0004) or heterozygous A/G individuals (p=0.001). Compared with the A/A genotype, G/G was significantly associated with Breslow thickness (p=0.045) and with risk of malignant melanoma (odds ratio 4.9 [95% CI 2.3-10.2], p<0.0001)., Interpretation: This study suggests that high EGF production might be important in the development of malignant melanoma.

We determined whether the glutathione S-transferase GSTP1 Ile105 --> Val105 substitution is associated with response to androgen ablation therapy in patients with advanced prostate cancer. As response may be associated with tumor grade, Gleason score, clinical T stage and presence of metastases we also determined if GSTP1 genotypes were associated with these prognostic parameters. We speculated that GSTP1 Ile105/Ile105 would be linked with good response to androgen ablation therapy and, low/moderate tumor grade, 1/2 clinical T-stage, Gleason score < 6 and, no metastases. Genotype frequencies in cases and controls were not significantly different (P = 0.70) indicating that allelism in GSTP1 is not associated with susceptibility. There was no association between GSTP1 (Ile105/Ile105 versus Ile105/Val105 and Val105/Val105) and grade (P = 0.28, OR = 0.92), Gleason score (P = 0.84, OR = 0.94) or metastatic state (P = 0.68, OR = 0.88) though the frequency of GSTP1 Ile105/Ile105 was higher in cases with stage 1/2 tumors than those with stage 3/4 tumors (P = 0.03, OR = 1.89). GSTP1 Val105/Val105 was also associated with response to hormone ablation therapy. Thus, the GSTP1 Ile105/Ile105 frequency was significantly higher in 86/118 patients who demonstrated a good response than in those with poor response (P = 0.03, OR = 2.70). We speculate that the association of GSTP1 with response results from an effect of the gene product early in carcinogenesis.

We have previously reported that the cyclin D1 (CCND1) GG870 genotype was associated with poorly differentiated tumors and reduced disease-free interval in patients with squamous cell carcinoma of the head and neck (SCCHN). We have now examined the association of this and a second CCND1 polymorphism with gene expression and outcome in SCCHN patients. Analysis of a CCND1 G/C1722 polymorphism revealed that CCND1 CC1722 genotype was associated with poorly differentiated tumors [P = 0.005; odds ratio (OR), 5.7; 95% CI, 1.7 to 19.2), and reduced disease-free interval (P = 0.003; Hazard Ratio (HR), 7.3; 95% CI, 1.1 to 27.2.) independently from the influence of CCND1 GG870 genotype. Patients whose tumors were negative for cyclin D1 were associated with reduced disease-free interval (P = 0.028; HR, 4.1; 95% CI, 1.4 to 14.2). Although G/C1722 genotypes were not associated with expression, we found a significant trend between reduced expression of cyclin D1 in patients with the CCND1 GG870 genotype (P = 0.04). Splicing of CCND1 mRNA in head and neck tissues was modulated by CCND1 A/G870 alleles, thus CCND1 transcript a was spliced equally from CCND1 A870 and G870 alleles, whereas CCND1 transcript b was spliced mainly from the CCND1 A870 allele. Our analysis has also identified differences in cyclin D1 genotype and protein expression and the pathogenesis of SCCHN in males and females. Thus, CCND1 CC1722 genotype was more common in female patients (P = 0.019; OR, 3.3; 95% CI, 1.3 to 10) and cyclin D1 expression was more frequent (chi-square1, 3.96; P = 0.046) and at higher levels (P = 0.004) in tumors from female patients. In summary, our data show that the two CCND1 polymorphic sites are independently associated with tumor biology and clinical outcome. CCND1 A/G870 alleles affect gene expression in head and neck tissues. We also provide preliminary evidence that the molecular genetics of SCCHN development may be influenced by patient gender.

The loci encoding the glutathione-S-transferase (GST) enzymes comprise a large supergene family located on at least seven chromosomes. The function of the GST enzymes has traditionally been considered to be the detoxication of electrophiles by glutathione conjugation. A wide variety of endogenous (e.g. by-products of reactive oxygen species activity) and exogenous (e.g. polycyclic aromatic hydrocarbons) electrophilic substrates have been identified. Interestingly, recent data has suggested a role, at least for the pi class gene product, in jun kinase inhibition. Since many GST genes are polymorphic, there has been considerable interest in determining whether particular allelic variants are associated with altered risk (or outcome) of a variety of diseases. We describe recent studies in patients with asthma and cutaneous basal cell carcinoma that demonstrate associations between GSTP1 and GSTT1 genotypes and disease phenotypes. Thus, GSTP1val(105)/val(105) was protective against asthma symptoms and GSTT1 null was associated with a subgroup of basal cell carcinoma patients who develop large numbers of primary tumours in clusters. Importantly, these associations were characterised by relatively large odds ratios (0.11 and 7.4, respectively) implying that the allelic variants exert a substantial biological effect. These and other data indicate the importance of GST polymorphism in determining disease phenotype.

