Genetic influences on blood pressure within the Stanislas Cohort

OBJECTIVE: To investigate the association of 21 polymorphisms within 13 genes, APOE, APOB, APOC3, CETP, LPL, PON1, MTHFR, FGB, F5, GPIIIa, SELE, ACE and AGT, with inter-individual blood pressure (BP) variation. PARTICIPANTS: Seven hundred and seventy-six men and 836 women, free of antihypertensive and lipid-lowering medications, were selected from the Stanislas Cohort. RESULTS: ANOVA on blood pressure values after adjustment for covariates [age, body mass index (BMI), contraceptive pill, tobacco and alcohol] showed that lipoprotein lipase (LPL) Ser447Ter and glycoprotein IIIA (GpIIIa) Pl polymorphisms were significantly associated with BP in women (0.01 < or = P < or = 0.05), whereas BP levels in men were significantly different according to apolipoprotein CIII (APOC3) 3206T/G and -482C/T polymorphisms (P < or = 0.05). In women, compared to the most common allele, the GpIIIa Pl allele was associated with increased mean arterial pressure (MAP) (P < 0.05) and pulse pressure (PP) (P < 0.001), and the LPL 447Ter allele was associated with decreased systolic blood pressure (SBP) and PP levels (0.001 < or = P < or = 0.05). These two polymorphisms appeared to act independently. In men, the APOC3 3206GG genotype was related to decreased diastolic blood pressure (DBP) and MAP levels (P < or = 0.01), and the APOC3 -482T allele with decreased PP levels (P < or = 0.05). The presence of both the -482C allele and the 3206GG genotype was related to decreased DBP, suggesting that specific haplotypes might be involved. CONCLUSION: The APOC3, LPL and GpIIIa genes were found to be associated with BP levels. The contributions of these genes, although modest, are consistent with the polygenic nature of BP levels.     

Genetic variation in the natriuretic Peptide system, circulating natriuretic Peptide levels, and blood pressure: an ambulatory blood pressure study

BackgroundIn a large collaborative study (n > 50,000), common variants in the natriuretic peptide (NP) genes were found to be associated with circulating NP levels and also with blood pressure (BP) levels based on office BP measurements (OBPMs). It is unknown if determining an individual's BP by 24-h ambulatory BP measurements (ABPMs) will influence the effect of NP gene variations on BP levels.MethodsWe used rs632793 at the NPPB (NP precursor B) locus to investigate the relationship between genetically determined serum N-terminal pro-brain NP (NT-proBNP) concentrations and BP levels determined by both 24-h ABPMs and OBPMs in a population consisting of 1,397 generally healthy individuals taking no BP-lowering drugs.Resultsrs632793 was significantly correlated with serum Nt-proBNP levels (r = 0.10, P = 0.0003), and participants with the A:A genotype had lower serum Nt-proBNP levels than participants with the G:G genotype (geometric mean (95% confidence interval (CI)): 34.8 (31.5-38.4) pg/ml vs. 48.1 (41.9-55.3) pg/ml, P = 0.0002), but higher 24-h ambulatory BP levels (mean difference (95% CI): 2.0 (0.1-4.1) mm Hg, P = 0.043, for systolic BP and 1.7 (0.4-3.1) mm Hg, P = 0.011, for diastolic BP). Office BP decreased across the genotypes from A:A to G:G, but the differences did not reach statistical significance (P ≥ 0.12).ConclusionsThis study suggests that 24-h ABPMs is a better method than OBPMs to detect significant differences in BP levels related to genetic variance and provides further evidence that the NP system plays an important role in BP regulation.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.96.     

Common variation in the adiponectin gene has an effect on systolic blood pressure

The genotype at the C-11377G single-nucleotide polymorphism (SNP) (rs266729) in the adiponectin gene promoter has been shown to affect the prevalence of coronary atherosclerosis and incidence of vascular events in men, and to affect carotid intima media thickness. We have examined the relationship between this polymorphism and blood pressure in a cohort ascertained to express variability in blood pressure measurements. We studied a cohort of 255 families comprising 1425 individuals ascertained via a hypertensive proband. Blood pressure was measured by ambulatory monitoring. The C-11377G SNP was genotyped using a TaqMan assay. There was evidence of association between this SNP and log systolic blood pressure (SBP), having adjusted for significant covariates including gender, age and drug treatment; P=0.009, 0.014 and 0.022, respectively, for daytime, night-time and clinic measurements. Replacing C by G caused an increase of 1.63, 1.83 and 1.61%, respectively, per gene copy. There were smaller effects on diastolic blood pressure and waist-hip ratio, which were of borderline significance. Genotype at the C-11377G (rs266729) polymorphism has independent effects both on waist-hip ratio and SBP. This may help in understanding the complex role that the adiponectin gene has in atherosclerosis.     

