Papers by Tomohiro Katsuya
Clinical and Experimental Hypertension, 2014
Background: An electronic system for salt intake assessment using a 24-h dietary recall method ha... more Background: An electronic system for salt intake assessment using a 24-h dietary recall method has been developed in Japan. We evaluated the validity of this salt intake system for assessing salt intake. Methods: We prospectively obtained data on estimated salt intake using 24-hour urinary sodium excretion (24-hUNaCl) and salt intake by the salt intake assessment system from 203 consecutive outpatients with essential hypertension (age: 67.8 AE 10.7 years; 53.7% men). Results: Mean values were 9.7 AE 2.9 g/day for 24-hUNaCl and 9.1 AE 2.9 g/day for the salt intake assessment system before corrections. The salt intake estimated by the present system was significantly correlated with 24-hUNaCl (r ¼ 0.66, p50.0001). After corrections for habitual use of discretionary seasonings, habitual intake of salty foods, and physical activity, correlation coefficients between salt intake and 24-hUNaCl increased from 0.60 to 0.66 in men 565 years, from 0.80 to 0.81 in men !65 years, from 0.64 to 0.75 in women 565 years, and from 0.52 to 0.59 in women !65 years. After further correction for regional differences in average salt intake, the correlation coefficient reached 0.72 in all patients. Conclusion: After correction for dietary habits, lifestyle factors, and differences in average salt intake by region, this system may be a useful tool in Japan to encourage salt restriction in the clinical treatment of hypertension and improve public health in terms of salt restriction overall.
Circulation, 1997
Background The availability of selective antagonists for angiotensin II receptors has focused int... more Background The availability of selective antagonists for angiotensin II receptors has focused interest on the gene expression of angiotensin II–receptor subtypes in the human heart. Methods and Results We analyzed expression of the AT 1 and AT 2 subtypes of the angiotensin II receptor in ventricular myocardium taken from 9 donor hearts before implantation and from 12 patients with heart failure (6 with dilated cardiomyopathy and 6 with ischemic heart disease). Competitive reverse transcription–polymerase chain reaction with synthetic RNA internal standards was used to detect mRNA for both subtypes and to quantify relative differences in levels between failing and nonfailing ventricular myocardium. AT 1 - and AT 2 -receptor mRNA could be detected in all samples. AT 1 -receptor gene expression was 2.5-fold greater in nonfailing hearts than in patients with failing hearts ( P =.015). There was no significant difference in AT 2 -receptor mRNA expression in failing and nonfailing hearts. Conclusions The level of expression of the angiotensin AT 1 receptor appears to decrease in the failing human ventricle whereas the level of AT 2 expression is unaffected. These changes parallel the changes found in human ventricular myocardium at the receptor level, suggesting that the changes in receptor level may result from changes in gene expression or mRNA stability.
Circulation
AAntihypertensive therapy is a powerful approach to prevent the cardiovascular disease. However, ... more AAntihypertensive therapy is a powerful approach to prevent the cardiovascular disease. However, the responsiveness of the therapy is highly individual due to the variability of genetic or environmental factors. To elucidate the genetic background underlying antihypertensive drug responsiveness, we carried out a genome-wide association study (GWAS). The subjects studied were recruited from the participants of HOMED-BP study (UMIN Registered ID C000000137, http://www.cpt.med.tohoku.ac.jp/HOMED-BP/) after obtaining the informed consent for the genetic analysis. After DNA extraction from peripheral blood, about half million single nucleotide polymorphisms (SNPs) were examined using GeneChip Genome-Wide Human SNP5.0 Array (Affymetrix). Home blood pressure (HBP) was measured every day within 1 hour after wake-up and before going to bed using HEM747-IC-N (Omron). The study protocol was approved by the ethical committee of Osaka University. SNP5.0 Array analysis was demonstrated for 300 pa...
