Renal decline in patients with non-valvular atrial fibrillation treated with rivaroxaban or warfarin: A population-based study from the United Kingdom.

BACKGROUND: Reports suggest that renal decline is greater among patients with non-valvular atrial fibrillation (NVAF) treated chronically with warfarin vs. some non-vitamin K antagonist oral anticoagulants. METHODS AND RESULTS: Using primary care electronic health records from the United Kingdom we followed adults with NVAF and who started rivaroxaban (20 mg/day, N = 5338) or warfarin (N = 6314), excluding those with estimated glomerular filtration rate (eGFR) <50 ml/min/1.73m2, end-stage renal disease (ESRD) or no eGFR or serum creatinine (SCr) values recorded in the previous year. Outcomes were: doubling SCr levels, ≥30% decline in eGFR and progression to ESRD. We calculated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome. Average eGFR slope was estimated using mixed model regression. After a mean follow-up 2.5 years, the number of incident cases of adverse renal events within the two cohorts was: doubling SCr (n = 322), ≥30% decline in eGFR (n = 1179), and progression to ESRD (n = 22). Adjusted HRs (95% CIs) for the renal outcomes among rivaroxaban vs. warfarin users were: doubling SCr, 0.63 (0.49-0.81); ≥30% decline in eGFR, 0.76 (0.67-0.86); ESRD, 0.77 (0.29-2.04). Similar results were observed among patients with diabetes or heart failure. Estimated mean decline in renal function over the study period was 2.03 ml/min/1.73 m2/year among warfarin users and 1.65 ml/min/1.73 m2/year among rivaroxaban users (p = 0.03). CONCLUSIONS: We found clear evidence that patients with NVAF, preserved renal function at baseline and treated with rivaroxaban had a markedly reduced risk and rate of renal decline compared with those treated with warfarin.

Incidence and risk factors for mortality and end-stage renal disease in people with type 2 diabetes and diabetic kidney disease: a population-based cohort study in the UK.

INTRODUCTION: We aimed to determine the incidence of, and risk factors for all-cause/cardiovascular disease (CVD) mortality, and end-stage renal disease (ESRD) among people with type 2 diabetes with/without diabetic kidney disease (DKD) in the UK general population. RESEARCH DESIGN AND METHODS: We undertook a population-based cohort study using primary care UK electronic health records. We followed 8413 people with type 2 diabetes and DKD and a matched comparison cohort of people with type 2 diabetes without DKD. Risk factors for all-cause/CVD mortality (using both cohorts) and ESRD (DKD cohort only) were evaluated by estimating HRs with 95% CIs using Cox regression. RESULTS: In the DKD cohort (mean age 66.7 years, 62.4% male), incidence rates per 1000 person-years were 50.3 (all-cause mortality), 8.0 (CVD mortality) and 6.9 (ESRD). HRs (95% CIs; DKD vs comparison cohort) were 1.49 (1.35 to 1.64) for all-cause mortality and 1.60 (1.24 to 2.05) for CVD mortality. In general, higher all-cause mortality risks were seen with older age, underweight (body mass index <20 kg/m2), reduced renal function, and cardiovascular/liver disease, and lower risks were seen with being female or overweight. In the DKD cohort, higher risks of ESRD were seen with reduced renal function at baseline, high material deprivation, cancer and non-insulin glucose-lowering drugs, and a lower risk was seen with overweight (≥25 kg/m2). CONCLUSIONS: Annually, one death will occur among every 20 people with type 2 diabetes and DKD. The identified risk factors in this study will help identify people with type 2 diabetes at most risk of death and progression of kidney disease, and help to direct effective management strategies.

Identification of undiagnosed dementia cases using a web-based pre-screening tool: The MOPEAD project.

INTRODUCTION: Innovative patient engagement models are required to identify people with prodromal and mild Alzheimer's disease who are "hidden" in their communities and not normally found in a memory clinic setting. METHODS: A marketing campaign and a web-based pre-screening tool were used to identify individuals at risk of dementia in five European countries. Harmonized clinical evaluation of these patients was performed in participating memory clinics within the MOPEAD project. RESULTS: A total of 1487 individuals completed the pre-screening, with 547 of them found to be at risk of dementia (36.8%). Among the subset of 91 patients with a positive pre-screening result that underwent full clinical evaluation, 49 (53.8%) were diagnosed with either mild cognitive impairment or Alzheimer's disease. CONCLUSION: This novel web-based pre-screening tool showed to be a valid strategy to identify undiagnosed people with cognitive impairment.

