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1.  Effects of a Pragmatic Lifestyle Intervention for Reducing Body Mass in Obese Adults with Obstructive Sleep Apnoea: A Randomised Controlled Trial 
BioMed Research International  2014;2014:102164.
This study investigated the effects of a pragmatic lifestyle intervention in obese adults with continuous positive airway pressure-treated obstructive sleep apnoea hypopnoea syndrome (OSAHS). Sixty patients were randomised 1 : 1 to either a 12-week lifestyle intervention or an advice-only control group. The intervention involved supervised exercise sessions, dietary advice, and the promotion of lifestyle behaviour change using cognitive-behavioural techniques. Outcomes were assessed at baseline (week 0), intervention end-point (week 13), and follow-up (week 26). The primary outcome was 13-week change in body mass. Secondary outcomes included anthropometry, blood-borne biomarkers, exercise capacity, and health-related quality of life. At end-point, the intervention group exhibited small reductions in body mass (−1.8 [−3.0, −0.5] kg; P = 0.007) and body fat percentage (−1 [−2, 0]%; P = 0.044) and moderate improvements in C-reactive protein (−1.3 [−2.4, −0.2] mg·L−1; P = 0.028) and exercise capacity (95 [50, 139] m; P < 0.001). At follow-up, changes in body mass (−2.0 [−3.5, −0.5] kg; P = 0.010), body fat percentage (−1 [−2, 0]%; P = 0.033), and C-reactive protein (−1.3 [−2.5, −0.1] mg·L−1; P = 0.037) were maintained and exercise capacity was further improved (132 [90, 175] m; P < 0.001). This trial is registered with NCT01546792.
PMCID: PMC4127266  PMID: 25136550
2.  Genetic Variation in the Beta 2 Subunit of the Voltage-Gated Calcium Channel (CACNB2) and Pharmacogenetic Association with Adverse Cardiovascular Outcomes in the International Verapamil SR-Trandolapril Study-Genetic Substudy (INVEST-GENES) 
Polymorphisms (SNPs) within the regulatory β2 subunit of the voltage-gated calcium channel (CACNB2) may contribute to variable treatment response to antihypertensive drugs and adverse cardiovascular outcomes.
Methods and Results
SNPs in CACNB2 from 60 ethnically diverse individuals were identified and characterized. Three common SNPs (rs2357928, rs7069292 and rs61839258) and a GWAS identified intronic SNP (rs11014166) were genotyped for a clinical association study in 5,598 hypertensive patients with coronary artery disease randomized to a beta-blocker (BB) or a calcium channel blocker (CCB) treatment strategy in INVEST-GENES. Reporter gene assays were conducted on the promoter SNP showing association with clinical outcomes. Twenty-one novel SNPs were identified. A promoter A>G SNP (rs2357928) was found to have significant interaction with treatment strategy for adverse cardiovascular outcomes (p for interaction = 0.002). In Caucasians, rs2357928 GG patients randomized to CCB were more likely to experience adverse outcome than those randomized to BB treatment strategy, with adjusted hazard ratio (CCB vs. BB) of 2.35 (1.19-4.66), p = 0.014. There was no evidence for such treatment difference in AG (1.16, 0.75-1.79, p = 0.69) and AA individuals (0.63, 0.36-1.11, p = 0.11). This finding was consistent in Hispanics and African Americans. CACNB2 rs11014166 showed similar pharmacogenetic effect in Hispanics, but not in Caucasians or African Americans. Reporter assay analysis of rs2357928 showed a significant increase in promoter activity for the G allele compared to the A allele.
These data suggest genetic variation within CACNB2 may influence treatment related outcomes in high risk hypertensive patients.
Clinical Trial Registration Information
Clinical trial identifier: NCT00133692, URL:
PMCID: PMC3060561  PMID: 21156931
Genetic variations; CACNB2; hypertension; cardiovascular outcomes; INVEST-GENES
3.  CACNA1C gene polymorphisms, cardiovascular disease outcomes and treatment response 
The gene encoding the target of calcium channel blockers, the α1c-subunit of the L-type calcium channel (CACNA1C) has not been well characterized and only small pharmacogenetic studies testing this gene have been published to date.
Methods and Results
Resequencing of CACNA1C was performed followed by a nested case-control study of the INternational VErapamil SR/trandolapril STudy (INVEST) GENEtic Substudy (INVEST-GENES). Of 46 polymorphisms identified, eight were assessed in the INVEST-GENES. Rs1051375 was found to have a significant interaction with treatment strategy (p=0.0001). Rs1051375 A/A genotype was associated with a 46% reduction in the primary outcome among those randomized to verapamil SR treatment compared to atenolol treatment (OR 0.54 95% CI 0.32-0.92). In heterozygous A/G individuals, there was no difference in the occurrence of the primary outcome when randomized to verapamil SR versus atenolol treatment (OR 1.47 95% CI 0.86-2.53), while homozygous G/G individuals had a greater than 4-fold increased risk of the primary outcome with verapamil treatment compared to those randomized to atenolol treatment (OR 4.59 95% CI 1.67-12.67). We did not identify allelic expression imbalance or differences in mRNA expression in heart tissue by rs1051375 genotype.
Variation in CACNA1C is associated with treatment response among hypertensive patients with stable coronary artery disease. Our data suggest a genetically-defined group of patients that benefit most from calcium channel blocker therapy, a group that benefits most from β-blocker therapy, and a third group in which calcium channel blocker and β-blocker therapy are equivalent.
PMCID: PMC2761685  PMID: 20031608
genetics; pharmacology; ion channels; calcium; pharmacogenetics

Results 1-3 (3)