Association study of the endothelial nitric oxide synthase gene polymorphisms with essential hypertension in northern Han Chinese.

BACKGROUND: Nitric oxide (NO) synthesized by endothelial nitric oxide synthase (eNOS) plays an important role in both the regulation of endothelial function and the control of blood pressure. Up to now, there has been conflicting data regarding the association between three clinically relevant polymorphisms (T-786C, intron4b/a and G894T) of the eNOS gene and essential hypertension. METHODS: To examine the contribution of the three eNOS gene polymorphisms to the development of hypertension in the northern Han Chinese, a case-control study including 503 hypertensive cases and 490 age-, gender-, and area-matched controls recruited from the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA) was conducted. Genotyping was performed by polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism (RFLP). RESULTS: The T-786C and intron4b/a polymorphisms were observed in significant linkage disequilibrium (D' = 0.87, P < 0.001). The minor allele frequencies of these three polymorphisms in healthy controls were much lower than those of Caucasians (9.3% vs 39.6% - 42.0%, 8.9% vs 15.0% - 16.0% and 10.9% vs 34.5% - 34.9% for -786C, intron4a and 894T, respectively). Genotype distributions and allele frequencies of the three polymorphisms did not differ between cases and controls (all P > 0.05). In addition, none of the eight estimated haplotypes significantly increased or decreased the risk of hypertension before or after adjustment for several known risk factors. CONCLUSION: The study results suggest that the three eNOS gene polymorphisms are unlikely to be major genetic susceptibility factors for essential hypertension in the northern Han Chinese population.

Linkage analysis of chromosome 14 and essential hypertension in Chinese population.

BACKGROUND: Hypertension is a complex biological trait that influenced by multiple factors. The encouraging results for hypertension research showed that the linkage analysis can be used to replicate other studies and discover new genetic risk factors. Previous studies linked human chromosome 14 to essential hypertension or blood pressure traits. With a Chinese population, we tried to replicate these findings. METHODS: A linkage scan was performed on chromosome 14 with 14-microsatellite markers with a density of about 10 centi Morgen (cM) in 147 Chinese hypertensive nuclear families. Multipoint non-parametric linkage analysis and exclusion mapping were performed with the GENEHUNTER software, whereas quantitative analysis was performed with the variance component method integrated in the SOLAR package. RESULTS: In the qualitative analysis, the highest non-parametric linkage score is 1.0 (P = 0.14) at D14S261 in the single point analysis, and no loci achieved non-parametric linkage score more than 1.0 in the multipoint analysis. Maximum-likelihood mapping showed no significant results, either. Subsequently the traditional exclusion criteria of the log-of-the-odds score-2 were adopted, and the chromosome 14 with lambda s > or = 2.4 was excluded. In the quantitative analysis of blood pressure with the SOLAR software, two-point analysis and multipoint analysis suggested no evidence for linkage occurred on chromosome 14 for systolic and diastolic blood pressure. CONCLUSION: There was no substantial evidence to support the linkage of chromosome 14 and essential hypertension or blood pressure trait in Chinese hypertensive subjects in this study.

Paraoxonase gene cluster variations associated with coronary heart disease in Chinese Han women.

BACKGROUND: The oxidative modification of low-density lipoprotein in the artery wall is currently believed to be central to the pathogenesis of atherosclerosis. Paraoxonase (PON1), an enzyme located on high-density lipoprotein (HDL), can prevent low-density lipoprotein (LDL) from oxidation at a certain extent. Recent studies show two other members of paraoxonase gene family, PON2 and PON3, possess antioxidant properties similar to PON1. The aim of the present study was to explore the role of PON gene cluster on coronary heart disease (CHD) in Chinese Han women. METHODS: Seven polymorphisms including PON1 -107C > T, -162G > A, -831G > A, R160G, Q192R, PON2 S311C, and PON3 -133C > A were genotyped in 184 female patients with CHD and 239 female controls. The plasma PON1 activity toward phenylacetate was determined in 50 cases and 50 controls randomly selected. RESULTS: The plasma PON1 activities were significantly lower in cases than in controls. Individual SNP analysis showed that cases had significantly higher frequencies of PON1 -107T, -831G and PON2 311S alleles than controls. The genotype distributions of -107C > T were also significantly different between two groups. The odds ratios for the development of CHD were 1.66 for -107TC carriers and 2.0 for -107TT carriers, compared with -107CC carriers. Haplotype analyses showed that the distributions of haplotypes comprised of PON1 -107C > T and PON2 S311C were significantly different between cases and controls, with cases having higher frequency of T-S haplotype (44.8% vs. 36.3%, P = 0.013). The T-S haplotype remained significantly associated with CHD after adjusting environmental risk factors (P = 0.0069). CONCLUSIONS: This association study suggested that lower plasma PON1 activity increased the risk of CHD in Chinese women, which may be mediated by the higher frequency of -107T allele in cases. Haplotype analyses indicated that there might be some synergistic effects between the PON1 -107C > T and PON2 S311C polymorphisms.