Impact of chronic kidney disease definition on assessment of its incidence and risk factors in patients with newly diagnosed type 1 and type 2 diabetes in the UK: A cohort study using primary care data from the United Kingdom.

AIM: To estimate the incidence and risk factors of chronic kidney disease (CKD) in patients with newly-diagnosed diabetes using different CKD definitions. METHODS: Using UK primary care data, patients with diabetes (type 1, 4691; type 2, 109,365) and no CKD were followed to identify newly-diagnosed CKD, classified by a broad and narrow CKD definition (to capture diabetes-induced CKD, termed diabetic kidney disease, DKD). Adjusted incidence rates of CKD/DKD were calculated, and risk factors identified using Cox regression. RESULTS: There were 404 CKD cases and 147 DKD cases among patients with type 1 diabetes (T1D), and 29,104 CKD cases, 9284 DKD cases among patients with type 2 diabetes (T2D). Adjusted incidence rates of CKD per 100 years were 5.4 (T1D) and 5.5 (T2D); for DKD they were 1.9 and 1.5, respectively. Risk factors for CKD/DKD were older age, high social deprivation, obesity, cardiovascular disease, hypertension and smoking. Poor glycaemic control in the year after diabetes diagnosis was a strong predictor of CKD/DKD occurrence beyond this first year, and a risk factor for CKD/DKD in T2D. CONCLUSIONS: CKD and DKD remain common in diabetics in the decade after diagnosis. Early prevention of T2D and aggressive treatment of risk factors is urgent.

PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8+ T lymphocytes.

BACKGROUND: Binding of the programmed death-1 (PD-1) receptor to its ligands (PD-L1/2) transduces inhibitory signals that promote exhaustion of activated T cells. Blockade of the PD-1 pathway is widely used for cancer treatment, yet the inhibitory signals transduced by PD-1 in T cells remain elusive. METHODS: Expression profiles of human CD8+ T cells in resting, activated (CD3 + CD28) and PD-1-stimulated cells (CD3 + CD28 + PD-L1-Fc) conditions were evaluated by RNA-seq. Bioinformatic analyses were used to identify signaling pathways differentially regulated in PD-1-stimulated cells. Metabolic analyses were performed with SeaHorse technology, and mitochondrial ultrastructure was determined by transmission electron microscopy. PD-1-regulated mitochondrial genes were silenced using short-hairpin RNA in primary cells. Blue native gel electrophoresis was used to determine respiratory supercomplex assembly. RESULTS: PD-1 engagement in human CD8+ T cells triggers a specific, progressive genetic program different from that found in resting cells. Gene ontology identified metabolic processes, including glycolysis and oxidative phosphorylation (OXPHOS), as the main pathways targeted by PD-1. We observed severe functional and structural alterations in the mitochondria of PD-1-stimulated cells, including a reduction in the number and length of mitochondrial cristae. These cristae alterations were associated with reduced expression of CHCHD3 and CHCHD10, two proteins that form part of the mitochondrial contact site and cristae organizing system (MICOS). Although PD-1-stimulated cells showed severe cristae alterations, assembly of respiratory supercomplexes was unexpectedly greater in these cells than in activated T cells. CHCHD3 silencing in primary CD8+ T cells recapitulated some effects induced by PD-1 stimulation, including reduced mitochondrial polarization and interferon-γ production following T cell activation with anti-CD3 and -CD28 activating antibodies. CONCLUSIONS: Our results suggest that mitochondria are the main targets of PD-1 inhibitory activity. PD-1 reprograms CD8+ T cell metabolism for efficient use of fatty acid oxidation; this mitochondrial phenotype might explain the long-lived phenotype of PD-1-engaged T cells.

Mortality in patients who discontinue low-dose acetylsalicylic acid therapy after upper gastrointestinal bleeding.

