Maria L. Mansego

Renin polymorphisms and haplotypes are associated with blood pressure levels and hypertension risk in postmenopausal women

Background Renin is a key protein of the renin–angiotensin system involved in the physiological control of blood pressure; the renin gene is therefore a candidate for essential hypertension in humans. We tested the association between polymorphisms and haplotypes of the renin gene and the risk of hypertension and blood pressure levels in two Spanish populations. Methods Two population-based studies from different regions of Spain were performed. Study A included 1502 individuals (748 women) 40–70 years old, and Study B included 670 women 45–70 years old. Fourteen polymorphisms of the renin gene were selected based on position, spacing, heterozygosity (> 10% for the minor allele frequency) and previous information, and were assessed by SNPlex. Results Genotype GG of the rs5707 polymorphism was significantly associated with blood pressure levels (P = 0.005) and with the risk of having hypertension (odds ratio, 6.16; 95% confidence interval, 1.19–31.8) in women 40–70 years old from study A, but not the men. This association was also present in the women of study B (P < 0.001 for blood pressure values; odds ratio, 2.11 and 95% confidence interval, 1.07–4.17 for hypertension). Two haplotypes defined by five selected polymorphisms were associated with increased risk of hypertension in these aged women. Conclusion Polymorphisms of the renin gene were associated with blood pressure levels and risk of hypertension in women over 40 years old. The interaction between the potential functional impact of this genetic background and the estrogen fall could explain the association in women of this age group.

Different Impacts of Cardiovascular Risk Factors on Oxidative Stress

The objective of the study was to evaluate oxidative stress (OS) status in subjects with different cardiovascular risk factors. With this in mind, we have studied three models of high cardiovascular risk: hypertension (HT) with and without metabolic syndrome, familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) with and without insulin resistance. Oxidative stress markers (oxidized/reduced glutathione ratio, 8-oxo-deoxyguanosine and malondialdehide) together with the activity of antioxidant enzyme triad (superoxide dismutase, catalase, glutathione peroxidase) and activation of both pro-oxidant enzyme (NAPDH oxidase components) and AGTR1 genes, as well as antioxidant enzyme genes (CuZn-SOD, CAT, GPX1, GSR, GSS and TXN) were measured in mononuclear cells of controls (n = 20) and patients (n = 90) by assessing mRNA levels. Activity of some of these antioxidant enzymes was also tested. An increase in OS and pro-oxidant gene mRNA values was observed in patients compared to controls. The hypertensive group showed not only the highest OS values, but also the highest pro-oxidant activation compared to those observed in the other groups. In addition, in HT a significantly reduced antioxidant activity and mRNA induction of antioxidant genes were found when compared to controls and the other groups. In FH and FCH, the activation of pro-oxidant enzymes was also higher and antioxidant ones lower than in the control group, although it did not reach the values obtained in hypertensives. The thioredoxin system was more activated in patients as compared to controls, and the highest levels were in hypertensives. The increased oxidative status in the presence of cardiovascular risk factors is a consequence of both the activation of pro-oxidant mechanisms and the reduction of the antioxidant ones. The altered response of the main cytoplasmic antioxidant systems largely contributes to OS despite the apparent attempt of the thioredoxin system to control it.

Polymorphisms of the UCP2 gene are associated with body fat distribution and risk of abdominal obesity in Spanish population.

Eur J Clin Invest 2011

Association of selected ABC gene family single nucleotide polymorphisms with postprandial lipoproteins: Results from the population-based Hortega study

The aim of the study was to determine the influence of twenty single nucleotide polymorphisms (SNPs) of the ABCA1, ABCG1, ABCG5 and ABCG8 genes on the plasmatic concentrations of total cholesterol (TC), HDL and LDL cholesterol (HDLc, LDLc) in the postprandial state with a representative Spanish Caucasian population (1473 individuals, 50.0% women, ages ranging 21-85 years). In men, subjects with the AA genotype of the ABCA1 rs2230806 (R219K) polymorphism were associated with increased plasma LDLc levels, while the ABCA1 haplotype, which included the rs2230806 A allele, was associated with higher TC and LDLc plasma concentrations. In women, significant relationships were found between rs1893590 polymorphisms (ABCG1 gene) and HDLc plasma concentrations (subjects with the AA genotype had lower HDLc levels). For the ABCG8 gene, the rs4148211 polymorphism was associated with higher plasma TC and LDLc concentrations in the total population. Moreover, an ABCG5-G8 haplotype, which included the rs6544718 T allele, was associated with higher HDLc plasma concentrations in women. In conclusion, different SNPs of the ABCA1, ABCG1 and ABCG5-ABCG8 genes were associated, some under gender-specific analysis, with variations in the plasma lipid levels under postprandial conditions in a representative Spanish population.

