[Show abstract][Hide abstract] ABSTRACT: The TH (tyrosine hydroxylase) gene encodes the rate-limiting enzyme of catecholamine biosynthesis, and is involved in the pathogenesis of hypertension, but the relationship of its variants with hypertension has not been extensively studied. We designed a case-controlled study consisting of 503 HT (hypertensive) individuals and 490 NT (normotensive) individuals matched by region, age and gender to systematically investigate the association between the TH gene and hypertension. Based on the HapMap and dbSNP (where SNP is single nucleotide polymorphism) data, four SNPs, rs6356 A>G, rs6357 G>A, rs2070762 T>C and rs1800033 A>G in the TH gene were selected for genotyping. Rs1800033 was not polymorphic in our study population. No significant differences were observed for distributions of rs6356 and rs6357 between the HT and NT groups. However, both the genotype and allele frequencies of rs2070762 showed significant differences between cases and controls (P<0.001 and P=0.005 respectively). In haplotype analysis, a total of eight haplotypes were observed in the entire population and the overall frequency distributions differed significantly between the HT and NT groups. Specifically, haplotype A-A-C (rs6356-rs6357-rs2070762) occurred only in the HT group and A-G-C occurred more commonly in HT subjects than in NT subjects (P=0.003 and P=0.013 respectively). Compared with the most common haplotype A-G-T, the adjusted OR (odds ratio) was 1.83 [95% CI (confidence interval), 1.20-2.79; P=0.0049] for haplotype G-G-C and 20 (P<0.0001) for the haplotype A-A-C. Functional analysis showed that the C allele of rs2070762 functioned as an enhancer in the absence of binding by unidentified transcriptional repressor(s). These results provide evidence for an association of the functional intronic rs2070762 with essential hypertension.
[Show abstract][Hide abstract] ABSTRACT: Results are accumulating that ACE2 (angiotensin I-converting enzyme 2) might act as a protective protein for cardiovascular diseases; however, only a few studies in human populations have been carried out. This prompted us to perform a case-control study to investigate the relationship of ACE2 polymorphisms with CHD (coronary heart disease) and MI (myocardial infarction). Three single nucleotide polymorphisms in the ACE2 gene (1075A/G, 8790A/G and 16854G/C) were genotyped by PCR-RFLP (restriction-fragment-length polymorphism) in 811 patients with CHD (of which 508 were patients with MI) and 905 normal controls in a Chinese population. The polymorphisms were in linkage disequilibrium (r(2)=0.854-0.973). Analyses were conducted by gender, because the ACE2 gene is on the X chromosome. In females, an association was detected with MI for 1075A/G (P=0.026; odds ratio=1.98) and 16854G/C (P=0.028; odds ratio=1.97) in recessive models after adjusting for covariates. In male subjects, two haplotypes (AAG and GGC) were common in frequency. In male subjects not consuming alcohol, the haplotype GGC was associated with a 1.76-fold risk of CHD [95% CI (confidence interval), 1.15-2.69; P=0.007] and a 1.77-fold risk of MI (95% CI, 1.12-2.81; P=0.015) with environmental factors adjusted, when compared with the most common haplotype AAG. In conclusion, the results of the present study indicate that common genetic variants in the ACE2 gene might impact on MI in females, and may possibly interact with alcohol consumption to affect the risk of CHD and MI in Chinese males.
[Show abstract][Hide abstract] ABSTRACT: To investigate the association between polymorphisms in the G protein-coupled receptor kinase 4 gene (GRK4) (R65L, A142V and A486V) and essential hypertension in northern Han Chinese, we conducted a case-control study consisting of 503 individuals with essential hypertension (HT) and 490 age-, gender-, and area-matched normotensive (NT) controls. The three GRK4 variants were genotyped by PCR-RFLP analysis. Both haplotype and single locus analysis were used to process the genotyping data. The A486 allele showed a significant association with HT (P < 0.001). A total of 6 haplotypes were observed in the entire population, with the haplotypes L-V-A and R-A-A being found to be significantly related to hypertension (P= 0.001).
