Nduna Dzimiri

Left ventricular global transcriptional profiling in human end-stage dilated cardiomyopathy

We employed ABI high-density oligonucleotide microarrays containing 31,700 sixty-mer probes (representing 27,868 annotated human genes) to determine differential gene expression in idiopathic dilated cardiomyopathy (DCM). We identified 626 up-regulated and 636 down-regulated genes in DCM compared to controls. Most significant changes occurred in the tricarboxylic acid cycle, angiogenesis, and apoptotic signaling pathways, among which 32 apoptosis- and 13 MAPK activity-related genes were altered. Inorganic cation transporter, catalytic activities, energy metabolism and electron transport-related processes were among the most critically influenced pathways. Among the up-regulated genes were HTRA1 (6.9-fold), PDCD8(AIFM1) (5.2) and PRDX2 (4.4) and the down-regulated genes were NR4A2 (4.8), MX1 (4.3), LGALS9 (4), IFNA13 (4), UNC5D (3.6) and HDAC2 (3) (p<0.05), all of which have no clearly defined cardiac-related function yet. Gene ontology and enrichment analysis also revealed significant alterations in mitochondrial oxidative phosphorylation, metabolism and Alzheimers disease pathways. Concordance was also confirmed for a significant number of genes and pathways in an independent validation microarray dataset. Furthermore, verification by real-time RT-PCR showed a high degree of consistency with the microarray results. Our data demonstrate an association of DCM with alterations in various cellular events and multiple yet undeciphered genes that may contribute to heart muscle disease pathways.

A European spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant inter-population pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective.

E-selectin S128R polymorphism and severe coronary artery disease in Arabs.

BackgroundThe E-selectin p. S128R (g. A561C) polymorphism has been associated with the presence of angiographic coronary artery disease (CAD) in some populations, but no data is currently available on its association with CAD in Arabs.MethodsIn the present study, we determined the potential relevance of the E-selectin S128R polymorphism for severe CAD and its associated risk factors among Arabs. We genotyped Saudi Arabs for this polymorphism by PCR, followed by restriction enzyme digestion.ResultsThe polymorphism was determined in 556 angiographically confirmed severe CAD patients and 237 control subjects with no CAD as established angiographically (CON). Frequencies of the S/S, S/R and R/R genotypes were found as 81.1%, 16.6% and 2.3% in CAD patients and 87.8%, 11.8%, and 0.4% in CON subjects, respectively. The frequency of the mutant 128R allele was higher among CAD patients compared to CON group (11% vs. 6%; odds ratio = 1.76; 95% CI 1.14 – 2.72; p = .007), thus indicating a significant association of the 128R allele with CAD among our population. However, the stepwise logistic regression for the 128R allele and different CAD risk factors showed no significant association.ConclusionAmong the Saudi population, The E-selectin p. S128R (g. A561C) polymorphism was associated with angiographic CAD in Univariate analysis, but lost its association in multivariate analysis.

Association of the angiotensinogen gene polymorphism with atherosclerosis and its risk traits in the Saudi population