Genetic and environmental influences on body fat and blood pressure in African-American adult twins

OBJECTIVE: African Americans have a particularly high prevalence of excessive body fat and high blood pressure. Genetic and environmental influences may be implicated for both of these risk factors. We investigated the potential for common genetic and environmental influences on body fat (waist circumference (WC), body mass index (BMI)) and blood pressure measures (systolic and diastolic pressure (SBP, DBP)) among African-American male and female subjects. RESEARCH METHODS AND PROCEDURES: Measurements were taken as part of the Carolina African-American Twin Study of Aging (CAATSA). The CAATSA sample contains 217 same-sex African-American male and female twins with average age of 47 years. This analysis included 39 monozygotic male pairs (MZ), 43 dizygotic male pairs (DZ); 63 MZ female pairs, and 72 DZ female pairs. Maximum likelihood quantitative genetic analyses were used. RESULTS: The total genetic variance for SBP was 22% in male subjects and 40.1% in female subjects. Of this total variance, 3.1% was in common with BMI in male subjects and 6% was in common with BMI in female subjects. After controlling for the effects of BMI, WC had less than 1% of its variance in common with SBP in male and female subjects. For DBP, the total genetic variance was 16.9% in male and 38.7% in female subjects. Of this total variance 6.1% was in common with BMI in male subjects and 3.7% was in common in female subjects. Again, WC had less than 1% of its genetic variance in common with DBP in both male and female subjects. The environmental variance common among these measures was also very small. The remaining variance was primarily accounted for by genetic and environmental effects unique to each measure as well as age. DISCUSSION: Based on the very small common genetic variance for BMI, SBP, and DBP as well as WC and the blood pressure measures, our results suggest that searching for common genes among these measures may be inconclusive.     

Relationship between diurnal blood pressure variation and diurnal blood glucose levels in type 2 diabetic patients

BACKGROUND: Hypertension and hyperglycemia are established risk factors for progression of microangiopathies and macroangiopathies in type 2 diabetes mellitus. Cardiovascular risk is even more increased in diabetic patients with nocturnal nondipping or postprandial hyperglycemia. We therefore investigated the relationship between diurnal hyperglycemia and diurnal blood pressure (BP) variation in patients. METHODS: One hundred seven hypertensive type 2 diabetic patients received a 24-h ambulatory BP recording. In addition, a diurnal blood glucose profile was assessed under standardized conditions on the same day: before breakfast, 2 h after breakfast, before lunch, 2 h after lunch, before dinner, 2 h after dinner, at 10:00 pm, at midnight, and 3:00 am of the following day. Degrees of fasting and postprandial hyperglycemia were calculated as area under the curve. RESULTS: Nocturnal nondipping occurred in 73% of our patients. Nondippers showed higher postprandial blood glucose excursions than dippers (59.5 +/- 29 v 40.7 +/- 33 mmol h/L), whereas fasting hyperglycemia or glycosylated hemoglobin (HbA(1c)) were not significantly different (56.6 +/- 49 v 54.1 +/- 44 mmol h/L and 8.8% +/- 1.9% v 8.2% +/- 1.8% for nondippers and dippers, respectively). Nocturnal nondipping was associated with a higher urinary protein excretion and lower day/night heart rate ratio. Multivariate analysis revealed postprandial hyperglycemia as an independent predictor for nondipping. CONCLUSIONS: Postprandial rather than fasting hyperglycemia was associated with abnormal diurnal BP variation. These observations might favor treatment regimes targeted on postprandial hyperglycemia, which could restore dipping pattern.     

