C-reactive protein as a predictor of hypertension in the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) cohort.

Inflammation contributes to the development of hypertension. Whether C-reactive protein (CRP) has a causal role in hypertension remains unknown. We studied the relationship between circulating CRP levels and hypertension. The role of single-nucleotide polymorphisms (SNPs) in the CRP gene as determinants of its plasma levels and the propensity to develop hypertension was investigated. Plasma CRP and genotypes of nine SNPs were determined in 1925 unrelated subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS-2) in 2000-2004. Among 1378 subjects normotensive in CRISPS-2, 1115 subjects had been followed up in CRISPS-3 after a median interval of 5.3 years, 236 of whom had developed hypertension. Plasma CRP was independently associated with the development of hypertension in CRISPS-3 (odds ratio per quartile=1.26, P=0.010). Six SNPs were associated with plasma CRP (all P<0.001). However, none of the SNPs was significantly associated with blood pressure, prevalent or incident hypertension, or change in blood pressure. In conclusion, plasma CRP predicts the development of hypertension. Genetic variants in the CRP gene are significantly associated with plasma CRP but not with hypertension. The future risk of hypertension is therefore more related to plasma CRP than SNPs in the CRP gene in this population.

Association of F11 receptor gene polymorphisms with central obesity and blood pressure.

OBJECTIVES: F11 receptor, also known as junctional adhesion molecule-1, in the autonomic nervous system is implicated in the development of hypertension in spontaneous hypertensive rats. We investigated the association of single nucleotide polymorphisms (SNPs) in the F11 receptor gene (F11R) with hypertension and central obesity in Hong Kong Chinese. METHODS: Seven tagging SNPs were identified in the HapMap database. Genotyping was performed using Sequenom MassArray in 263 hypertensive subjects and 393 normotensive controls, of whom 263 matched the cases in age and sex. RESULTS: When subjects on anti-hypertensive medication were excluded, rs790056 and rs2774276 were associated with lower systolic blood pressure (TT:124.8 +/- 18.3 mmHg vs. TC + CC: 120.2 +/- 15.5 mmHg, P = 0.004 and CC: 124.7 +/- 18.5 mmHg vs. CG+GG: 120.5 +/- 15.1 mmHg, P = 0.007 respectively). Comparing 213 subjects with central obesity with 213 controls matched for sex and age, rs2481084 and rs3737787 were associated with lower odds of central obesity (odds ratio = 0.516, P = 0.002 and odds ratio = 0.540, P = 0.005 respectively). All these associations remained significant after correction for multiple testing. Analysis of statistically similar SNPs suggested that the causative variants for systolic blood pressure were located in F11R, whilst those for central obesity could be due to causative variants in the transcription factor 1 gene immediately upstream. CONCLUSIONS: F11 receptor plays a role in blood pressure regulation, not only in rats but also in man. The link between F11 receptor and central obesity merits further investigation.

Single-nucleotide polymorphisms near the microsatellite D17S1303 and the development of hypertension in a 6-year longitudinal study.

This study examined the association of tagging single-nucleotide polymorphisms (SNPs) in the 130 kb region surrounding the microsatellite D17S1303 on chromosome 17p12 with the development of hypertension after 6 years in a cohort of 232 Hong Kong Chinese adults. Four SNPs (rs9899362, rs10491093, rs11658572 and rs9913883) were associated with the development of hypertension (P<0.05), but these associations require confirmation in future studies. Nevertheless, our study provides further evidence for the presence of an unidentified gene or a regulatory element predisposing to hypertension in a region approximately 24 kb downstream of D17S1303.

Plasma levels of fibrinogen and C-reactive protein are related to interleukin-6 gene -572C>G polymorphism in subjects with and without hypertension.

Hypertension is an important risk factor for cardiovascular diseases. There is increasing evidence suggesting that inflammation is involved in the development of hypertension. Interleukin-6 (IL-6) is an important mediator of inflammatory response and the major regulator of hepatic production of acute phase proteins, such as fibrinogen and C-reactive protein (CRP), which have been associated with hypertension and cardiovascular diseases. Therefore, we studied the association of single nucleotide polymorphism (SNP) in the IL-6 gene (IL6) promoter with plasma levels of fibrinogen, CRP and hypertension. Five hundred and two Hong Kong Chinese subjects (282 normotensives and 220 hypertensives) were recruited. IL-6 gene promoter was examined for polymorphism and the study subjects were genotyped for any SNP identified. The IL6 -572C>G polymorphism (rs1800796) was found with a frequency of 0.23 for the minor G allele. Subjects with the -572G allele had significantly higher plasma fibrinogen (3.06+/-0.57 vs 2.83+/-0.60, P=0.002) and CRP (interquartile range 0.33-1.56 vs 0.12-0.93, P=0.003) levels than those without. The -572C>G polymorphism was found to be an independent predictor of fibrinogen and CRP levels after adjusting for confounding factors. Plasma concentrations of fibrinogen and CRP correlated with systolic blood pressure. However, the -572C/G genotype frequencies did not differ between hypertensive and normotensive subjects, and there was no association between -572C>G polymorphism and blood pressure. Our results provide evidence that there is a clear genetic influence of IL6 -572C>G polymorphism on plasma levels of fibrinogen and CRP, but this polymorphism does not lead to elevated blood pressure.

Intron 2 (T/C) CYP46 polymorphism is associated with Alzheimer's disease in Chinese patients.