[Association analysis between polymorphisms of PON gene cluster with coronary heart disease in Chinese].

An extensive association analysis of PON gene cluster (PONs) with coronary heart disease (CHD) was performed in Chinese Han population. Eleven polymorphisms of PON1, PON2 and PON3 gene were investigated for association with CHD in 474 male patients and 475 controls. Univariate analyses showed the cases had significantly higher frequencies of PON1 192Q allele, 160R allele, -162A allele and PON2 311C allele than were seen in the controls. Logistic regression analyses revealed only the PON1 R160G and -162G/A polymorphisms remained significantly associated with CHD (P = 0.0054 and P = 0.0002). Haplotype analyses for various polymorphism combinations further confirmed the results of individual polymorphism analyses. Only the frequencies of haplotypes containing -162A allele were significantly higher,whereas only the frequencies of haplotypes containing 160G allele significantly lower in cases than those in controls in various polymorphism combinations. This extensive association study has identified the PON1 -162G/A and R160G polymorphisms to be independently associated with CHD in Chinese Han population,and warrants further study to elucidate the biological mechanism.

[Prevalence of isolated systolic hypertension in Chinese adult population].

OBJECTIVE: To evaluate prevalence of isolated systolic hypertension and other subtypes of hypertension, as well as their distribution in Chinese adults. METHODS: A cross-sectional survey was conducted in the mainland China during 2000-2001 with a multistage cluster sampling to select a nationally representative sample of 15,540 Chinese adults aged 35-74, by InterASIA project. Hypertension subtypes were defined among individuals not receiving antihypertensive therapy as follows: isolated systolic hypertension as a systolic blood pressure > or = 140 mm Hg and a diastolic blood pressure < 90 mm Hg, isolated diastolic hypertension as a systolic pressure < 140 mm Hg and a diastolic pressure > or = 90 mm Hg, and combined systolic/diastolic hypertension as a systolic pressure > or = 140 mm Hg and a diastolic pressure > or = 90 mm Hg. Blood pressure for each subject was measured for three readings at sitting position after rest for at least five minutes and an average reading was recorded. A standardized structured questionnaire was used to collect history of hypertension and antihypertensive treatment. RESULTS: Overall, 7.6% (1,181 cases) of adults had isolated systolic hypertension, 7.4% (1,150 cases) combined systolic/diastolic hypertension and 4.4% (683 cases) isolated diastolic hypertension in the sample of 15,540 adults at age 35-74. Prevalence of systolic hypertension increased with age, and was more common in the older women than in the older men. There was no significant difference in prevalence of isolated systolic hypertension between north and south China, but, rural residents had a higher prevalence than urban residents. CONCLUSION: There existed a higher prevalence of systolic hypertension in China, to which enough attention should be paid.

[Polymorphisms screening of PON gene cluster].

To identify all putative functional polymorphisms of PON gene cluster in Chinese Han population. Common polymorphisms of PON1, PON2 and PON3 gene were identified by directly sequencing of genomic DNAs derived from 48 randomly selected patients with coronary heart disease. We designed PCR arrays to amplify regions up to about 1kb upstream from transcription-initiation sites, i.e., putative promoter regions, all exons and adjacent non-coding regions. In a total length of 13.9 kb explored, we identified thirty-one SNPs, of which, 17 were first reported. A new coding polymorphism was detected in PON1 gene, which gives rise to amino acid substitutions of arginine (R) for glycine (G) at codon 160, whereas L54M polymorphism, which is common in white population, was not detected in our Han population. Among the five polymorphisms identified in PON3 gene, one in the promoter regions at position -133 (C/A) was located in a potential binding site for transcription factor LF-A1. Allele frequencies of some polymorphisms are significantly different from those reported in Caucasian populations. Complete or nearly complete association between polymorphisms was frequently observed. The identified multiple putative functional polymorphisms in PON gene cluster and their linkage disequilibrium patterns in combination with the population specific frequencies are of values for futher association studies of PON gene cluster with cardiovascular disease.