Annals of Human Genetics 12/2006; 70(Pt 6):778-83. DOI:10.1111/j.1469-1809.2006.00278.x · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
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.
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.
Chinese medical journal 07/2006; 119(13):1065-71. · 1.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Essential hypertension is considered to be a typical complex disease with multifactorial etiology, which leads to inconsistent findings in genetic studies. One possibility of failure to replicate some single-locus results is that the underlying genetics of hypertension are not only based on multiple genes with minor effects but also on gene-gene interactions. To test this hypothesis, a case-control study was constructed in Chinese subjects, detecting both single locus and multilocus effects. Eleven candidate genes were selected from biochemical pathways that have been implicated in the development and progression of hypertension, and 33 polymorphisms were evaluated in 503 hypertension patients and 490 age- and gender-matched controls. Single-locus associations, using traditional logistic regression analyses, and multilocus associations, using classification and regression trees and multivariate adaptive regression splines, were both explored in this study. Final models were selected using either Bonferroni correction or cross-validation. Three polymorphisms, TH*rs2070762, ADRB2*Q27E, and GRK4*A486V, were found to be independently associated with essential hypertension in Chinese subjects. In addition to these individual predictors, a potential interaction of CYP11B2-AGTR1 is also involved in the etiology of hypertension. These findings support the multigenic nature of the etiology of essential hypertension and propose a potential gene-gene interactive model for future studies.
[Show abstract][Hide abstract] ABSTRACT: We previously reported a significant linkage between human chromosome 8p22 with essential hypertension and systolic blood pressure levels. On the basis of this, we used an efficient age, sex and area-matched case-control scheme to test the association of the polymorphisms in the human alpha1A adrenergic receptor (ADRA1A) gene, located on chromosome 8p21-p11.2, with essential hypertension in a northern Han Chinese population.
Seven polymorphisms were identified by direct sequencing of genomic DNA derived from 48 randomly recruited hypertensive and 48 healthy subjects. They were also examined for association with essential hypertension in 480 stage 2 hypertensive individuals and their individually matched controls.
We observed significantly higher frequencies of the 347Arg allele and 2547G alleles in the cases compared with their controls (P = 0.04 and 0.007, respectively). McNemar's test revealed that carriers of 2547G alleles were at a greater risk of essential hypertension with an odds ratio of 3.00 [95% confidence interval (CI) 1.23-8.35]. We then performed a conditional logistic regression to adjust the effects of conventional risk factors, revealing an odds ratio of 2.84 for carriers of the 2547G allele (95% CI 1.15-6.99). With the haplotypic probabilities estimated using PHASE software, we performed haplotype trend regression analysis, showing a significant association between haplotype 7 and essential hypertension (P = 0.02), after adjustment for conventional risk factors.
Our findings suggest that the genetic variations in the ADRA1A gene are significantly associated with essential hypertension, and may play an important role in the development of essential hypertension in this Chinese population.
Journal of Hypertension 07/2006; 24(6):1049-56. DOI:10.1097/01.hjh.0000226194.21311.2f · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent evidence points to considerable transcription occurring in non-protein-coding regions of eukaryote genomes. However, their lack of conservation and demonstrated function have created controversy over whether these transcripts are functional. Applying a novel cloning strategy, we have cloned 100 novel and 61 known or predicted Caenorhabditis elegans full-length ncRNAs. Studying the genomic environment and transcriptional characteristics have shown that two-thirds of all ncRNAs, including many intronic snoRNAs, are independently transcribed under the control of ncRNA-specific upstream promoter elements. Furthermore, the transcription levels of at least 60% of the ncRNAs vary with developmental stages. We identified two new classes of ncRNAs, stem-bulge RNAs (sbRNAs) and snRNA-like RNAs (snlRNAs), both featuring distinct internal motifs, secondary structures, upstream elements, and high and developmentally variable expression. Most of the novel ncRNAs are conserved in Caenorhabditis briggsae, but only one homolog was found outside the nematodes. Preliminary estimates indicate that the C. elegans transcriptome contains approximately 2700 small non-coding RNAs, potentially acting as regulatory elements in nematode development.