BACKGROUND: Cholesterol metabolism has been implicated in the pathophysiology of Alzheimer's disease (AD), and cholesterol-related genes are plausible candidate genes for AD. Genetic association of CYP46A1 polymorphisms with AD had been under extensive investigations; however, observations on intron 2 T-->C (rs754203) generated inconclusive results. OBJECTIVE: To analyse an independent data set in a Chinese population to see whether the polymorphic site rs754203 of the CYP46A1 gene is associated with AD. METHODS: We analysed 130 sporadic AD patients and 110 healthy controls of the Southern Chinese origin. RESULTS: An association between the genotype frequency and AD was suggested in the general population (p = 0.047, odds ratio, OR = 1. 61, 95% confidence interval, CI = 0.96-2.70), while the association was most significant in the apolipoprotein E (ApoE) epsilon4-negative group (p = 0.004, OR = 2.54, 95% CI =1.31-4.95). Linkage disequilibrium block prediction results also favoured this association. Consistent with previous reports, intron 3 C-->T (rs4900442) polymorphism did not show any evidence of association; in our data set ApoEepsilon4 was confirmed to be a genetic risk factor for AD (p = 0.0016, OR = 2.76, 95% CI = 1.50-5.11).

Association of hypertension with single nucleotide polymorphisms in the quantitative trait locus for abdominal obesity-metabolic syndrome on chromosome 17.

Genome scan in Chinese revealed an association of blood pressure with the microsatellite marker D17S1303, which lies in a quantitative trait locus for the abdominal obesity-metabolic syndrome (AOMS2) at 17p12 on chromosome 17. We previously reported that D17S1303 was associated with hypertension and obesity. Therefore, we studied 10 single nucleotide polymorphisms (SNP) within 3 kb of D17S1303. One hundred and eighty hypertensive subjects (91 men, 89 women, age 53+/-12 years) and 180 normotensive matched controls (91 men, 89 women, age 52+/-11) were genotyped using the Sequenom genotyping platform. Allelic frequencies in these Chinese subjects differed from those reported for Caucasians. Three SNPs (rs11656507, rs1357926, rs852319) were homozygous in our subjects. The genotype frequencies of rs852320, rs852321 and rs852322 did not differ between hypertensive and normotensive subjects. However, there were significant differences for rs1525402 (P=0.048), rs2692343 (P=0.022), rs2692344 (P=0.017) and rs2321313 (P=0.028). A four-locus haplotype comprising G at rs1525402, C at rs2692343, C at rs2692344 and G at rs2321313 was associated with lower systolic blood pressure (P=0.023) and normotension (P=0.048). Our results provide further evidence that there is a gene, as yet unidentified, influencing blood pressure in the vicinity of D17S1303 in a quantitative trait locus for abdominal obesity-metabolic syndrome at 17p12.

Association of essential hypertension with a microsatellite marker on chromosome 17.

Hypertension is related to sodium intake, and many patients with essential hypertension are overweight and have the metabolic syndrome. We therefore studied microsatellite markers close to the thiazide-sensitive Na-Cl cotransporter on chromosome 16 and a quantitative trait locus for abdominal obesity-metabolic syndrome (AOMS2) on chromosome 17, which have been found to be linked to hypertension in a previous genome scan in Chinese. There were 84 hypertensive subjects (44 men, 40 women, age 53+/-13 years) and 88 normotensive controls (40 men, 48 women, age 54+/-13 years) recruited. Specific oligonucleotide primers were used to amplify genomic DNA spanning the microsatellite markers D16S3396 and D17S1303 that consist of ATA and GATA repeats, respectively. We did not find any association between D16S3396 and blood pressure. In contrast, the distribution of D17S1303 genotypes differed between hypertensive subjects and normal controls (P = 0.014). The number of GATA repeats correlated inversely with diastolic blood pressure (r = -0.18, P = 0.02) and body mass index (r = -0.12, P = 0.01). Nine GATA repeats in D17S1303 were associated with hypertension (OR 2.19, 95% CI 1.08-4.44, P = 0.027), while 14 GATA repeats were associated with normotension (OR 0.26, 95% CI 0.10-0.66, P = 0.002). The diastolic blood pressure in those with or without the (GATA)9 allele was 85.9+/-13.6 and 79.2+/-13.6 mmHg respectively (P = 0.01), and in those with or without the (GATA)14 allele it was 73.8+/-11.0 and 81.8+/-14.0 mmHg respectively (P = 0.003). Our results provide further evidence that a gene predisposing to hypertension in Chinese is in the vicinity of the microsatellite D17S1303.

Increased adrenomedullin expression in lungs in endotoxaemia.

Adrenomedullin (AM) is a peptide involved in cardiovascular homeostasis and in inflammation. We examined its expression in a rat model of endotoxaemia. Male Sprague-Dawley rats received intraperitoneal injection of 5 or 10 mg/kg lipopolysaccharide (LPS), or saline as control. Rats were killed at 1, 3, 6, 12 and 24 h after injection. LPS at 5 mg/kg, but not saline, increased plasma AM significantly at 3 h. At 10 mg/kg, plasma AM was raised at 3, 6 and 12 h. Immunoreactive AM concentration in lung increased after 5 or 10 mg/kg LPS, but not saline. PreproAM mRNA level in lung was significantly increased at 3 and 6 h. In conclusion, endotoxin stimulates the expression of AM in the lungs and increases its circulatory concentration. AM may be involved in the systemic response to sepsis.