Genetic variation at the human alpha2B-adrenergic receptor locus: role in blood pressure variation and yohimbine response

Exaggerated response to alpha2-adrenergic receptor (alpha2-AR) blockade by yohimbine in normotensive subjects is an intermediate phenotype that predicts increased risk for development of hypertension. Here, we assessed the 3 alpha2-AR loci (alpha2A, alpha2B, alpha2C) as candidate genes for their influence on baseline and yohimbine-mediated increase in mean arterial pressure. Because initial results with 173 individuals implicated a possible association of yohimbine response with genetic variation at a site in the alpha2B-AR gene, but not at sites in the other 2 alpha2-AR, we sequenced the alpha2B-AR gene (4.4 kb, including 1.2 kb upstream and 1.9 kb distal to the coding sequence) in those subjects and an additional 81 individuals to search for other alpha2B-AR variants. We identified 25 polymorphisms, of which 14 are previously unreported, and 2 major haplotypes that differ by the presence/absence of a 9-bp in-frame deletion that encodes Glu301 to Glu303. Frequency differences in haplotypes were observed between blacks and whites but did not predict response to yohimbine. Genotyping of 2 additional white cohorts, including 1269 individuals with extremes in blood pressure selected from >50,000 subjects, also failed to reveal an association of the 2 major alpha2B-AR haplotypes with differences in blood pressure. Thus, despite considerable polymorphism in alpha2-AR genes, such variation is not a major determinant of variability in yohimbine response and by inference, in susceptibility to essential hypertension.     

Genetic variation in PNPLA3 but not APOC3 influences liver fat in non-alcoholic fatty liver disease

Background and Aim: A recent study in Indian subjects suggested common variants in apolipoprotein C3 (APOC3) (T‐455C at rs2854116 and C‐482T at rs2854117) to contribute to non‐alcoholic fatty liver disease (NAFLD), plasma apoC3 and triglyceride concentrations. Our aim was to determine the contribution of genetic variation in APOC3 on liver fat content and plasma triglyceride and apoC3 concentrations in a larger European cohort. Methods: A total of 417 Finnish individuals were genotyped for rs2854116 and rs2854117 in APOC3 and the known rs738409 in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) influencing liver fat. Plasma apoC3 concentration was measured enzymatically, and liver fat by proton magnetic resonance spectroscopy. Results: APOC3 wild‐type homozygotes and variant allele (T‐455C or C‐482T or both) carriers did not differ with regard to liver fat, apoC3 concentrations, triglyceride‐, high density lipoprotein‐, fasting plasma glucose, insulin‐, alanine aminotransferase‐ and aspartate aminotransferase‐concentrations, nor was there a difference in prevalence of NAFLD. In contrast, carriers of the PNPLA3 GG genotype at rs738409 had a 2.7‐fold (median 11.3%) higher liver fat than those with the CC (median 4.2%) genotype. The PNPLA3 rs738409 was also an independent predictor of liver fat, together with age, gender, and body mass index. Conclusion: Genetic variants in PNPLA3 but not APOC3 contribute to the variance in liver fat content due to NAFLD.     

Classification of blood pressure levels by ambulatory blood pressure in hypertension

Whereas clinic blood pressure (CBP) above normality is divided into stages, no corresponding classifications are available for 24-hour ambulatory blood pressure (ABP). We conducted a study (1) to define stages of hypertension by ABP corresponding to CBP stages and (2) to evaluate if these stages have prognostic impact similar to CBP stages. Seven hundred thirty-six hypertensive patients were included. Mean systolic blood pressure was 149+/-15.2/87+/-8.6 mm Hg for CBP and 135+/-13/79+/-9.7 mm Hg for ABP. The mean bias between both methods was -13.3 mm Hg (95% CI, -14.3 to -12.2; 1.96xSD limits of agreement, 15.7 to -42.3) and -7.3 mm Hg (95% CI, -7.9 to -6.6; 1.96xSD limits of agreement, 9.8 to -24.3) for systolic and diastolic blood pressure (P>0.0001 for both), respectively. Classification of hypertension by ABP revealed lower cutoff values for the different stages of hypertension compared with the corresponding cutoff values for CBP (CBP versus ABP: 140/90 versus 132/81 mm Hg; 160/100 versus 140/88 mm Hg; 180/110 versus 148/94 mm Hg, P<0.001). Overall, 82 (11.1%) patients had nonfatal clinical cardiovascular events and 9 (1.2%) patients died of a cardiovascular cause during follow-up. The distribution of cardiovascular events was significantly associated with increasing ABP value (P<0.006). Staging of hypertension by ABP may facilitate the use of this method in daily clinical practice, as ABP can now be used not only to confirm the diagnosis of hypertension but also to assess the severity and prognosis of hypertensive disease.     