PURPOSE: Discontinuing low-dose acetylsalicylic acid (ASA) therapy after upper gastrointestinal bleeding (UGIB) may increase the risk of cardiovascular-related death. Our aim was to compare mortality in UK primary care patients who discontinue ASA after UGIB with that in patients who continue therapy. METHODS: ASA users at the time of UGIB and who were alive 30 days after were selected using The Health Improvement Network. Predictors of survival were assessed using adjusted Cox proportional hazards regression models. RESULTS: Of 547 ASA users, half did not re-initiate ASA during a mean follow-up of 4.1 years. Increasing age (a 10% increased risk for each yearly increase in age; hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.07-1.14), female sex (HR: 1.61; 95%CI: 1.09-2.38), current smoking (HR: 2.11; 95%CI: 1.23-3.63), heavy alcohol use (HR: 3.31; 95%CI: 1.50-7.31), diabetes mellitus (HR: 1.93; 95%CI: 1.25-3.00), and chronic obstructive pulmonary disease (HR: 1.75; 95%CI: 1.03-2.99) were significantly associated with increased mortality. Most deaths (115/139) occurred in patients taking ASA for secondary prevention. In these patients, mortality tended to be lower among ASA continuer periods (HR: 0.74; 95%CI: 0.34-1.62) and higher among discontinuer periods (HR: 1.37; 95%CI: 0.81-2.30) than among non-users. Current use of clopidogrel was associated with decreased mortality in this population (HR: 0.49; 95%CI: 0.28-0.86). CONCLUSIONS: ASA therapy for secondary prevention should continue after UGIB because the risk of death tends to increase when ASA is stopped. However, a significantly increased risk was not found in these patients, likely owing to the relatively small number of ASA users and deaths that occurred during follow-up. Further studies with larger samples sizes are needed to confirm these findings among UGIB survivors taking ASA at the time of UGIB. Copyright © 2016 John Wiley & Sons, Ltd.

New-onset type 2 diabetes, elevated HbA1c, anti-diabetic medications, and risk of pancreatic cancer.

BACKGROUND: Associations between type 2 diabetes, anti-diabetic medications and pancreatic cancer are controversial. This study aims to clarify such associations with new-onset type 2 diabetes and repeated measurements of glycated haemoglobin (HbA1c) levels. METHODS: A nested case-control study was initiated from the Health Improvement Network (THIN) in UK from 1996 to 2010. Information of pancreatic cancer cases was retrieved electronically from the medical records and manually validated. Control subjects were randomly selected and frequency-matched to the cases on sex, age, and calendar years. Multivariable unconditional logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI), and adjusted for potential confounders. RESULTS: Among 1,574,768 person-years of follow-up, 529 pancreatic cancer cases and 5000 controls were identified. Type 2 diabetes, or changed HbA1c levels (rather than HbA1c levels at diabetes diagnosis) in diabetes patients (⩾4 mmol mol(-1) compared with <0 mmol mol(-1)) were followed by an increased OR of pancreatic cancer (OR, 2.16, 95% CI 1.72-2.72 and OR, 5.06, 95% CI 1.52-16.87, respectively). Among the anti-diabetic medications in diabetes patients, the OR for insulin users was 25.57 (95% CI 11.55-56.60), sulphonylureas 2.22 (95% CI 1.13, 4.40), and metformin users 1.46 (95% CI 0.85-2.52), compared with no use of any anti-diabetic medications. CONCLUSIONS: New-onset type 2 diabetes and, particularly, diabetes with rising HbA1c seem to be independent risk factors for pancreatic cancer. The relation between different anti-diabetic medications and pancreatic cancer seems to vary in strength, with the highest risk among users of insulin.

A colorectal cancer susceptibility new variant at 4q26 in the Spanish population identified by genome-wide association analysis.

BACKGROUND: Non-hereditary colorectal cancer (CRC) is a complex disorder resulting from the combination of genetic and non-genetic factors. Genome-wide association studies (GWAS) are useful for identifying such genetic susceptibility factors. However, the single loci so far associated with CRC only represent a fraction of the genetic risk for CRC development in the general population. Therefore, many other genetic risk variants alone and in combination must still remain to be discovered. The aim of this work was to search for genetic risk factors for CRC, by performing single-locus and two-locus GWAS in the Spanish population. RESULTS: A total of 801 controls and 500 CRC cases were included in the discovery GWAS dataset. 77 single nucleotide polymorphisms (SNP)s from single-locus and 243 SNPs from two-locus association analyses were selected for replication in 423 additional CRC cases and 1382 controls. In the meta-analysis, one SNP, rs3987 at 4q26, reached GWAS significant p-value (p = 4.02×10(-8)), and one SNP pair, rs1100508 CG and rs8111948 AA, showed a trend for two-locus association (p = 4.35×10(-11)). Additionally, our GWAS confirmed the previously reported association with CRC of five SNPs located at 3q36.2 (rs10936599), 8q24 (rs10505477), 8q24.21(rs6983267), 11q13.4 (rs3824999) and 14q22.2 (rs4444235). CONCLUSIONS: Our GWAS for CRC patients from Spain confirmed some previously reported associations for CRC and yielded a novel candidate risk SNP, located at 4q26. Epistasis analyses also yielded several novel candidate susceptibility pairs that need to be validated in independent analyses.