Non-melanoma skin cancer (NMSC) represents a significant cause of morbidity and mortality among renal transplant recipients, with tumors behaving more aggressively than those in nontransplant patients. Not all immunosuppressed patients develop NMSC, however, and in those that do, the rate of accrual and numbers of lesions vary considerably. Though ultraviolet light is critical, it is unlikely that this alone explains the observed phenotypic diversity, suggesting the possible involvement of genetic factors. Furthermore, although twin studies in nontransplant patients with NMSC suggest a low genetic component, several genes associated with susceptibility and outcome in these patients have been identified. Thus, having previously shown that polymorphism in members of the glutathione S-transferase (GST) supergene family is associated with altered NMSC risk in nontransplant patients, we examined allelism in GSTM1, GSTP1, GSTM3, and GSTT1 in 183 renal transplant recipients. GSTM1 null was associated with increased squamous cell carcinoma (SCC) risk (p = 0.042, OR = 3.1). This remained significant after correction for age, gender, and ultraviolet light exposure (p = 0.012, OR = 8.4) and was particularly strong in patients with higher ultraviolet light exposure (e.g., sunbathing score > 3, p = 0.003, OR = 11.5) and in smokers (p = 0.021, OR = 4.8). Analysis of the interaction between GSTM1 null and sunbathing score showed that the two factors were synergistic and individuals with both risk parameters demonstrated a shorter time from transplantation to development of the first SCC (p = 0.012, hazard ratio = 7.1). GSTP1*Ile homozygotes developed larger numbers of SCC (p = 0.002, rate ratio = 7.6), particularly those with lower ultraviolet light exposure and cigarette consumption. GSTM3 and GSTT1 also demonstrated significant associations, though some genotype frequencies were low. These preliminary data suggest that genetic factors mediating protection against oxidative stress are important in NMSC development in immunosuppressed patients and may be useful in identifying high-risk individuals.

The glutathione S-transferases (GST) are a supergene family of dimeric, enzymes that catalyse the conjugation of glutathione (GSH) to a variety of electrophiles including arene oxides, unsaturated carbonyls, organic halides and other substrates. Their importance is suggested by the finding that GST enzymes are expressed in probably all life forms. In humans, polymorphism in GST genes has been associated with susceptibility to various diseases though some recent data indicate that these genotypes modify disease phenotype. Thus, GST genotypes alone and in combination have been linked with clinical outcome.

Allelic variants in the melanocyte stimulating hormone receptor (MC1R) gene are susceptibility/outcome candidates for cutaneous basal cell carcinoma (BCC). We identified the val92met (V92M) and asp294his (A294H) alleles in 311 cases and 190 controls. The cases included four homo- and 53 heterozygotes for V92M and 12 heterozygotes for A294H and two compound heterozygotes (V92M/A294H). Allele frequencies were similar in controls. In the cases, we found no association between the alleles and skin type though A294H was more common in those with red hair (4/19) than with other hair colours (6/163) (P = 0.012). V92M was not associated with BCC numbers. Cases with A294H had fewer BCC in comparison with those without the allele though the difference was not significant. After inclusion of red hair in the model, A294H was significantly associated with fewer tumours. While MCIR alleles are attractive candidates for BCC, the variants studied did not influence susceptibility. The association with outcome was relatively weak. The large number of MC1R alleles and their low frequency, make assessment of the importance of this gene in the pathogenesis of skin cancers difficult.