The cuff width influences the toe blood pressure value

BACKGROUND: Toe blood pressure is a valuable and often used parameter when lower limb ischaemia is evaluated in patients with diabetes, but little has been done to standardise the method. The aim of this study was to evaluate if the cuff size influences the toe blood pressure values obtained in patients with diabetes. PATIENTS AND METHODS: Eleven patients with diabetes without a history of peripheral vascular disease, and six age matched healthy subjects were investigated. Their blood pressures were measured in the upper arm and at the ankle level repetitively. For measurement of toe blood pressure two different cuff widths were used. RESULTS: All blood pressures were similar in patients and control subjects, as well as over time. The toe blood pressure values were 18 mmHg higher (p < 0.01) if measured with a 2.0-cm compared to a 2.5-cm wide cuff. There was a relationship (r = 0.63, p < 0.05 for patients) between toe circumference and the toe blood pressure value, where smaller hallluxes gave lower values. CONCLUSIONS: The cuff width influences the obtained toe blood pressure value and needs to be considered when evaluating limb ischemia in patients with diabetes.     

Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis

Objective

Smad3 (or, MADH3) is a key intracellular messenger in the transforming growth factor β signaling pathway. In mice, Smad3 deficiency accelerates growth plate chondrocyte maturation and leads to an osteoarthritis (OA)–like disease. We undertook this study to investigate the role of genetic variation in SMAD3 in the risk of large‐joint OA in humans.

Methods

Ten tag single‐nucleotide polymorphisms (SNPs) in the SMAD3 gene region were tested in a discovery set: 313 patients who had undergone total knee replacement, 214 patients who had undergone total hip replacement, and 520 controls from the UK. The SNP associated with both hip and knee OA was subsequently genotyped in 1,221 controls and 1,074 cases from 2 cohorts of patients with hip OA and 2,537 controls and 1,575 cases from 4 cohorts of patients with knee OA.

Results

A SNP (rs12901499) mapping to intron 1 of SMAD3 was associated with both knee and hip OA (P < 0.0022 and P < 0.021, respectively) in the discovery set. In all study cohorts, the major allele (G) was increased among OA patients relative to controls. A meta‐analysis for knee OA yielded an odds ratio (OR) of 1.22 (95% confidence interval [95% CI] 1.12–1.34), P < 7.5 × 10⁻⁶. For hip OA, the OR was 1.22 (95% CI 1.09–1.36), P < 4.0 × 10^–4. No evidence for heterogeneity was found (I² = 0%).

Conclusion

Our data indicate that genetic variation in the SMAD3 gene is involved in the risk of both hip OA and knee OA in European populations, confirming the results from animal models on the potential importance of this molecule in the pathogenesis of OA.

     

Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians

A recent genome-wide study revealed an association between variation in the PNPLA3 gene and liver fat content. In addition, the PNPLA3 single-nucleotide polymorphism rs738409 (M148I) was reported to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of Mestizo descent. We therefore evaluated the impact of rs738409 on the manifestation of alcoholic liver disease in two independent German cohorts. Genotype and allele frequencies of rs738409 (M148I) were determined in 1,043 alcoholic patients with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Relative to alcoholic patients without liver damage (n = 439), rs738409 genotype GG was strongly overrepresented in patients with alcoholic liver cirrhosis (n = 210; OR 2.79; P(genotype) = 1.2 × 10(-5) ; P(allelic) = 1.6 × 10(-6) ) and in alcoholic patients without cirrhosis but with elevated alanine aminotransferase levels (n = 219; OR 2.33; P(genotype) = 0.0085; P(allelic) = 0.0042). The latter, biochemically defined association was confirmed in an independent population-based cohort of at-risk drinkers with a median alcohol intake of 300 g/week (OR 4.75; P(genotype) = 0.040; P(allelic) = 0.022), and for aspartate aminotransferase (AST) levels. Frequencies of allele PNPLA3 rs738409(G) in individuals with steatosis and normal alanine aminotransferase (ALT) and AST levels were lower than in alcoholics without steatosis and normal ALT/AST (P(combined) = 0.03). The population attributable risk of cirrhosis in alcoholic carriers of allele PNPLA3 rs738409(G) was estimated at 26.6%. CONCLUSION: Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians.     