[The association of single nucleotide polymorphism of slow delayed rectifier K+ channel genes with atrial fibrillation in Han nationality Chinese].

OBJECTIVE: To investigate the association between atrial fibrillation and the single nucleotide polymorphism (SNP) of slow delayed rectifier K(+) channel (I(Ks)) genes in Han nationality Chinese. METHODS: Three hundred and eighty of Han nationality Chinese (142 atrial fibrillation, 120 in-hospital and 118 out-hospital control) were enrolled in this study. Asian specific non-synonymous SNPs of KCNQ1 P448R, KCNQ1 R519H, KCNQ1 G643S, KCNE1 G38S and KCNE1 D85N were genotyped by restriction fragment length polymorphism analysis. A newly cloned KCNE4 gene was also screened for any possible SNP. RESULTS: The minor allele frequency of KCNQ1 P448R, KCNQ1 R519H, KCNQ1 G643S, KCNE1 G38S and KCNE1 D85N in out-hospital subjects was 0.079, 0, 0.042, 0.317 and 0.004, respectively. None of these SNPs was relationed with any atrial fibrillation phenotype. A KCNE4 E145D was discovered and proven statistically to relation significantly to atrial fibrillation by logistic regression analysis (OR = 1.66, P = 0.044). The minor allele frequency of KCNE4 E145D was as high as 0.271 in out-hospital subjects. CONCLUSIONS: None of the SNPs of KCNQ1 P448R, KCNQ1 R519H, KCNQ1 G643S, KCNE1 G38S and KCNE1 D85N was associated with atrial fibrillation phenotype, but KCNE4 E145D may relation to atrial fibrillation. The effect of KCNE4 E145D variation on the function of I(Ks) channel is to be determined.

[Two approaches of quantitative-trait linkage analysis].

ln this article, we discussed two model-free methods for detecting genetic linkage for quantitative traits, Haseman-Elston regression approach and variance components approach. The former is a regression approach for detecting linkage based on the squared difference or squared sums in quantitative trait values of sib-pairs and their estimated marker IBD scores. The latter can jointly model covariate effects along with variance components, including genetic component and non-genetic sources of variability. We have outlined the model assumption, the algorithm and the extensions for the both methods.

[Prevalence, awareness, treatment and control of hypertension in Chinese adults].

OBJECTIVE: To identify the prevalence, distribution, current status of awareness and control of hypertension in Chinese adult population. METHODS: A cross-sectional survey was conducted in mainland of China in 2000 - 2001 as a part of work coordinated with InterASIA Program. A total of 15,838 nationally representative subjects aged 35 to 74 were selected with multistage cluster sampling. Measurement of blood pressure was taken for all of them with three readings in a mercuric-column sphygmomanometer after resting for five minutes. Standard structured questionnaire was used to collect their histories and treatment and prevention for hypertension. A case of hypertension was defined as any person with systolic blood pressure equal to or greater than 140 mmHg, or with diastolic blood pressure equal to or greater than 90 mmHg, or being administered with antihypertensive agents. RESULTS: A total of 15,838 adults aged 35 - 74 years were included in this survey. Overall, the prevalence of hypertension was 27.2%, representing 130 million persons with hypertension nationwide as estimated. Age-specific prevalence of hypertension was 10.7%, 26.8%, 38.9% and 50.2% for women and 17.4%, 28.2%, 40.7% and 47.3% for men aged 35 - 44, 45 - 54, 55 - 64 and 65 - 74 years, respectively. Among hypertensive patients, 44.7% were aware of their high blood pressure, 28.2% were taking antihypertensive medication, and 8.1% achieved their blood pressure under control (< 140/90 mm Hg). All these data indicated that percentages of awareness, treatment and control of hypertension increased by 86.2%, 92.6% and 145.4%, respectively in the past ten years, as compared with the data in 1991. CONCLUSIONS: In the past ten years, percentages of awareness, treatment and control of hypertension in Chinese adults increased significantly, who had a relatively high prevalence of hypertension, but lower awareness and much lower percentages of treatment and control of hypertension. It is urgently needed to improve prevention, detection and treatment for hypertension in adults.