Allelic variation at the melanocyte stimulating hormone receptor (MC1R) gene has been linked with sun-sensitive skin types, suggesting it is a susceptibility candidate for melanoma. We determined the frequency of the val92met, asp294his, and asp84glu MC1R alleles in 190 Caucasian controls and 306 melanoma cases and studied their association with skin type and hair color. The percentage of controls with at least one val92met, asp294his, or asp84glu allele was 17.3%, 6.8%, and 3.5%, respectively. Individually, frequencies of the val92met, asp294his, or asp84glu alleles in the controls with skin types 3 and 4 were similar to those with skin types 1 and 2. Trend analysis, however, did identify an association (exact p = 0.048, two-sided test) between skin type and MC1R variants in the group comprising all controls with any one or more of these alleles. There was no association between MC1R alleles and hair color. Allele frequencies were not different in melanoma cases and controls. There were no associations between skin types and the proportion of cases with the asp294his or asp84glu alleles, though the association between skin type and the val92met allele approached significance (exact p = 0.09, two-sided test). Unexpectedly, in the group comprising all cases with one or more variant alleles, the proportion of subjects with variant alleles increased with skin types associated with tanning rather than burning, although trend analysis showed that this association did not quite reach statistical significance (exact p = 0.08, two-sided test). Asp84glu (but not val92met or asp294his) variant alleles were more common in subjects with blonde hair, although the relationship between the asp84glu allele and hair color did not achieve statistical significance (chi(2)3 = 6.16, exact p = 0.10). We interpret the data presented as indicating that polymorphism at MC1R does not appear a major determinant of skin type, at least in terms of these allelic variants. Furthermore, considered alone, these alleles are not susceptibility candidates for malignant melanoma.

The glutathione S-transferase supergene family includes several loci that demonstrate well characterised polymorphisms. The apparently critical role of these enzymes in cellular protection from the cytotoxic and mutagenic effects of electrophiles suggest that alleles associated with impaired detoxification will confer an increased susceptibility to a wide range of diseases. This hypothesis has been examined in case control studies and while data in some diseases such as lung cancer are conflicting, an increasing body of evidence suggests the importance of several glutathione S-transferase polymorphisms. In particular, GST genotypes have been associated with an increased susceptibility or worse outcome in diseases associated with oxidative stress. For example, both GSTM1 and GSTT1 genotypes are associated with susceptibility and outcome in cutaneous basal cell carcinoma. It still remains unclear however, why particular glutathione S-transferase loci are associated with altered risk in some diseases but not others. Further, the true in vivo substrates of these enzymes is unknown, consequently their mechanism of action remains unclear.

Basal cell carcinoma (BCC) places increasing burdens on clinicians; incidence is rising and patients may develop multiple primary tumors. Although UV exposure is critical, many patients develop tumors at less-exposed sites, such as the trunk, suggesting a genetic predisposition. We previously showed that polymorphism in loci encoding the detoxifying enzymes, glutathione S-transferase (GSTM1, GSTM3, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) influences susceptibility to BCC. We now describe a case-control approach in 345 patients with BCC that examines the role of these polymorphisms and patient characteristics (age, gender, skin type, hair color, eye color, smoking, occupation) in determining susceptibility to truncal tumors. GST and CYP genotypes were identified using polymerase chain reaction-based methods. Patients with one or more truncal tumors were significantly younger (p = 0.0170) than those with no truncal tumors. Male gender also appeared more common in the truncal tumor group, although this did not achieve significance (p = 0.0925). Patients whose first tumor was truncal had significantly more tumors (p = 0.0297). GSTT1 null (p = 0.0245, odds ratio 2.24) and CYP1A1 Ile/Ile (p = 0.0386, odds ratio 2.86) were associated with truncal site after correction for age and gender. The combination, GSTT1 null and CYP1A1 Ile/Ile, was particularly significant (p = 0.0059, odds ratio = 2.95). These effects were present after correction for tumor numbers. These data show first, patients with truncal tumors constitute a high-risk group for BCC, second, a significant genetic influence on BCC site, and third, a significant interaction between GSTT1 and CYP1A1 genotypes.

This study examined the effect of the angiotensin converting enzyme (ACE) inhibitor, enalaprilat, on mesangial cell (MC) DNA synthesis induced by H2O2, IL-6 and PDGF. MC were incubated with enalaprilat (2.5-100 mumol/l) alone and together with combinations of H2O2 (3 daily pulses of 10(-6) mol/l), IL-6 (5 ng/ml) and PDGF (10 ng/ml). DNA synthesis was assessed after 72 h using [3H]thymidine (3H-TdR) incorporation. Enalaprilat alone had no effect on MC DNA synthesis. Stimulation of MC by H2O2, PDGF and IL-6 alone resulted in increases in 3H-TdR of 4936.6 +/- 1147.5, 5640.5 +/- 1537.6 and 4413.5 +/- 998.4 cpm, respectively (P < 0.05 above control). Only 2.5 mumol/l enalaprilat effected a significant reduction in IL-6 and PDGF-induced DNA synthesis. Incubation of MC with H2O2 + PDGF or H2O2 + IL-6 resulted in increases of 3H-TdR of 6471.9 +/- 1785.1 and 5507.2 +/- 1270 cpm, respectively (P < 0.05 above control). Addition of enalaprilat with either H2O2 + PDGF or H2O2 + IL-6 effected significant reductions in DNA synthesis over the range 2.5-100 mumol/l. These data demonstrate that ACE inhibitors modulate MC DNA synthesis induced by reactive oxygen species.