Dietary polyunsaturated fatty acids may increase plasma LDL-cholesterol and plasma cholesterol concentrations in carriers of an ABCG1 gene single nucleotide polymorphism: Study in two Spanish populations

BACKGROUND ABCG1 mediates cellular cholesterol transport, but there is very little known about the influence of ABCG1 polymorphisms on human plasma lipoprotein cholesterol concentrations or on the interactions of these polymorphisms with diet. OBJECTIVE Our objective was to investigate whether interactions between PUFA intake and ABCG1 polymorphisms modulate associations with plasma total cholesterol (TC), LDL- and HDL-cholesterol in two Spanish populations. METHODS We grounded our investigation on two general population-based studies: the Hortega study (population A) and the Pizarra study (population B). Participants included 1178 individuals (50.0% women, age range 21-85 years) and 763 individuals (66% women, age range 23-73 years) from populations A and B, respectively, without lipid lowering drugs. Subjects were genotyped for ABCG1 variants. Biochemical measurements were taken by standard procedures. Dietary intakes were estimated with a validated questionnaire. RESULTS In population A, the A allele homozygotes of SNP rs4148102 had higher TC and LDLc concentrations in subjects on a high PUFA diet than did the carriers of the G allele (242.1 ± 38.9 vs. 198.0 ± 36.0mg/dL, p = 0.003, and 149.8 ± 37.9 vs. 111.4 ± 32.1mg/dL, p = 0.005, respectively), and significant gene-diet interactions were observed (p=0.020 and p = 0.013, respectively). In population B, similar differences in TC and LDLc concentrations were also found in association with this SNP under a high PUFA diet (253.2±24.9 vs. 197.7 ± 39.9 mg/dL, p = 0.009, and 171.8 ± 20.5 vs. 120.4 ± 34.2mg/dL, p = 0.004, respectively), but the gene-diet interactions observed were not significant (p = 0.379 and p = 0.422, respectively). In the pooled populations, differences in the TC and LDLc concentrations increased (246.8 ± 32.9 vs. 198.0 ± 37.5, p = 6 × 10(-5), and 159.0±32.6 vs. 114.3 ± 33.1, p = 3 × 10(-5), respectively), and significant gene-diet interactions were maintained (p = 0.006 and p = 0.003, respectively). CONCLUSION In two Spanish populations, the ABCG1 polymorphism rs4148102 was associated with variations in plasma lipoprotein cholesterol concentrations in subjects with high PUFA intakes. Carriers of the AA genotype consuming high PUFA diet showed higher plasma LDLc concentrations.

Impact of obesity-related genes in Spanish population.

BackgroundThe objective was to investigate the association between BMI and single nucleotide polymorphisms previously identified of obesity-related genes in two Spanish populations. Forty SNPs in 23 obesity-related genes were evaluated in a rural population characterized by a high prevalence of obesity (869 subjects, mean age 46 yr, 62% women, 36% obese) and in an urban population (1425 subjects, mean age 54 yr, 50% women, 19% obese). Genotyping was assessed by using SNPlex and PLINK for the association analysis.ResultsPolymorphisms of the FTO were significantly associated with BMI, in the rural population (beta 0.87, p-value <0.001). None of the other SNPs showed significant association after Bonferroni correction in the two populations or in the pooled analysis. A weighted genetic risk score (wGRS) was constructed using the risk alleles of the Tag-SNPs with a positive Beta parameter in both populations. From the first to the fifth quintile of the score, the BMI increased 0.45 kg/m2 in Hortega and 2.0 kg/m2 in Pizarra. Overall, the obesity predictive value was low (less than 1%).ConclusionThe risk associated with polymorphisms is low and the overall effect on BMI or obesity prediction is minimal. A weighted genetic risk score based on genes mainly acting through central nervous system mechanisms was associated with BMI but it yields minimal clinical prediction for the obesity risk in the general population.

Inefficient arterial hypertension control in patients with metabolic syndrome and its link to renin-angiotensin-aldosterone system polymorphisms