Lipoprotein lipase gene polymorphisms and blood pressure levels in the Northern Chinese Han population.

The lipoprotein lipase (LPL) gene has been investigated extensively in linkage studies and in studies of its association with lipid profiles and coronary artery disease (CAD), and this gene has also been reported to have an association with hypertension. In our previous linkage study on 148 Chinese hypertensive families, the regions at or near the LPL gene were found to be associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP). Thus the LPL gene is a logical candidate gene for involvement in the underlying cause of essential hypertension (EH). In the present study, we identified 22 sequence variants by directly sequencing 10 exons and flanking regions of the LPL gene, and investigated the occurrence of 3 of these variants, IVS4-214C>T, 7754C>A and S447X, in a case-control study including 501 normotensive (NT) subjects and 497 EH subjects. In males, the frequencies of the genotypes of each of the 3 variants did not differ significantly between the NT and EH groups. Among the EH group in females, ANCOVA revealed no significant difference in blood pressure levels according to the 7754C>A genotype. However, in female, the distribution of the 7754C>A genotype and the frequency of the A allele of 7754C>A differed significantly between the NT and EH groups (p=0.032 and p=0.027, respectively) with 0.78 (95% confidence interval (CI): 0.56 to 1.07; p=0.12) of odds ratio for the A allele. Moreover, haplotype analysis revealed that T-A-C and T-C-G haplotypes (in the order of IVS4-214C>T, 7754C>A and S447X) were statistically more frequent in the NT group than in the EH group in females and males, respectively. Our indivisual single nucleotide polymorphism (SNP) analysis did not provide substantial evidence of an association between polymorphisms in the LPL gene and hypertension status and/or blood pressure levels in this cohort, but the more powerful haplotypes analysis suggested an association between the LPL gene and hypertension.     

Association of leptin levels with obesity and blood pressure: possible common genetic variation

OBJECTIVE: To ascertain the extent to which relationships between obesity (OB) and blood pressure (BP) can be explained by an individual's leptin plasma levels. DESIGN: Pedigree-based cross-sectional study in an apparently healthy population of European origin. SUBJECTS: The study sample is comprised of 90 nuclear and more complex families totaling 210 male and 213 female subjects aged 18-75 y, randomly recruited in Bashkorstan Autonomic region, Russia. MEASUREMENTS: Various fatness and fat distribution traits (including nine circumferences (CRCs), and eight skinfolds (CKFs) by anthropometry), blood pressure, and plasma leptin levels (by ELISA kits). RESULTS: Adjustment for circulating leptin led to attenuation of the magnitude of correlations between OB and BP, regardless of trait pair and sex cohort. Some of these correlations became statistically nonsignificant. All familial effects were gone, and heritability estimates became virtually zero after adjustment of each of the OB traits and systolic blood pressure (SBP) in offspring for leptin values in parents. CONCLUSION: BP and OB covariation is substantially mediated by circulating leptin levels. As a result, body fat has only a weak independent effect on BP variation after adjustment for leptin levels. Our findings also strongly suggest that genetic variation in body mass index, SKFs, and even body CRCs, as well as of SBP is due to genetic variation of leptin. Genetic variation of diastolic blood pressure in the present sample, however, shared very little with that of leptin.     

Genetic and environmental influences on thyroid hormone variation in Mexican Americans

Thyroid hormones play major roles in the regulation of a wide range of metabolic and physiologic processes, but the genes and environmental factors that affect normal, quantitative variation in thyroid hormone concentrations are largely unknown. Using quantitative genetic methods, we evaluated the effects of genes and environmental factors on thyroid hormone variation in 586 women and 425 men from 27 randomly ascertained Mexican-American families from the San Antonio Family Heart Study. Data were available on free and total T(4), free and total T(3), TSH, thyroglobulin, and T(4)-binding globulin, as well as on covariates, including sex, age, weight, lifestyle habits, physical activity, and others. These covariates accounted for 2-18% of total phenotypic variation, whereas genes accounted for 26-64% of the variation. Overall, free T(3) had the highest heritability, which is noteworthy because it is the most biologically active thyroid hormone and accounts for the vast majority of metabolic and physiologic effects of thyroid hormones. Our results indicate that genes account for a substantial portion of variation in human thyroid hormone levels, and suggest that further studies to identify the genes involved in this variation could reveal important insights into the processes that govern thyroid-mediated metabolism.