BackgroundAngiotensinogen (AGT) constitutes a central component of the renin-angiotensin system that controls the systemic blood pressure and several other cardiovascular functions and may play an important role in atherosclerosis pathways. In this study, we employed TaqMan genotyping assays to evaluate the role of 8 AGT variants in primary hypertension (HTN), type 2 diabetes mellitus (T2DM), and obesity as a possible trigger of coronary artery disease (CAD) in a population of 4615 angiographed native Saudi individuals.MethodsLinkage analysis was done by using the Affymetrix Gene Chip array, sequencing by using the MegaBACE DNA analysis system and genotyping accomplished by TaqMan chemistry using the Applied Biosystem real-time Prism 7900HT Sequence Detection System.ResultsSix variants, rs2067853 GG [Odds ratio(95% Confidence Interval)u2009=u20091.44(1.17-1.78); pu2009=u20090.001], rs7079 [1.49(1.20-1.85); pu2009<u20090.0001], rs699 G [1.19(1.08-1.13); pu2009<u20090.0001], rs3789679 A [1.51(1.14-1.99); pu2009=u20090.004], rs2148582 GG [1.31(1.11-1.55); pu2009=u20090.002] and rs5051 TCu2009+u2009CC [1.32(1.13-1.60); pu2009=u20090.001] conferred risk for HTN (3521 cases versus 1094 controls). The rs2067853 (pu2009=u20090.042), rs699G (pu2009=u20090.007) and rs5051 (pu2009=u20090.051) also conferred risk for myocardial infarction (MI; 2982 vs 1633), while rs3789679 A (pu2009<u20090.0001) and GAu2009+u2009AA (pu2009<u20090.0001) as well as rs4762G (pu2009=u20090.019) were associated with obesity (1576 vs 2458). However, while these variants appeared to be also associated with CAD (2323 vs 2292), only the rs7079G (pu2009=u20090.035) retained its significant relationship. Interestingly, among the haplotypes constructed from these SNPs, the baseline 8-mer haplotype, GGTGGGGT (χ2u2009=u20097.02; pu2009=u20090.0081) and another GGCGGAGT (χ2u2009=u20095.10; pu2009=u20090.024), together with several of their derivatives were associated with HTN. T2DM was associated with two 8-mer haplotypes, GGTAGGAC (χ2u2009=u20095.66; pu2009=u20090.017) and ATTGAGAC (χ2u2009=u20095.93; pu2009=u20090.015), obesity with GGCGGAGT (χ2u2009=u20099.49; pu2009=u20090.0021) and MI was linked to ATTGGGAC (χ2u2009=u20096.68; pu2009=u20090.010) and GGTGGGAT (χ2u2009=u20094.25; pu2009=u20090.039). Furthermore, several causative haplotypes were also shared among the risk traits as well as with CAD.ConclusionThese results point to AGT as independently conferring risk for various cardiovascular traits, and possibly interacting with these traits in events leading to atherosclerosis.

A study of the role of GATA2 gene polymorphism in coronary artery disease risk traits

The GATA2 is a multi-catalytic transcription factor believed to play an important role in regulating inflammatory processes, largely contributory to cardiovascular-related events. However, its role in coronary artery disease (CAD) risk traits remains poorly understood. In a preliminary study using Affymetrix 250K, we established a link on chromosome (chr) 3, which harbors the GATA2 gene, to early onset of CAD in two families with heterozygous familial hyperlipidemia (HFH), suggesting a role for the gene in metabolic-related CAD in the general population. We then sequenced the gene in the families and an additional 200 individuals in the general population, followed by an association study for 8 SNPs on CAD metabolic risk traits in a total of 4557 individuals (2386 CAD cases versus 2171 angiographed controls) by the Applied Biosystems real-time PCR system. The rs1573949_C [1.15(1.00-1.32); p=0.049] was associated with MI, rs7431368_AA [5.2(1.05-26.60); p=0.43] conferred risk for harboring low high density lipoprotein, and obesity was linked to rs10934857_AA [5.69(1.04-30.98); p=0.045] following Bonferroni corrections and multivariate adjustments for confounders. Furthermore, a haplotype CCCGGGTC (χ(2)=4.23; p=0.04) constructed from the eight studied SNPs and its 6-mer derivative CGGGTC (χ(2)=5.05; p=0.025) were associated with CAD. Obesity was associated with the 6-mer CATAAA (χ(2)=3.66; p=0.049), and hypercholesterolemia was linked to the 8-mer CCTGGACC (χ(2)=6.02; p=0.014), but most significantly so with its 5-mer derivative, CTGGA (χ(2)=6.75; p=0.009). On the other hand, high low density lipoprotein was linked to TGG (χ(2)=4.48; p=0.034). Our study points to an association of GATA2 at both SNP and haplotype levels with important metabolic risk traits for atherosclerosis.

A new susceptibility locus for myocardial infarction, hypertension, type 2 diabetes mellitus, and dyslipidemia on chromosome 12q24.

We examined the role of hepatic nuclear factor-1 alpha (HNF1a) gene polymorphism on coronary artery disease (CAD) traits in 4631 Saudi angiographed individuals (2419 CAD versus 2212 controls) using TaqMan assay on ABI Prism 7900HT sequence detection system. Following adjustment for confounders, the rs2259820_CC (1.19 (1.01–1.42); P = 0.041), rs2464196_TT (1.19 (1.00–1.40); P = 0.045), and rs2259816_T (1.13 (1.01–1.26); P = 0.031) were associated with MI. The rs2259820_T (1.14 (1.03–1.26); P = 0.011) and rs2464196_C (1.12 (1.02–1.24); P = 0.024) were associated with type 2 diabetes mellitus (T2DM), while the rs2393791_T (1.14 (1.01–1.28); P = 0.032), rs7310409_G (1.16 (1.03–1.30); P = 0.013), and rs2464196_AG+GG (1.25 (1.05–1.49); P = 0.012) were implicated in hypertension. Hypertriglyceridemia was linked to the rs2393791_T (1.14 (1.02–1.27); P = 0.018), rs7310409_G (1.12 (1.01–1.25); P = 0.031), rs1169310_G (1.15 (1.04–1.28); P = 0.010), and rs1169313_CT+TT (1.24 (1.06–1.45); P = 0.008) and high low density lipoprotein-cholesterol levels were associated with rs2259820_T (1.23 (1.07–1.41); P = 0.004), rs2464196_T (1.22 (1.06–1.39); P = 0.004), and rs2259816_T (1.18 (1.02–1.36); P = 0.023). A 7-mer haplotype CATATAC (χ 2 = 7.50; P = 0.0062), constructed from the studied SNPs, was associated with MI, and CATATA implicated in T2DM (χ 2 = 3.94; P = 0.047). Hypertriglyceridemia was linked to TGCGGG (χ 2 = 4.26; P = 0.039), and obesity to ACGGGT (χ 2 = 5.04; P = 0.025). Our results suggest that the HNF1a is a common susceptibility gene for MI, T2DM, hypertension, and dyslipidemia.

The 3′-UTR of the adiponectin Q gene harbours susceptibility loci for atherosclerosis and its metabolic risk traits

BackgroundAdiponectin Q is a hormone that modulates several metabolic processes and contributes to the suppression of biochemical pathways leading to metabolic syndrome. Hence, polymorphic changes in the adiponectin Q (ADIPOQ) gene are likely to contribute to metabolic disorders, and consequently lead to atherosclerosis. In the present study, we performed a population-based association study for 8 SNPs in 4646 Saudi individuals (2339 CAD cases versus angiographed 2307 controls) by real-time PCR.MethodsLinkage analysis was done by the Affymetrix Gene Chip array, sequencing by the MegaBACE DNA analysis system and genotyping accomplished by TaqMan chemistry with the Applied Biosystem real-time Prism 7900HT Sequence Detection System.ResultsThe rs2241766 (TGu2009+u2009GG) [Odds ratio(95% Confidence Intervalu2009=u20091.35(1.01-1.72); pu2009=u20090.015] and rs9842733Au2009>u2009T [1.48(1.01-2.07); pu2009=u20090.042] were associated with hypertension [HTN; 3541 cases vs 1101 controls), following adjustment for the presence of other cardiovascular risk traits. The rs2241766 (TGu2009+u2009GG) was further implicated in harbouring of low high density lipoprotein levels (LHDL; 1353 versus 2156 controls) [1.35(1.10-1.67); pu2009=u20090.005], but lost its association with obesity after the adjustment for confounders. Besides, low high density lipoprotein was also linked with rs6444174 (TCu2009+u2009CC) [1.28(1.05-1.59)]. On the other hand, while initial univariate logistic regression analysis pointed to rs1063537 Cu2009>u2009T (pu2009=u20090.010), rs2082940 Cu2009>u2009T (pu2009=u20090.035) and rs1063539 Gu2009>u2009C (pu2009=u20090.035) as being associated with myocardial infarction, significance levels of these relationships were diminished following adjustment for the influence of confounding covariates. Interestingly, haplotyping showed that an 8-mer haplotype GTGCCTCA and several of its derivatives constructed from the studied SNPs were commonly implicated in MI (χ2u2009=u20094.12; pu2009=u20090.042), HTN (χ2u2009=u20096.40; pu2009=u20090.011) and OBS (χ2u2009=u20095.18; pu2009=u20090.023).ConclusionThese results demonstrate that the ADIPOQ 3′UTR harbours common susceptibility variants for metabolic risk traits and CAD, pointing to the importance of this region in atherosclerosis disease pathways.

The potential role of the sodium iodide symporter gene polymorphism in the development of differentiated thyroid cancer

The sodium iodide symporter (NIS) (solute carrier family 5; SLC5A), mediates the active transport of iodine anion (I(-)) into thyroid follicular cells to facilitate thyroid hormone biosynthesis. Considering its fundamental role in thyroid function, our objective in this study is to explore its potential involvement in the pathogenesis of differentiated thyroid cancer (DTC). Following a preliminary sequencing of the gene in a representative sample of the general population, five variants, (1) rs45602038, (2) rs4808708, (3) rs4808709, (4) rs7250346 and (5) rs12327843, were selected for a larger population-based association study consisting of 507 cases and 597 controls, of which only the rs45602038_TT [Odds ratio (95% confidence interval)=1.90 (1.26-2.88); p=0.002] was associated with disease following adjustment for other confounders using the multivariate analysis. Furthermore, a 5-mer haplotype CGAGT constructed from the five studied SNPs conferred a significant risk (χ(2)=10.98; p=0.0009) for DTC. This association trickled down through shorter derivatives, with the 4-mer haplotype CGAG (χ(2)=13.25; p=0.0003) displaying the most significant association and the 3-mer GAG (χ(2)=11.80; p=0.0006) being equally strongly linked to the disease. Comparison of the flanking derivatives of the primary 5-mer haplotype also indicated that the 3-mer CGA (χ(2)=4.04; p=0.045) constructed from SNP block 1-3 was a lot weaker than that of the AGT (χ(2)=6.73; p=0.0095) constructed from the blocks 3-5 from the other end of the gene. Put together, these data implicate the three nucleotide changes at the rs4808708, rs4808709 and rs7250346 loci (blocks 2-4) as the core for this relationship.

A study of the role of GATA4 polymorphism in cardiovascular metabolic disorders

BackgroundThe study was designed to evaluate the association of GATA4 gene polymorphism with coronary artery disease (CAD) and its metabolic risk factors, including dyslipidaemic disorders, obesity, type 2 diabetes and hypertension, following a preliminary study linking early onset of CAD in heterozygous familial hypercholesterolaemia to chromosome 8, which harbours the GATA4 gene.ResultsWe first sequenced the whole GATA4 gene in 250 individuals to identify variants of interest and then investigated the association of 12 single-nucleotide polymorphisms (SNPs) with the disease traits using Taqman chemistry in 4,278 angiographed Saudi individuals. Of the studied SNPs, rs804280 (1.14 (1.03 to 1.27); pu2009=u20090.009) was associated with CAD (2,274 cases vs 2,004 controls), hypercholesterolaemia (1,590 vs 2,487) (1.61 (1.03–2.52); pu2009=u20090.037) and elevated low-density lipoprotein-cholesterol (hLDLC) (575 vs 3,404) (1.87 (1.10–3.15); pu2009=u20090.020). Additionally, rs3729855_T (1.52 (1.09–2.11; pu2009=u20090.013)) and rs17153743 (AGu2009+u2009GG) (2.30 (1.30–4.26); pu2009=u20090.005) were implicated in hypertension (3,312 vs 966), following adjustments for confounders. Furthermore, haplotypes CCCGTGCC (χ2u2009=u20094.71; pu2009=u20090.041) and GACCCGTG (χ2u2009=u20093.84; pu2009=u20090.050) constructed from the SNPs were associated with CAD and ACCCACGC (χ2u2009=u20096.58; pu2009=u20090.010) with myocardial infarction, while hypercholesterolaemia (χ2u2009=u20093.86; pu2009=u20090.050) and hLDLC (χ2u2009=u20094.94; pu2009=u20090.026) shared the AACCCATGT, and AACCCATGTC was associated with hLDLC (χ2u2009=u20094.83; pu2009=u20090.028). A 10-mer GACCCGCGCC (χ2u2009=u20097.59; pu2009=u20090.006) was associated with obesity (1,631 vs 2,362), and the GACACACCC (χ2u2009=u20094.05; pu2009=u20090.044) was implicated in type 2 diabetes mellitus 2,378 vs 1,900).ConclusionOur study implicates GATA4 in CAD and its metabolic risk traits. The finding also points to the possible involvement of yet undefined entities related to GATA4 transcription activity or gene regulatory pathways in events leading to these cardiovascular disorders.

Correction: A European Spectrum of Pharmacogenomic Biomarkers: Implications for Clinical Pharmacogenomics.

[This corrects the article DOI: 10.1371/journal.pone.0162866.].