Genome Research 02/2006; 16(1):20-9. DOI:10.1101/gr.4139206 · 14.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Chinese medical journal 01/2006; 118(23):1939-44. · 1.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently a novel C825T polymorphism in the G protein beta3 subunit gene was identified that showed an association with hypertension in a German population; the results of studies in other populations have been inconsistent. To examine the contribution of GNB3 polymorphisms to the development of hypertension in the northern Chinese Han population, we conducted a case-control study consisting of 501 hypertensive cases and 503 controls using the G(-350)A, C825T and C1429T polymorphisms. Genotypes of samples were determined by PCR and restriction digestion. Single locus analysis showed a significant association between G(-350)A and hypertension (P = 0.01) but no association for C825T or C1429T. The three polymorphisms were in tight linkage disequilibrium (D'=-1 for G(-350)A-C825T, D'= 0.92 for C825T-C1429T) and a total of 7 haplotypes were observed in the entire population. Haplotype A-C-C was found to be significantly related to hypertension (P = 0.032) and A-C-C carriers had a more than two-fold higher risk of hypertension than non-carriers, after adjustment for BMI and glucose. In conclusion, our study suggests that G(-350)A is a potential functional polymorphism that may be related to hypertension, whereas the C825T and C1429T polymorphisms are not associated with hypertension in the northern Chinese Han population.
Annals of Human Genetics 08/2005; 69(Pt 4):468-73. DOI:10.1111/j.1529-8817.2005.00172.x · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Hypertension Research 06/2004; 27(6):373-8. DOI:10.1291/hypres.27.373 · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Y-chromosomes from 76 Chinese men covering 33 ethnic minorities throughout China as well as the Han majority were collected as genetic material for the study of Chinese nonrecombinant Y-chromosome (NRY) phylogeny. Of the accepted worldwide NRY haplogroups, three (haplogroups D, C, O) were significant in this sample, extending previous assessments of Chinese genetic diversity. Based on geographic, linguistic, and ethnohistorical information, the 33 Chinese ethnic minorities in our survey were divided into the following four subgroups: North, Tibet, West, and South. Inferred from the distribution of the newly found immediate ancestor lineage haplogroup O*, which has M214 but not M175, we argue that the southern origin scenario of this most common Chinese Y haplogroup is not very likely. We tentatively propose a West/North-origin hypothesis, suggesting that haplogroup O originated in West/North China and mainly evolved in China and thence spread further throughout eastern Eurasia. The nested cladistic analysis revealed in detail a multilayered, multidirectional, and continuous history of ethnic admixture that has shaped the contemporary Chinese population. Our results give some new clues to the evolution and migration of the Chinese population and its subsequence moving about in this land, which are in accordance with the historical records.
Journal of Human Genetics 02/2004; 49(7):339-48. DOI:10.1007/s10038-004-0154-3 · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypertension, among diabetes, obesity and others, is one of the common human dis- eases that is genetically expressed as complex traits to which genetic, environmental, and demo- graphic factors contribute interactively. Identifying the underlying genes and examining their inter- actions, a crucial step in understanding the molecular pathogenesis of complex diseases, is both a statistical and a computational challenge, stressing the need for novel strategies to move this pro- cess forward. In this paper we propose a new method to study the association of multiple gene interactions for complex diseases. Our method is carried out by two steps. First, we sequentially select additionally associated SNP loci combinations by minimizing the p-value of a test based on an information measure, measure of information discrepancy. Therefore, this approach is called MID method. Second, the significance of the selected associated loci combinations is assessed by an c 2 independence-test. The MID method is model-free and nonparametric, it is easy to compute and implement. The capability of the MID method is confirmed by applying it to investigate the multiple gene interactions on risk of hypertension in northern Han Chinese, where thirty-three SNP loci with three-genotype in eleven candidate genes are examined. Some results are consistent with