Genome-wide association study of multiple sclerosis confirms a novel locus at 5p13.1.

Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80-0.89; p = 1.36 × 10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS.

Estrogen receptor alpha gene variants are associated with Alzheimer's disease.

The present research is aimed at assessing the role of 3 estrogen receptor alpha (ESR1) gene variants in late onset Alzheimer's disease (AD) susceptibility. One thousand one hundred thirteen unrelated late onset sporadic AD patients, 1109 healthy controls and 121 neurologically healthy elderly controls were used to carry out case-control genetic association studies with ESR1 rs3844508, rs2234693, and ESR1 noncoding deletion 1 (ESR1-NCD1) polymorphisms. Thirty-five healthy male samples were used for molecular analyses. The rs2234693 polymorphism is associated with AD in our population (odds ratio [OR], 1.29; p = 0.008). The rs3844508 marker confers protection against AD in males (OR, 0.57; p = 0.001) and the deletion ESR1-NCD1 is a risk factor for AD in women (OR, 1.67; p < 0.001). Molecular analyses on ESR1-NCD1 indicate that this deletion confers a higher response to estradiol activity on ESR1 receptor and it is also associated with differential expression of ESR1 isoforms. Our results support the involvement of ESR1 gene in AD and point to the existence of sexual dimorphism for ESR1 markers. In addition, carriers of ESR1-NCD1 deletion could overrespond to estradiol action.

Calpain 10 gene and laryngeal cancer: a survival analysis.

BACKGROUND: Laryngeal carcinoma is a common upper respiratory tract cancer with different environmental and genetic factors involved in its development. Calpains are Ca2+-dependent cysteine proteases that modulate cellular function. A novel association between calpain 10 (CAPN10) haplotypes and laryngeal cancer has been found recently. Therefore, the goal of this study was to analyze the contribution of CAPN10 alleles to laryngeal cancer survival. METHODS: Patients were recruited from southern Spain. Genotypes were determined using pyrosequencing technology. We analyzed CAPN10 UCSNP-44, UCSNP-43, UCSNP-19, and UCSNP-63 allelic distributions in 199 patients with unrelated laryngeal cancer. Survival curves were calculated from the date of the intervention to the date of death. Multivariate analyses were done using the Cox proportional risk model. RESULTS: UCSNP-19, UCSNP-43, and UCSNP-44 were unrelated to survival in both univariate and multivariate analyses. However, for UCSNP-63 genotype 12 a significant relationship was observed in multivariate analysis (hazard ratio [HR] = 2.73; 95% confidence interval [CI], 1.21-6.20). CONCLUSION: CAPN10 UCSNP-63 genotype 12 seems to be related with a worse prognosis in laryngeal cancer.

WWOX gene is associated with HDL cholesterol and triglyceride levels.

BACKGROUND: Altered lipid profile, and in particular low HDL and high triglyceride (TG) plasma levels, are within the major determinants of cardiovascular diseases. The identification of quantitative trait loci (QTL) affecting these lipid levels is a relevant issue for predictive purposes. The WWOX gene has been recently associated with HDL levels. This gene is located at chromosome 16q23, a region previously linked to familial combined hyperlipidemia (FCHL) and HDL. Our objective is to perform a genetic association analysis at the WWOX gene region with HDL, TG and TG/HDL ratio. METHODS: A quantitative association analysis performed in 801 individuals selected from the Spanish general population. RESULTS: For HDL levels, two regions of intron 8 display clustering of positive signals (p < 0.05) but none of them was associated in the haplotypic analysis (0.07 ≤ p ≤ 0.165). For TG levels not only intron 8 but also a 27 kb region spanning from the promoter region to intron 4 are associated in this study. For the TG/HDL genetic association analysis, positive signals are coincident with those of the isolated traits. Interestingly, haplotypic analysis at the 5' region showed that variation in this region modified both HDL and TG levels, especially the latter (p = 0.003). CONCLUSIONS: Our results suggest that WWOX is a QTL for both TG and HDL.

Acute pancreatitis in association with type 2 diabetes and antidiabetic drugs: a population-based cohort study.

OBJECTIVE: Previous observational studies have found an increased risk of acute pancreatitis among type 2 diabetic patients. However, limited information is available on this association and specifically on the role of antidiabetic treatment. Our aim, therefore, was to further assess the risk of acute pancreatitis in adult patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a population-based case-control analysis nested in a cohort of 85,525 type 2 diabetic patients and 200,000 diabetes-free individuals from the general population using data from The Health Improvement Network database. Subjects were followed up to ascertain incident cases of acute pancreatitis. RESULTS: We identified 419 cases of acute pancreatitis, 243 in the general population and 176 in the diabetes cohort. Incidence rates were 30.1 and 54.0 per 100,000 person-years in the general population and the diabetes cohort, respectively. In the cohort analysis, the adjusted incidence rate ratio of acute pancreatitis in diabetic patients versus that in the general population was 1.77 (95% CI 1.46-2.15). The magnitude of this association decreased with adjustment for multiple factors in the nested case-control analysis (adjusted odds ratio 1.37 [95% CI 0.99-1.89]). Furthermore, we found that the risk of acute pancreatitis was decreased among insulin-treated diabetic patients (0.35 [0.20-0.61]). CONCLUSIONS: Type 2 diabetes may be associated with a slight increase in the risk of acute pancreatitis. We also found that insulin use in type 2 diabetes might decrease this risk. Further research is warranted to confirm these associations.

A digenic combination of polymorphisms within ESR1 and ESR2 genes are associated with age at menarche in the Spanish population.

In the present study, the authors look at an association of genetic variants within estrogen synthesis and signaling pathways and age at menarche (AAM) in Spanish women. They analyzed 9 polymorphisms in 6 different genes in 714 well-characterized postmenopausal women from Spain. They performed a quantitative trait locus study of these markers individually or in digenic combinations in relation to AAM. None of the studied markers, with the exception of the follicle-stimulating hormone receptor (P = .013), were significantly associated with AAM in the Spanish population, and no marker demonstrated an association of statistical significance after multiple testing corrections (P > .0055). In contrast, linear regression analysis suggests epistatic interactions including ESR1 and ESR2 loci in relation to AAM in the series (P = .003). The results suggest that epistatic interactions of ESR1 and ESR2 alleles could be associated with advancing AAM among Spanish women.

Analysis of the ERalpha germline PvuII marker in breast cancer risk.

BACKGROUND: Prolonged exposure to estrogens was found to be a risk factor for breast cancer. The molecular mechanism has been suggested to be the binding of estrogen receptors in mammary tissue, which promotes the proliferation of breast tissue. Different biomarkers mapping estrogen receptor alpha (ESR1) have been associated with breast cancer risk, although the size of the effect is not consistent among different reports. Variation in the estrogen receptor gene PvuII has been associated with an increased risk of developing breast cancer. However, some studies suggest that its effect might be constrained to a definite subgroup of patients. MATERIAL/METHODS: In this study the involvement of PvuII in breast cancer was analyzed in an independent sample of 444 unrelated breast cancer cases and 704 controls of Spanish origin. A case-control comparison was performed and the genotype distributions examined according to different tumor and population parameters. RESULTS: A trend towards association was observed in adjusted case-control association analysis (p=0.07). PvuII was associated with the familial forms of breast cancer (OR=3.81, p=0.02). T allele frequency was higher among patients with highly differentiated tumors (p=0.02), positive for steroid receptors (p=0.06), and negative for p53 (p=0.02). However, the PvuII genetic background did not affect disease-free survival time (p=0.65). CONCLUSIONS: The PvuII T allele may be a germline risk factor for familial forms of breast cancer and is associated with a specific subset of immunohistochemical tumor phenotype.

Genetic analysis of the GRM1 gene in human melanoma susceptibility.

Data obtained from a mouse model indicated that the ectopic expression of the Grm1 gene is sufficient for transforming melanocytes and causing malignant melanoma in vivo. In addition, it has also been documented that the GRM1 gene is aberrantly expressed in human melanomas. Here we have performed a genetic association study to elucidate whether the GRM1 gene contributes to human melanoma susceptibility. To carry out this study, we initially genotyped 250 melanoma patients and 329 nonselected and nonrelated controls with three single nucleotide polymorphisms, rs854145, rs362962 and rs6923492, located in the intron 1, intron 4 and exon 10 of the GRM1 gene, respectively. To perform sample genotyping, we used pyrosequencing techniques. Regarding rs854145 and rs6923492, there were no differences in genotypic distribution or allelic frequency between patients and controls. However, we observed (i) a higher frequency of patients carrying the C allele of rs362962 than in controls (OR=1.40, CI=[1.01-1.95], P=0.045), and (ii) that difference became greater in a subgroup of patients with a low level of sun exposure and tumours located on the trunk and extremities (OR=2.10, CI=[1.26-3.51], P=0.0039). To confirm these observations, the sample size of both patient and control groups was increased. In total, 464 patients and 561 controls were genotyped for the rs362962 polymorphism. Only the second observation was confirmed (OR=1.69, CI=[1.16-2.47], P=0.0064). Our results suggest that the GRM1 gene may contribute to melanoma susceptibility in that specific group of patients.