Stroke: Journal of the American Heart Association, 2003
Background and Purpose— The association of the methylenetetrahydrofolate reductase gene (MTHFR) w... more Background and Purpose— The association of the methylenetetrahydrofolate reductase gene (MTHFR) with carotid atherosclerosis remains inconsistent. This may be due to small sample size and inappropriate analysis. We investigated the association of C677T/MTHFR with blood pressure and carotid atherosclerosis in a Japanese general population. Methods— Subjects (30 to 89 years of age; 1693 women, 1554 men) who gave informed consent were randomly selected from a general population in Suita, Japan. MTHFR genotypes were determined by TaqMan polymerase chain reaction. Carotid atherosclerosis was evaluated by high-resolution ultrasonography with atherosclerotic indexes of intimal-medial thickness (IMT), maximum IMT in the common carotid artery (CCA), plaque score, and stenosis (>50%). Results— Age-adjusted diastolic blood pressure was significantly higher in women with the TT genotype than in those with the CC genotype. In a recessive model (CC +CT versus TT), all adjusted odds ratios for ...
Nippon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics
Nature Communications
Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic l... more Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.
PloS one, 2018
Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which ... more Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously repo...
American journal of human genetics, Mar 13, 2018
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk fact... more Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 ...
PloS one, 2017
The contemporary Japanese populations largely consist of three genetically distinct groups-Hondo,... more The contemporary Japanese populations largely consist of three genetically distinct groups-Hondo, Ryukyu and Ainu. By principal-component analysis, while the three groups can be clearly separated, the Hondo people, comprising 99% of the Japanese, form one almost indistinguishable cluster. To understand fine-scale genetic structure, we applied powerful haplotype-based statistical methods to genome-wide single nucleotide polymorphism data from 1600 Japanese individuals, sampled from eight distinct regions in Japan. We then combined the Japanese data with 26 other Asian populations data to analyze the shared ancestry and genetic differentiation. We found that the Japanese could be separated into nine genetic clusters in our dataset, showing a marked concordance with geography; and that major components of ancestry profile of Japanese were from the Korean and Han Chinese clusters. We also detected and dated admixture in the Japanese. While genetic differentiation between Ryukyu and Hond...
Clinical and experimental hypertension (New York, N.Y. : 1993), Jan 23, 2017
White coat effect (WCE), the blood pressure (BP) difference between clinical and non-clinical set... more White coat effect (WCE), the blood pressure (BP) difference between clinical and non-clinical settings, can lead to clinical problems such as misdiagnosis of hypertension. Etiology of WCE has been still unclear, especially from genetic aspects. The present article investigated association between genome-wide single nucleotide polymorphisms (SNPs) and WCE in patients with essential hypertension. The present cross-sectional analyses were based on 295 Japanese essential hypertensive outpatients aged ≧40 years enrolled in randomized control study, Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) study, who were not taking antihypertensive medications before the randomization. Home and clinic BP were measured. WCE was defined by subtracting home BP from clinic BP. Genotyping was conducted with 500K DNA microarray chips. Association between genome-wide SNPs and WCE were analyzed. For replication (p < 10(-4)), we analyzed participa...
American Journal of Hypertension
defined as PDH. All patients had their pulse pressure pattern confirmed by ambulatory blood press... more defined as PDH. All patients had their pulse pressure pattern confirmed by ambulatory blood pressure monitoring (ABPM). The II, ID and DD genotype variants of ACE were characterized by the triple primer nested-PCR method. Results were compared to 36 normotensive controls individuals. Statistical significance was assessed by Chi square method. Hypertensive patients (31 males, mean age: 41Ϯ8,3; BMI: 25,2Ϯ 3,4) had IIϭ10 (20%), IDϭ17 (35%), DDϭ22 (45%), while normotensive controls (11 males; mean age: 59Ϯ9; BMI: 25,1Ϯ2,1) IIϭ14(39%), IDϭ12(33%), DDϭ10(28%). DD vs. ID vs. II (pϽ0,05). ACE allele frequencies in PDH patients and controls were Dϭ0,625, Iϭ0,375 and Dϭ0,55, Iϭ0,45, respectively (PϽ0,01). These results are the first to show an association between the DD ACE polymorphism and predominantly diastolic hypertension.
