Naomi Tago

Genetic analysis of 22 candidate genes for hypertension in the Japanese population

Objective We performed association studies between 118 single-nucleotide polymorphisms (SNPs) of 22 candidate genes (or gene family) and hypertension in a Japanese population. Design and participants The study population consisted of 1880 subjects representing the general population in Japan, recruited from the Suita study. The candidate genes were selected based on their functions, including insulin resistance (APM1, CD36, HSD11B1), oxidative stress (CYBA, GPX1, GSTMs), steroid hormone (ESR1, ESR2, HSD11B2), renal functions (PTGS2, KLK1, NPHS1, NPHS2, SGK, SLC12A1, PTGES), and others related to cardiovascular physiology (GJA4, NOS1, NTRK3, P2RX4, SPP1, ALDH2). Results Multiple logistic analyses, with age and body mass index as covariates, indicated that 13 SNPs (eight genes), six SNPs (four genes) and 11 SNPs (four genes) were associated with hypertension (P < 0.05) in the total, male, and female populations, respectively. PTGS2 seems to be a promising candidate gene for hypertension in men. GSTM3 and SLC12A1 seem to be promising candidate genes for hypertension in women. Especially, a polymorphism in SLC12A1 was significantly associated with hypertension in women even after correction by the Bonferroni method (corrected P = 0.0236). Multiple logistic analyses, with age and body mass index as covariates, indicated that the prevalence of hypertension in females was significantly higher in subjects with the CC genotype than in those with the TT + TC genotypes (P < 0.0001, odds ratio = 1.967, 95% confidence interval = 1.430–2.712). Conclusion Although the present results should be replicated in other study populations for confirmation, the present results suggest that SLC12A1 may contribute to hypertension in Japanese women.

Klk1 as One of the Genes Contributing to Hypertension in Dahl Salt-Sensitive Rat

A genome-wide quantitative trait loci analysis for blood pressure was performed using 107 male F2 rats derived from Dahl salt-sensitive and Lewis rats. Blood pressure was assessed by telemetry, and >400 microsatellite markers were used for genotyping. Two major quantitative trait loci for blood pressure were identified at chromosome 1 and chromosome 10. The expression levels of 366 transcripts around the chromosome 1 quantitative trait loci were assessed by RT-PCR, and we found that the Klk1 (kallikrein 1) and Ngfg (nerve growth factor gamma) mRNA levels were significantly reduced in the kidneys of Dahl salt-sensitive rats compared with those in Lewis rats. The expression levels of kallikrein 1 protein were also suppressed in Dahl salt-sensitive rats compared with those in Lewis rats. Because the kallikrein–kinin system has been shown to be involved in renal function, including salt homeostasis, it is likely that the reduced expression of Klk1 contributes to salt-sensitive hypertension in Dahl salt-sensitive rats.

A promoter variant of the ATP-binding cassette transporter A1 gene alters the HDL cholesterol level in the general Japanese population

AbstractTo investigate the effects of polymorphisms in the ATP-binding cassette transporter A1 (ABCA1) gene on the high-density lipoprotein cholesterol (HDL-C) level and the incidence of myocardial infarction (MI), we performed association studies. Sequence analysis identified 14 polymorphisms in the promoter region of ABCA1. After considering linkage disequilibrium, three polymorphisms in the promoter region and 11 polymorphisms from the JSNP database were determined in 1,880 subjects recruited from the Suita Study, representing the general population in Japan. We evaluated the association between the ABCA1 genotype and HDL-C level adjusted not only for standard factors, but also for genetic factors including ApoA1 and ApoE genotypes. Of the 14 polymorphisms tested, the G(−273)C (P=0.0074), C(−297)T (P=0.0195), and IMS-JST071749 (P=0.0093) polymorphisms were significantly associated with the HDL-C level in the Suita population. We could reconfirm that the G(−273)C genotype was influential in another set of subjects (P=0.0310, n=743). However, the distribution of the ABCA1 G(−273)C genotype in subjects with MI (n=598) was not different from that in the control population (n=801). These results indicate that ABCA1 G(−273)C has a significant effect on the HDL-C level in the general Japanese population, but not on the incidence of MI.