We sought to identify novel pharmacogenomic markers for HDL-C response to

We sought to identify novel pharmacogenomic markers for HDL-C response to atenolol in participants with moderate to moderate hypertension. and 11 GG at rs2144300) and expression of was measured in 35 PEAR African Americans (11 AC and 24 CC at rs12595985). RNA was isolated from whole blood using the PAXgene Blood RNA Kit IVD (Qiagen Valenica CA USA) before atenolol treatment and converted to cDNA. Gene expression was measured by quantitative real-time RT-PCR using Taqman Gene Expression Assays and the Taqman 7900HT Real Time PCR System (Applied Biosystems Foster City CA USA). Expression levels were normalized to the reference gene β-2-microglobulin. Relative gene expression was calculated using the 2-ΔCt method [22]. Expression levels between genotype groups at baseline (before atenolol treatment) were compared using a pattern test ((is located at chromosome 1q31.1 and encodes the IL15RA antibody cytosolic phospholipase A2. In African Americans the strongest association was seen at rs3213619 on chromosome 7q21.12 with a with the A allele of rs2144297 and a decrease ML 786 dihydrochloride in HDL-C in response to atenolol (Regional Plots and adjusted HDL-C response by genotype. The second gene Regional Plots and adjusted HDL-C response by genotype. Top initial signals with low minor allele frequencies were further investigated to determine if single study participants with an extreme HDL-C response to atenolol were driving the observed signals. One white participant with an HDL-C change of ML 786 dihydrochloride -36.4 mg/dL was identified and the individual was removed in a sensitivity analysis (Table S2). All of the initial signals in whites remained except for rs9652472 (sensitivity (Table S3). The signal remained under both a dominant genetic model collapsing the AA homozygote with the AC heterozygotes (sensitivity (low density lipoprotein receptor-related protein 5) is usually a non-synonymous SNP causing a conservative amino acid change of an alanine to valine at amino acid position 1330. Additionally rs3736228 was predicted by FastSNP to affect splicing regulation. All of the other SNPs identified were located in intronic regions or upstream or downstream of the nearest gene. In order to examine the possible function of two the top SNPs we measured gene expression at baseline (before atenolol treatment) of by rs2144300 genotype in 34 whites and of by rs12595985 genotype in 35 African Americans. For (data not shown). Physique 3 Plot of relative gene expression of by rs2144300 genotype. Discussion We report for the first time to our knowledge a genome-spanning analysis using the HumanCVD Beadchip which contains cardiovascular metabolic and inflammatory candidate genes ML 786 dihydrochloride to identify ML 786 dihydrochloride genetic variants associated with atenolol induced changes in HDL-C in hypertensive study participants. While no SNPs achieved a Bonferroni corrected [11 25 have previously been associated with both HDL-C and triglyceride levels in numerous GWAS analyses and subsequently validated [11 23 Additionally altered expression of in mouse models both knockdown and over expression has been inversely correlated with altered HDL-C levels [11]. This is similar to what we observed; where those individuals with higher gene expression at baseline (G carriers at rs2144300) had greater decreases in HDL-C in response to atenolol resulting in lower HDL-C levels. These prior data the association of common SNPs in ML 786 dihydrochloride this gene with HDL-C response to atenolol in whites and African Americans and the difference in expression by rs2144300 genotype in whites suggest may be an important mediator of the observed atenolol associated HDL-C response. have been previously associated with BMI obesity and type 2 diabetes [24]. Additionally was recently associated with HDL-C in a large gene centric analysis [25] and it was suggested that this association with and HDL-C may be mediated through and HDL-C lost significance after BMI adjustment [25]. However in our data when we add BMI to the model rs12595985 remains associated with HDL-C response to atenolol (expression by rs12595985 genotype at baseline this does not preclude that expression differences might exist in more relevant tissues (e.g. liver). Other top genes are also of note. (multi-drug resistance protein 1) belongs to the MDR/TAP subfamily responsible for transporting various molecules across cell membranes. Evidence indicates a link of variants with circulating lipid profiles mainly LDL-C and the efficacy of statins [26]. Furthermore 3435 (rs1045642) has been associated with efavirenz induced changes in HDL-C [32]. We did not observe association with HDL-C.