American Journal of Hypertension
The association between angiotensin-converting enzyme (ACE)-gene polymorphism and insulin resista... more The association between angiotensin-converting enzyme (ACE)-gene polymorphism and insulin resistance (IR) in hypertensives remains controversial.Thus, we evaluated the possible association between IR and ACE-gene polymorphism in a group of hypertensive never treated patients in comparison with normotensive control group. We enrolled 200 (114M/86F; age ϭ 45.5Ϯ4.7 years) hypertensive patients compared with 96 (54M/42F; age ϭ 44.0Ϯ4.7 years) normotensive subjects. Using a double PCR assay identified ACE genotypes. We determined fasting glucose and insulin by using the glucose oxidase method and standard radioimmunoassay technique. IR was estimated by using the homeostasis model assessment (HOMAIR). Both fasting glucose (5.0Ϯ0.3 mmol/L vs 4.7Ϯ0.3 mmol/L; pϽ0.0001), insulin levels (12.3Ϯ4.7 mcU/mL vs 4.9Ϯ1.5 U/mL; pϽ0.0001), and HOMAIR (2.7Ϯ1.1 vs 1.1Ϯ0.3; pϽ0.0001) were significantly higher in hypertensive patients than in normotensive control group. When we subdivided hypertensive patients according to ACE genotype, we observed: fasting insulin and HOMAIR were 16.3Ϯ3.3 U/mL and 3.6Ϯ0.8 in DD genotype, 9.4Ϯ3.1 mcU/mL and 2.1Ϯ0.7 in ID, and 8.3Ϯ2.8 mcU/mL and 1.9Ϯ0.7 II group (pϽ0.0001, by ANOVA). No significant differences were observed in the normotensive control group. In conclusion, we extended previous data regarding the relationship of hypertension and IR by demonstrating a dependence of this relationship upon the ACE gene polymorphism.
American Journal of Hypertension
Hypertension is a complex phenotype induced by various environmental and genetic factors. Quantit... more Hypertension is a complex phenotype induced by various environmental and genetic factors. Quantitative trait locus (QTL) analysis is a powerful method for identifying genomic regions containing genetic polymorphisms underlying complex diseases, such as hypertension. We previously identified overlapping hypertension QTL on mouse Chr 1 in separate crosses between C57BL6/J and A/J mice and between C3H/HeJ and SWR/J mice. We utilized haplotype analysis to identify regions of the QTL where the strains carrying high blood pressure allele (C57BL6/J and SWR/J) shared a common allele that differed from the strains carrying low blood pressure allele (A/J and C3H/HeJ). We found a 1.9 Mb region fitting these criteria that contained the gene encoding PODO-CIN (Nphs2), which is important in glomerular filtration and podocyte signaling. We found a serine to proline substitution in exon 8 of PODO-CIN in the high allele strains. These strains showed abnormal podocyte foot process structure. This QTL is concordant with hypertension QTL in humans. We found that Nphs2 was significantly associated with hypertension (Pϭ0.002) in humans. Our data suggest that PODOCIN is a conserved disease gene underlying hypertension in both mice and humans.
American Journal of Hypertension
An impaired baroreceptor reflex sensitivity controlling the heart period through the vagus nerves... more An impaired baroreceptor reflex sensitivity controlling the heart period through the vagus nerves (BRS) and sympatho-humoral activation following acute myocardial infarction (AMI) represent adverse prognostic indices. The occurrence of AMI in patients with hypertension (HT-AMI) is not unexpected, and has been associated with a greater mortality than that occurring in normotensive subjects (NT-AMI). This study was planned to determine whether HT-AMI patients have a greater central sympathetic output and BRS impairment than NT-AMI patients. We examined 11 HT-AMI, 10 NT-AMI patients 2-4 days following AMI and 10 normal control (NC). The groups were matched according to age, body mass index (BMI) and gender (Table). The two AMI groups were also matched according to heart rate (HR). Muscle sympathetic nerve activity (MSNA) was measured by microneurography from the peroneal nerve and quantified in terms of bursts per 100 cardiac beats (b/100b). BRS was obtained from the Valsalva maneuver as the steepest slope between the RR interval (ms) and systolic pressure (mmHg). Data were expressed as mean Ϯ SEM and summarised in the table below. Mean arterial pressure (MBP) was insignificantly lower in NT-AMI and the HR was higher in NC than NT-AMI (PϽ0.05; ANOVA posttests). MSNA hyperactivity relative to NC was greater in HT-AMI than in NT-AMI (at least PϽ0.05) whilst BRS impairment (at least PϽ0.01) was insignificantly greater in HT-AMI than NT-AMI. These results in patients following AMI indicate that pre-existent hypertension leads to an excessive level of sympathetic activation and BRS impairment, and may at least partly explain the adverse prognosis seen in hypertensive patients following AMI.
Human molecular genetics, May 21, 2017
Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci ... more Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the...
European journal of human genetics : EJHG, Apr 18, 2017
The Asian Diversity Project (ADP) assembled 37 cosmopolitan and ethnic minority populations in As... more The Asian Diversity Project (ADP) assembled 37 cosmopolitan and ethnic minority populations in Asia that have been densely genotyped across over half a million markers to study patterns of genetic diversity and positive natural selection. We performed population structure analyses of the ADP populations and divided these populations into four major groups based on their genographic information. By applying a highly sensitive algorithm haploPS to locate genomic signatures of positive selection, 140 distinct genomic regions exhibiting evidence of positive selection in at least one population were identified. We examined the extent of signal sharing for regions that were selected in multiple populations and observed that populations clustered in a similar fashion to that of how the ancestry clades were phylogenetically defined. In particular, populations predominantly located in South Asia underwent considerably different adaptation as compared with populations from the other geographi...
Circulation Journal Official Journal of the Japanese Circulation Society, Mar 1, 2006
Circulation, Nov 22, 2011
Journal of Hypertension, Jun 1, 2002
Objective: Angiotensin-converting enzyme (ACE) I/D polymorphism in intron 16 of the ACE gene was ... more Objective: Angiotensin-converting enzyme (ACE) I/D polymorphism in intron 16 of the ACE gene was analyzed in a general Japanese population in relation to self-blood pressure (BP) measurement at home (home BP) and ambulatory BP monitoring (ABPM) to determine the association between genetic variants of this polymorphism and hypertension. Design: A cross-sectional study. Methods and results: We genotyped the ACE I/D polymorphism in 1245 subjects with home BP and 803 subjects with ABPM in Ohasama, a rural community in Japan. All the subjects were 40 years of age and over, and gave written informed consent for the present genetic analysis. Hypertensive subjects were defined as those receiving antihypertensive drugs and those who had a home BP higher than 135 mmHg in systole and/or higher than 85 mmHg in diastole. The frequencies of the II, ID, and DD genotypes in these Japanese subjects were 0.45, 0.45, and 0.10, indicating a lower frequency of the D allele (0.33) than in Caucasians. There was no significant difference of BP level, prevalence of hypertension or nocturnal decline in BP among the genotypes. There were no differences in the prevalence of previous cardiovascular disease, age, body mass index, male gender, smoking, or biochemical and hormonal parameters among the three genotypes. Conclusion: The present results indicate the absence of direct effects of the ACE D-allele on BP level, prevalence of hypertension, prevalence of cardiovascular disease, and circadian BP variation. We conclude there is little association between ACE I/D polymorphism and hypertension in the general Japanese population.
Circulation Journal Official Journal of the Japanese Circulation Society, Mar 31, 2002
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Papers by Tomohiro Katsuya