There is evidence that uncontrolled arterial hypertension (AHT) in patients with metabolic syndrome (MS) increases cardiovascular risks. The renin–angiotensin–aldosterone system (RAAS) and its polymorphisms apparently confer a genetic risk for uncontrolled AHT. This study aims to investigate the influence of RAAS polymorphisms on AHT control in patients diagnosed with MS. This is a two-stage population-based nested case–control pilot study (n=1514). We differentiated between MS-diagnosed patients and non-MS patients (ATP-III criteria) and selected those individuals diagnosed with AHT from each group (n=161 and n=156, respectively). Those who successfully controlled their AHT (controls) and those who did not were compared. In the MS population, the C/G and G/G genotypes of single-nucleotide polymorphism rs1040288 (NR3C2) and A/G and G/G of rs11099680 (NR3C2) were associated with uncontrolled AHT (odds ratio (OR)=2.94 (1.34–6.47) and OR=2.54 (1.09–5.93), respectively). According to Akaikes information criteria, the best adjusted model included gender and age as confounding variables (adjusted OR (ORa)=2.91 (1.31–6.46) and ORa=2.67 (1.13–6.31), respectively). Regarding rs1040288, an ORa of 4.03 (1.44–11.26) was obtained for the saturated model (adjusted for gender, age, waist-to-hip ratio, body mass index, biochemical profile, renal damage, smoking habit and anti-AHT treatment). Yet, when the same analysis was performed on the non-MS population, no association was found between rs11099680 and the failure to control AHT. The results reveal a possible association between the rs11099680 RAAS polymorphism and uncontrolled AHT in MS-diagnosed patients. rs1040288 appears to be associated with uncontrolled blood pressure regardless of MS profile.

How ineffective hypertension control in subjects treated with angiotensin-converting enzyme inhibitors is related to polymorphisms in the renin-angiotensin-aldosterone system

PURPOSE To investigate how genetic polymorphisms of the renin-angiotensin-aldosterone system (RAAS) influence hypertension (HT) control with angiotensin-converting enzyme inhibitor drugs (ACEI). METHODS A case-control, cross-sectional population-based nested study (n=1514) included hypertensive patients treated with ACEI drugs, either alone or with other antihypertensive drugs. We differentiated between those who did not control their HT (cases) with those who did (controls). Each groups characteristics were compared to determine the risk of non-controlled HT associated with RAAS polymorphisms by adjusting for different variables. RESULTS rs11571074 obtained an ORa of 5.26 for T/T (1.25-20). rs5945377 obtained an ORa 16.16 (1.61-162.62) for genotypes G/G-G/C. rs909383, rs275649 and rs4681444 obtained an ORa of 4.00 (1.19-14.28), 5.89 (1.53-25) and 3.89 (1.53-25) when genotypes C/C and A/A were expressed for the first and for the other two, respectively. For rs2272089, rs13117325 and rs11099680, a higher non-control risk was seen in A/G-G/G carriers (ORa: 4.9 (1.3-18.3); ORa: 3.7 (1.0-13.4); ORa: 6.5 (1.7-24.7). Finally, rs6535598 obtained an ORa of 10.4 (1.2-92.9) in T/T carriers. CONCLUSIONS Although this study shows a possible association of polymorphisms of RAAS genes with the risk of non-control of HT in ACEI-treated patients and indicates the importance of all this systems components in regulating HT, it needs to be replicated in other data sources.

Genetic Variants in CCNB1 Associated With Differential Gene Transcription and Risk of Coronary In-Stent Restenosis

Background—The development of diagnostic tools to assess restenosis risk after stent deployment may enable the intervention to be tailored to the individual patient, for example, by targeting the use of drug-eluting stent to high-risk patients, with the goal of improving safety and reducing costs. The CCNB1 gene (encoding cyclin B1) positively regulates cell proliferation, a key component of in-stent restenosis. Therefore, we hypothesized that single-nucleotide polymorphisms in CCNB1 may serve as useful tools in risk stratification for in-stent restenosis. Methods and Results—We identified 3 single-nucleotide polymorphisms in CCNB1 associated with increased restenosis risk in a cohort of 284 patients undergoing coronary angioplasty and stent placement (rs350099: TT versus CC+TC; odds ratio [OR], 1.82; 95% confidence interval [CI], 1.09–3.03; P=0.023; rs350104: CC versus CT+TT; OR, 1.82; 95% CI, 1.02–3.26; P=0.040; and rs164390: GG versus GT+TT; OR, 2.27; 95% CI, 1.33–3.85; P=0.002). These findings were replicated in another cohort study of 715 patients (rs350099: TT versus CC+TC; OR, 1.88; 95% CI, 0.92–3.81; P=0.080; rs350104: CC versus CT+TT; OR, 2.23; 95% CI, 1.18–4.25; P=0.016; and rs164390: GG versus GT+TT; OR, 1.87; 95% CI, 1.03–3.47; P=0.040). Moreover, the haplotype containing all 3 risk alleles is associated with higher CCNB1 mRNA expression in circulating lymphocytes and increased in-stent restenosis risk (OR, 1.43; 95% CI, 1.00–1.823; P=0.039). The risk variants of rs350099, rs350104, and rs164390 are associated with increased reporter gene expression through binding of transcription factors nuclear factor-Y, activator protein 1, and specificity protein 1, respectively. Conclusions—Allele-dependent transcriptional regulation of CCNB1 associated with rs350099, rs350104, and rs164390 affects the risk of in-stent restenosis. These findings reveal these common genetic variations as attractive diagnostic tools in risk stratification for restenosis.