RESUMO
Purpose: Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other beta-blockers, there is variability in response to bisoprolol, but the underlying reasons for this have not been clearly elucidated. Our aim was to investigate genetic factors that affect bisoprolol pharmacokinetics (PK) and pharmacodynamics (PD), and potentially the clinical outcomes. Patients and Methods: Patients with non-ST elevation acute coronary syndrome were recruited prospectively on admission to hospital and followed up for up to 2 years. Patients from this cohort who were on treatment with bisoprolol, at any dose, had bisoprolol adherence data and a plasma sample, one month after discharge from index hospitalisation were included in the study. Individual bisoprolol clearance values were estimated using population pharmacokinetic modeling. Genome-wide association analysis after genotyping was undertaken using an Illumina HumanOmniExpressExome-8 v1.0 BeadChip array, while CYP2D6 copy number variations were determined by PCR techniques and phenotypes for CYP2D6 and CYP3A were inferred from the genotype. GWAS significant SNPs were analysed for heart rate response to bisoprolol in an independent cohort of hypertensive subjects. Results: Six hundred twenty-two patients on bisoprolol underwent both PK and genome wide analysis. The mean (IQR) of the estimated clearance in this population was 13.6 (10.0-18.0) L/h. Bisoprolol clearance was associated with rs11029955 (p=7.17×10-9) mapped to the region of coiled-coil domain containing 34 region (CCDC34) on chromosome 11, and with rs116702638 (p=2.54×10-8). Each copy of the minor allele of rs11029955 was associated with 2.2 L/h increase in clearance. In an independent cohort of hypertensive subjects, rs11029955 was associated with 24-hour heart rate response to 4-week treatment with bisoprolol (p= 9.3×10-5), but not with rs116702638. Conclusion: A novel locus on the chromosomal region 11p14.1 was associated with bisoprolol clearance in a real-world cohort of patients and was validated in independent cohort with a pharmacodynamic association.
RESUMO
The pathogenesis of Crohn's disease (CD) involves an abnormal immune response to enteric bacteria in genetically susceptible individuals. There are no family studies regarding the association of CD with human leucocyte antigens (HLA) class II. In the present study, we have studied the association of HLA class II antigens in patients with CD and their first-degree relatives. Nine patients with CD and their first-degree relatives were studied. A group of 110 healthy unrelated and ethnically matched subjects were used as controls. Molecular HLA typing was done using the sequence-specific primer-based method. The transmission disequilibrium test (TDT) was used to analyze the results. A total of 65 individuals were included in the study; 52/56 first-degree relatives (92.8%) of 9 patients with CD consented to the study. The median age of patients was 40 years. When the distribution of the HLA class II antigens in patients was compared to that in controls no significant differences were observed even after applying the Yates correction. As the sample size of the population was small, the association of CD with DR and DQ alleles was further analyzed by using the TDT. Even after applying TDT, no significant association was observed. Familial aggregation of CD is uncommon in India. Crohn disease is not associated with HLA class II antigens in Indian patients. Genes of the major histocompatiblity complex are likely to contribute little to the susceptibility to Crohn disease in Indian patients.
