The role of IREB2 and transforming growth factor beta-1 genetic variants in COPD: a replication case-control study

<p>Abstract</p> <p>Background</p> <p>Genetic factors are known to contribute to COPD susceptibility and these factors are not fully understood. Conflicting results have been reported for many genetic studies of candidate genes based on their role in the disease. Genome-wide association studies in combination with expression profiling have identified a number of new candidates including <it>IREB2</it>. A meta-analysis has implicated transforming growth factor beta-1 (<it>TGFbeta1</it>) as a contributor to disease susceptibility.</p> <p>Methods</p> <p>We have examined previously reported associations in both genes in a collection of 1017 white COPD patients and 912 non-diseased smoking controls. Genotype information was obtained for seven SNPs in the <it>IREB2 </it>gene, and for four SNPs in the <it>TGFbeta1 </it>gene. Allele and genotype frequencies were compared between COPD cases and controls, and odds ratios were calculated. The analysis was adjusted for age, sex, smoking and centre, including interactions of age, sex and smoking with centre.</p> <p>Results</p> <p>Our data replicate the association of <it>IREB2 </it>SNPs in association with COPD for SNP rs2568494, rs2656069 and rs12593229 with respective adjusted p-values of 0.0018, 0.0039 and 0.0053. No significant associations were identified for <it>TGFbeta1</it>.</p> <p>Conclusions</p> <p>These studies have therefore confirmed that the <it>IREB2 </it>locus is a contributor to COPD susceptibility and suggests a new pathway in COPD pathogenesis invoking iron homeostasis.</p

Association of MMP - 12 polymorphisms with severe and very severe COPD: A case control study of MMPs - 1, 9 and 12 in a European population

BACKGROUND: Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease--antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. METHODS: To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. RESULTS: Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. CONCLUSIONS: Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity

Discordance between Treatment Guideline Recommendations and Real-World Practice in a Group of Large Integrated Delivery Networks for Venous Thromboembolism (VTE) Patients: A Closer Look at VTE Patients with Cancer

Background: For patients with VTE, current American Society of Hematology (ASH) guideline panel suggests using direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs) where VKAs are required to be bridged with a parenteral anticoagulant (PAC). For patients with VTE and cancer, current guidelines recommend DOACs over low molecular weight heparin (LMWH) and LMWH over unfractionated heparin (heparin) for the initial treatment of VTE. Limited evidence is available about the patterns of anticoagulant treatment for VTE in routine clinical practice of large healthcare delivery networks in the United States (US) and whether the VTE treatments are aligned with current guidelines. This study aimed to assess real-world anticoagulant treatment patterns among VTE patients using harmonized electronic health record (EHR) data from four Integrated Delivery Networks (IDNs) in the US. Methods: This was a retrospective, longitudinal, multicenter, cohort study using harmonized EHR data from both inpatient and outpatient settings. The study population included adult patients prescribed DOACs, warfarin, and/or PAC therapy as inpatient or outpatient treatment within ≤30 days of VTE diagnosis, between June 2015 through May 2018. Data from the four IDNs was pooled to describe demographic characteristics and treatment patterns among VTE patients overall and by subgroups. Results: A total of 10,527 patients who were treated with OACs after VTE diagnosis were included for analysis. The mean (SD) age was 61.9 (5.98) years, with 46.1% aged 65 or older. More than half (53.2%) were female, and White patients comprised the majority (74.4%), followed by African American patients (22.8%). Obese and morbidly obese patients comprised 39.1% and 16.1% of patients, respectively. Among all VTE patients, warfarin-only (n=3545; 33.7%) was the most commonly used OAC treatment, followed by warfarin + PAC (n=3128; 29.7%), rivaroxaban-only (n=1357; 12.9%), rivaroxaban + PAC (n=853; 8.1%), apixaban + PAC (n=839; 8.0%), apixaban-only (n=762; 7.2%), and Other OAC (n=357; 3.4%) (Table 1). When stratifying VTE patients by age, gender, race and BMI, some variations in OAC treatment were observed. Among both older (≥65 years) and younger (\u3c65 years) patients, warfarin-only was most commonly used, then warfarin + PAC. Warfarin-only was more commonly used among obese (36.3%) and morbidly obese (40.4%) patients than non-obese (29.8%) patients. OAC treatment patterns were generally comparable among men and women. Among White patients, approximately equal proportions of patients received warfarin + PAC (31.9%) and warfarin-only (31.0%). However, among African-American patients, a higher proportion of patients used warfarin-only (40.9%) vs. warfarin + PAC (24.5%). Patterns of anticoagulant treatments including OACs and/or parental anticoagulants among VTE patients with cancer were further analyzed (Figure 1). Among VTE patients with cancer (n=3657), heparin had the highest use (26.7%), then enoxaparin (22.7%); approximately the same proportion of cancer patients received warfarin-only (16.0%) and warfarin + PAC (16.9%). Of DOACs, rivaroxaban-only was the most commonly used treatment (4.9%), then apixaban + PAC (3.5%), and lastly, rivaroxaban + PAC (3.4%) among cancer patients. Conclusion: Current VTE treatment guidelines recommend warfarin to be bridged with PAC, however, warfarin-only therapy remained the most used treatment option followed by warfarin + PAC. While rivaroxaban and apixaban are not required to be bridged with PAC, such practices were observed for a large proportion of apixaban- and rivaroxaban-treated VTE patients. VTE treatment among patients with cancer was not completely aligned with current guidelines, as heparin was more commonly used than LMWH (enoxaparin). Our findings suggest greater efforts are needed to improve anticoagulant treatment practices among VTE patients

Association of MMP-2 polymorphisms with severe and very severe COPD: a case control study of MMPs-1, 9 and 12 in a European population.

BACKGROUND: Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease--antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. METHODS: To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. RESULTS: Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. CONCLUSIONS: Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity