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) = 1.44(1.17-1.78); p = 0.001], rs7079 [1.49(1.20-1.85); p < 0.0001], rs699 G [1.19(1.08-1.13); p < 0.0001], rs3789679 A [1.51(1.14-1.99); p = 0.004], rs2148582 GG [1.31(1.11-1.55); p = 0.002] and rs5051 TC + CC [1.32(1.13-1.60); p = 0.001] conferred risk for HTN (3521 cases versus 1094 controls). The rs2067853 (p = 0.042), rs699G (p = 0.007) and rs5051 (p = 0.051) also conferred risk for myocardial infarction (MI; 2982 vs 1633), while rs3789679 A (p < 0.0001) and GA + AA (p < 0.0001) as well as rs4762G (p = 0.019) were associated with obesity (1576 vs 2458). However, while these variants appeared to be also associated with CAD (2323 vs 2292), only the rs7079G (p = 0.035) retained its significant relationship. Interestingly, among the haplotypes constructed from these SNPs, the baseline 8-mer haplotype, GGTGGGGT (χ2 = 7.02; p = 0.0081) and another GGCGGAGT (χ2 = 5.10; p = 0.024), together with several of their derivatives were associated with HTN. T2DM was associated with two 8-mer haplotypes, GGTAGGAC (χ2 = 5.66; p = 0.017) and ATTGAGAC (χ2 = 5.93; p = 0.015), obesity with GGCGGAGT (χ2 = 9.49; p = 0.0021) and MI was linked to ATTGGGAC (χ2 = 6.68; p = 0.010) and GGTGGGAT (χ2 = 4.25; p = 0.039). 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.

BackgroundThe muscle Ras (MRAS) gene resides on chromosome 3q22.3 and encodes a member of the membrane-associated Ras small GTPase proteins, which function as signal transducers in multiple processes including cell growth and differentiation. Its role in cardiovascular disease is not fully understood yet. In a preliminary study in heterozygous familial hypercholesterolaemia, we identified a locus linking the early onset of coronary artery disease (CAD) to chromosome 3q.22 and elected to sequence the MRAS gene using the MegaBACE DNA analysis system. In the present study, we investigated the association of seven single-nucleotide polymorphisms (SNPs) at this locus with CAD and its dyslipidaemia-related risk traits in 4,650 Saudi angiographed individuals using TaqMan assays by the Applied Biosystems real-time Prism 7900HT Sequence Detection System.ResultsAmong the studied SNPs, rs6782181 (p = 0.017) and rs9818870T (p = 0.009) were associated with CAD following adjustment for sex, age and other confounding risk factors. The rs6782181_GG also conferred risk for obesity (1,764 cases vs. 2,586 controls) [1.16(1.03–1.30); p = 0.017], hypercholesterolaemia (1,686 vs. 2,744) [1.23(1.02–1.47); p = 0.019], hypertriglyceridaemia (1,155 vs. 3,496) [1.29(1.01–1.45); p = 0.043] and low high-density lipoprotein-cholesterol (lHDL-chol) levels (1,935 vs. 2,401) [1.15(1.02–1.30); p = 0.023] after adjustment. Additionally, rs253662_(CT+TT) [1.16(1.01–1.32); p = 0.030] was associated with lHDL-chol levels. Interestingly, rs253662 (p = 0.014) and rs6782181 (p = 0.019) were protective against acquiring high low-density lipoprotein-cholesterol (hLDL-chol) levels (p = 0.014), while rs1720819 showed similar effects against CAD (p < 0.0001). More importantly, a 7-mer haplotype, ACCTGAC (χ2 = 7.66; p = 0.0056), constructed from the studied SNPs, its 6-mer derivative CCTGAC (χ2 = 6.90; p = 0.0086) and several other shorter derivatives conferred risk for obesity. hLDL-chol was weakly linked to CTAA (χ2 = 3.79; p = 0.052) and CCT (χ2 = 4.32; p = 0.038), while several other haplotypes were protective against both obesity and hLDL-chol level.ConclusionOur results demonstrate that the genomic locus for the MRAS gene confers risk for CAD, obesity and dyslipidaemia and point to the possible involvement of other genes or regulatory elements at this locus, rather than changes in the M-Ras protein function, in these events.

No abstract

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 (TG + GG) [Odds ratio(95% Confidence Interval = 1.35(1.01-1.72); p = 0.015] and rs9842733A > T [1.48(1.01-2.07); p = 0.042] were associated with hypertension [HTN; 3541 cases vs 1101 controls), following adjustment for the presence of other cardiovascular risk traits. The rs2241766 (TG + GG) was further implicated in harbouring of low high density lipoprotein levels (LHDL; 1353 versus 2156 controls) [1.35(1.10-1.67); p = 0.005], but lost its association with obesity after the adjustment for confounders. Besides, low high density lipoprotein was also linked with rs6444174 (TC + CC) [1.28(1.05-1.59)]. On the other hand, while initial univariate logistic regression analysis pointed to rs1063537 C > T (p = 0.010), rs2082940 C > T (p = 0.035) and rs1063539 G > C (p = 0.035) 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 (χ2 = 4.12; p = 0.042), HTN (χ2 = 6.40; p = 0.011) and OBS (χ2 = 5.18; p = 0.023).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.

Angiotensinogen (AGT) is an important component of the renin-angiotensin system which is involved in the regulation of systemic blood pressure and many other cardiovascular functions. In the present study, we evaluated possible interaction of the AGT gene polymorphism with cardiovascular risk traits in triggering atherosclerosis in 4525 angiographed candidates, including 3232 coronary artery disease (CAD) and 2292 non-CAD individuals. Association studies were performed for 8 SNPs by the Applied Biosystems real-time PCR system. Four of the studied variants, i.e. recessive TT of rs699C>T [Odds ratio(95% Confidence Interval) = 1.29(1.16-1.43); p<0.00001], combined CT+TT of rs2148582C>T [1.28(1.08-1.52); p=0.004], AG+GG of rs5051A>G [1.30(1.09-1.55); p=0.003] and AG+GG [1.44(1.16-1.77); p=0.001] of rs2067853C>T conferred risk for primary hypertension (HTN; 3521 cases versus 1094) as well as CAD. Interestingly, the rs699 was also causative for hypercholesterolaemia [1.15(1.05-1.28); p<0.0002] and hypertriglyceridaemia 1.22(1.11-1.35); p<0.00001]. In contrast, the rs2148582 [0.90(0.82-0.980; p=0.012] and rs5051 [0.89(0.82-0.98); 0.011] showed some protective properties against acquiring type 2 diabetes mellitus (T2DM; 2544 cases versus 2070 controls), while the rs3789679 appeared be protective against HTN (0.0001) but causative for T2DM. Several haplotypes constructed from the 8 studied SNPs were either independently associated, or shared by some of the traits among themselves or with CAD. Important ones include two 8-mers GTGGGTGG (χ 2 =6.97; p=0.0083) and GTAGGCGG (χ 2 =5.69; p=0.017) associated with HTN, ACGAGTAT (χ 2 =6.76; p=0.0093) and ACGGATAT (χ 2 =9.83; p=0.0017) associated with T2DM, GTAGGCGG (χ 2 =9.43; p=0.0021) associated with obesity, and ACGGATAT (χ 2 =6.56; p=0.0104) associated with hyperlipidaemia. Put together, the data shows that AGT causative variants are partly shared among cardiovascular risk traits and CAD, pointing to the likelihood of gene-disease interaction as important contributing factor in atherosclerosis disease pathways.