Multiple allelism at loci encoding detoxicating enzymes is associated with cancer risk. We have studied genetic variation at the glutathione S-transferase GSTM1 locus to see whether phenotypes confer altered susceptibility to basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM), or multiple skin tumours of different histological types. The frequency of GSTM1 null in cases and controls (52%) was similar, except for patients with two or more tumours of different types (71%, p = 0.033). GSTM1 A/B was reduced in frequency (p < 0.05) in patients with single or multiple BCC. Thus GSTM1 A/B may be protective, and effectiveness of detoxication may be a factor determining susceptibility to skin cancer.

The putative involvement of reactive oxygen species in the etiology of lung damage in infants receiving mechanical ventilation has been examined by comparing the levels of peroxidation and expression of the antioxidant enzymes, CuZn and Mn superoxide dismutase, in lungs from control and affected infants as well as from fetuses and infants who died postnatally after term delivery. Mean levels (+/- SD) of lung peroxidation, determined with a thiobarbituric acid method, were similar in affected and control premature neonates and in fetal subjects (1.87 +/- 1.26, 1.92 +/- 2.07, and 1.19 +/- 1.36 nmol/mg protein, respectively). Expression of CuZn and Mn superoxide dismutases was also similar in these subjects and in the patients who died postnatally. Thus activity measurements and immunoblotting studies showed continuous expression of these enzymes throughout development with no apparent change in protein levels or size. Immunohistochemical examination of lung tissue showed expression of CuZn and Mn superoxide dismutases in epithelial, smooth muscle, endothelial, and some mesenchyme components. In patients with bronchopulmonary dysplasia, alveolar walls were thickened by an excess of fibrous tissue and terminal air spaces were lined mainly by type II pneumatocytes. All structures, including abnormal fibrous components, were positive for both CuZn and Mn superoxide dismutase. Our data show that, unlike some experimental animals, expression of at least these antioxidant enzymes in human infants born prematurely is similar to that in adults, and indicate that such infants are better adapted for life in an oxygen-containing environment than previously suspected.(ABSTRACT TRUNCATED AT 250 WORDS)

The glutathione S-transferases of human platelets have been compared with those of erythrocytes. Although wide variations in activity were found, in individual subjects, the activity in these cell types was significantly correlated. The enzymes demonstrated similar isoelectric points and electrophoretic mobilities and it appears that the platelet enzyme is also a product of the GST3 locus. There was no correlation between platelet enzyme activity and plasma concentrations of retinol and cholesterol, but in men, the relationship between activity and carotene was significant. It is suggested that GST3 isoenzyme activity depends on vitamin A.

To determine if fasting bile salt concentrations are an accurate indicator of pre-existing and methotrexate-induced liver disease in patients with psoriasis, the plasma concentrations of conjugated cholate, chenodeoxycholate and sulpholithocholate were measured in 18 patients being assessed for methotrexate therapy and 21 receiving long-term therapy. The results were compared with other liver function tests and liver histology. The liver function tests were a poor indicator of occult liver disease and, whilst fasting bile salts appeared more sensitive, they were still unreliable and inadequate for the clinical assessment of the hepatopathy associated with psoriasis. The reasons for these discrepancies are discussed.

Glutathione S-transferase activity has been measured in erythrocytes from 101 subjects. Specific activity in the female subjects was significantly greater than that in the males, but there was no relationship in either sex between enzyme activity and age or between enzyme activity and the most common erythrocyte antigens. Separation of erythrocytes by age using isopycnic centrifugation showed that enzyme activity was constant during the life of the cell.

Several reports have been published commending the use of 14C-labelled triglyceride breath tests in the assessment of fat malabsorption. We report further studies using gyceryl [14C]tripalmitate. Corrections for age, weight or metabolic rate failed to improve the test's ability to discriminate between malabsorbers and control subjects. A correction for respiratory quotient improved the linear correlation observed between the breath test results and daily faecal fat excretion. The significance of these findings is discussed and a number of problems identified which, at present, are preventing the introduction of breath tests for fat malabsorption into routine clinical practice.