Identification of a protective haplogenotype within CAPN10 gene influencing colorectal cancer susceptibility.

BACKGROUND AND AIM: Colorectal cancer (CRC) is one of the most prevalent types of cancer affecting both men and women in developed countries. Clinical and molecular evidence suggests that there are multiple biochemical pathways involved in its susceptibility, pathogenesis and prognosis. Several studies have reported a significant association between the incidence of CRC and type 2 diabetes mellitus (T2DM). However, genes associated with both conditions are rare. METHOD: We have analyzed the CAPN10 gene, a T2DM locus, using UCSNP-43, -44, -19, and -63 markers, looking for differences between 371 CRC patients and 605 unrelated controls of Spanish origin. RESULTS: We found that UCSNP-44 allele C is swept out from cases (OR = 0.16, P = 0.005). Moreover, the frequency of 2111/2111 haplogenotype is also statistically lower than expected in CRC patients (P = 0.006). CONCLUSION: Taken together, our results indicate a recessive model for the effect of CAPN10 variant UCSNP-44 influencing the risk of CRC and suggest a novel genetic link between T2DM and colon carcinoma.

Gallbladder disease in the general population: association with cardiovascular morbidity and therapy.

PURPOSE: Both gallbladder (GB) and cardiovascular disease are very common diagnoses that carry substantial economic costs. Prior studies suggest that personal history of ischaemic heart disease (IHD) could determine the occurrence of GB disease. Additionally the use of thiazide diuretics may also be a risk factor for this condition. We aimed to evaluate different cardiovascular conditions and related drugs that could be associated with GB disease. METHODS: We identified all incident cases of gallbladder disease occurring during 1996 among patients aged 20-79 years old registered in the General Practitioner Research Database. We performed a nested case control analysis using 2353 cases and 10,000 controls frequency matched to the cases by age and sex. RESULTS: After adjusting for potential confounders IHD was associated with a small increased risk of GB disease (1.29, 95%CI:1.08-1.55). When only cases requiring cholecystectomy were considered in the analysis, the resulting estimate was 1.06 (95%CI:0.83-1.35). Users of thiazide diuretics presented an OR of 1.36 (95%CI:1.08-1.71). Other antihypertensive drugs were not associated with GB disease. CONCLUSIONS: Our results confirm the small increased risk of GB disease associated with thiazide diuretics. On the other hand, our data do not support a major association between IHD and GB disease.

Cancer incidence in a general population of asthma patients.

PURPOSE: Several studies have assessed the association between asthma and cancer but none of them revealed a clear pattern of association. We aimed to examine the association between asthma, chronic obstructive pulmonary disease (COPD), and cancer. METHODS: We performed a cohort study with a nested case-control analysis using the General Practitioner Research Database in the UK. We defined three cohorts: patients with asthma, patients with COPD, and general population. During the follow-up, we identified a total of 5263 incident cases of cancer. We conducted a nested case-control analysis that included all cancer cases as well as 20 000 controls free of cancer frequency-matched on age, sex, and calendar year. RESULTS: Patients with asthma did not have an overall greater risk of cancer compared with the general population (odds ratio = 0.93, 95% confidence interval (CI): 0.86-1.00). However, they presented an elevated risk of experiencing lung cancer (odds ratio = 1.84, 95%CI: 1.58-2.15). Controlling for smoking and other potential confounding factors yielded a lower estimate (odds ratio = 1.35, 95%CI: 1.15-1.59). This estimate contrasted with that observed for non-smoking related cancer (0.87, 95%CI: 0.80-0.94). Overall, respiratory drugs did not seem to be associated with cancer among asthmatic patients. Patients with COPD had an Odds ratio of cancer of 1.26 (95%CI: 1.12-1.43) compared with the general population. CONCLUSIONS: Asthma was not associated with an increased risk of cancer. In fact, the risk of non-smoking related cancer was slightly reduced. However, we observed a small-elevated risk of lung cancer among asthmatic patients. Whether this result is a due to residual confounding and/or protopathic bias remains unclear. Further investigation is warranted to confirm or discard these associations.