Buaijiaer Hasimu

Haplotype Analysis of the Human Renin Gene and Essential Hypertension

Abstract—The human renin gene is an attractive candidate for involvement in the underlying cause of essential hypertension (EH). Despite extensive examination, the relation between the renin gene and hypertension remains unclear. The aims of the present study were to discover new genetic markers of EH and to investigate the relations between polymorphisms of the renin gene and EH in the Japanese. Using the polymerase chain reaction–single strand conformation polymorphism (PCR-SSCP) method, we isolated 3 novel variants of the renin gene; a single nucleotide polymorphism (SNP) in intron 4 (T+17int4G), a variable number of tandem repeats (VNTR) polymorphism in intron 7, and a missense mutation in exon 9 (G1051A). We performed an association study with these polymorphisms in 212 patients with EH and 209 age-matched normotensive (NT) subjects. The frequency of genotypes VNTR and T+17int4G did not differ significantly between the 2 groups, whereas the overall distribution of G1051A was significantly different between EH and NT. Haplotype analysis revealed that the overall distribution of haplotypes differed significantly between the EH and NT groups. PRA levels in patients with EH with the G/G genotype were significantly higher than in subjects with EH with G/A and A/A genotypes. These data suggest that the missense mutation in exon 9 may affect the enzymatic function of renin and consequently may be involved in the etiology of hypertension.

Ankle brachial index as a marker of atherosclerosis in Chinese patients with high cardiovascular risk.

To obtain reliable data on the epidemiology, co-morbidities and risk factor profile of peripheral arterial disease (PAD), we evaluated the clinical significance of the ankle brachial index (ABI) as an indicator of PAD in Chinese patients at high cardiovascular (CV) risk. ABI was measured in 5,646 Chinese patients at high CV risk, and PAD was defined as an ABI<0.9 in either leg. Multivariable logistic regression analyses were performed to identify factors associated with PAD. A total of 5,263 patients were analyzed, 52.9% male, mean age 67.3 years, mean body mass index (BMI) 24.2 kg/m2, mean systolic/diastolic blood pressure (SBP/DBP) 139/80.7 mmHg. The prevalence of PAD in the total group of patients was 25.4%, and the prevalence was higher in females than in males (27.1% vs. 23.9%; odds ratio [OR]: 1.64). Patients with PAD were older than those without PAD (72.3±9.9 years vs. 65.6±11.7 years; OR: 1.06), and more frequently had diabetes (43.3% vs. 31.3%; OR: 2.02), coronary heart disease (CHD) (27.0% vs. 18.8%; OR: 1.67), stroke (44.4% vs. 28.3%; OR: 1.78), lipid disorders (57.2% vs. 50.7%; OR: 1.3) and a smoking habit (42.7% vs. 38.6%; OR: 1.52). The ORs for the PAD group compared with the non-PAD group demonstrated that these conditions were inversely related to ABI. Statin, angiotensin-converting enzyme-inhibitors and antiplatelet agents were only used in 40.5%, 53.6% and 69.1% of PAD patients, respectively. The data demonstrated the high prevalence and low treatment of PAD in Chinese patients at high CV risk. A lower ABI was associated with generalized atherosclerosis. Based on these findings, ABI should be a routine measurement in high risk patients. Aggressive medication was required in these patients.

Splicing mutation of the prostacyclin synthase gene in a family associated with hypertension

Prostacyclin inhibits platelet aggregation, smooth muscle cell proliferation, and vasoconstriction. The prostacyclin synthase (PGIS) gene is a candidate gene for cardiovascular disease. The purpose of this study was to locate possible mutations in the PGIS gene related to hypertension and cerebral infarction. Using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method, we discovered a T to C transition at the +2 position of the splicing donor site of intron 9 in patients with essential hypertension (EH). In vitro expression analysis of an allelic minigene consisting of exons 8-10 revealed that the nucleotide transition causes skipping of exon 9. This in turn alters the translational reading frame of exon 10 and introduces a premature stop codon (TGA). A three-dimensional model shows that the splice site mutation produces a truncated protein with a deletion in the heme-binding region. This splice site mutation was found in only one subject in 200 EH patients and 200 healthy controls. Analysis of the patients family members revealed the mutation in two of the three siblings. The urinary excretion of prostacyclin metabolites in subjects with the mutation was significantly decreased. All subjects displaying the splice site mutation in the PGIS gene were hypertensive. In this study, we report a novel splicing mutation in the PGIS gene, which is associated with hypertension in a family. It is thought that this mechanism may involve in the pathophysiology of their hypertension.