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.     

Extensive genetic analysis of 10 candidate genes for hypertension in Japanese

The identification of genes that contribute to essential hypertension has been hampered because of a lack of statistical power and problems with multiple testing. In the present study, we performed association analyses between the 161 single nucleotide polymorphisms of 10 candidate genes and hypertension in a Japanese population recruited from the Suita Study (n=3654). We found that 5 polymorphisms in the 3 genes (SLC9A2, UMOD, and ELN) were associated with hypertension status, and 4 of these 5 polymorphisms were also associated with blood pressure values with a classical criterion of P<0.05. However, when a Bonferroni correction for multiple testing was applied, none of the polymorphisms were associated with blood pressure levels. We also performed association analyses between these 5 polymorphisms and intermediate phenotypes corresponding with the functions of candidate genes, including the renin/aldosterone profile, plasma uric acid levels, and pulse wave velocity. The ELN 3'-untranslated region (-/A) polymorphism was found to significantly affect pulse wave velocity, an indicator of arterial stiffness. Associations of the ELN 3'-untranslated region (-/A) polymorphism with hypertension and pulse wave velocity were reconfirmed in another set of the study population. Thus, ELN seems to contribute to blood pressure regulation by affecting arterial stiffness in Japanese.     

Positional identification of hypertension susceptibility genes on chromosome 2

Chromosome 2 has been consistently identified as a genomic region with genetic linkage evidence suggesting that one or more loci contributes to blood pressure and hypertension status. As with all complex disease traits, following-up linkage evidence to identify the underlying susceptibility gene(s) is an arduous yet biologically and clinically important task. Using combined positional candidate gene methods, the Family Blood Pressure Program (FBPP) has concentrated efforts in narrowing a large region of chromosome 2, demonstrating evidence for linkage in several populations, and identifying underlying candidate hypertension susceptibility gene(s). Initial informatics efforts identified the boundaries of the region and the known genes within it. A total of 82 polymorphic sites in 8 genes were genotyped in a large hypothesis-generating sample consisting of 1640 African Americans, 1339 whites, and 1616 Mexican Americans. After resampling-based false discovery adjustment, SLC4A5, a sodium bicarbonate transporter, was identified as a primary candidate gene for hypertension. Polymorphisms in SLC4A5 were subsequently genotyped and analyzed for validation in two other subcomponents of the FBPP, each contributing African Americans (N=461; N=778) and whites (N=550; N=967). Again, single nucleotide polymorphisms within this gene were significantly associated with blood pressure levels and hypertension status. Although not identifying a single causal gene variant that is significantly associated with blood pressure levels and hypertension status across all samples, the results further implicate SLC4A5 as a candidate hypertension susceptibility gene. Moreover, the present study validates previous evidence for one or more genes on chromosome 2 that influence hypertension-related phenotypes in the population-at-large.     

Association between renin-angiotensin-aldosterone system-related genes and blood pressure in a Korean population

AIMS. Blood pressure control is influenced by various genetic and environmental factors, and genetic susceptibility is important in the development of essential hypertension. Because the renin-angiotensin-aldosterone system (RAAS) has a key role in vasoconstriction, vasodilation, and sodium and electrolyte balance, it is central in blood pressure control and so is an appropriate target in hypertension treatments. The present study assessed the association of RAAS-related genes with blood pressure and hypertension in a Korean population. Single nucleotide polymorphisms (SNPs, n = 114) in nine RAAS-related genes (AGT, REN, ACE, ACE2, AGTR1, CYP11B2, NR3C2, MAS1, and CMA1) were assessed for their correlation with blood pressure and hypertension using genotype data of 8842 individuals from the Korea Association Resource subject pool. MAJOR FINDINGS. Linear regression analysis revealed a statistically significant association with blood pressure of 10 SNPs in six genes (ACE, ACE2, CYP11B2, NR3C2, MAS1, and CMA1). An additional hypertension case-control study identified 10 SNPs in NR3C2 and ACE that were linked to hypertension. PRINCIPAL CONCLUSION. Three SNPs (rs11737660, rs6810951, and rs10519963) in NR3C2 correlate with both blood pressure and hypertension. Genetic polymorphisms in RAAS-related genes appear to be associated with hypertension in a Korean population.     

Epidemiological evidence of an association between SLC6A2 gene polymorphism and hypertension.

Selective blockade of the norepinephrine transporter with reboxetine has been reported to induce a slight but significant increase in blood pressure. This study was designed to examine the relation of genetic variants of the norepinephrine transporter gene (solute carrier family 6, member 2; SLC6A2) with hypertension in a Japanese population. We genotyped five genetic variants of SLC6A2, three in the promoter region and two in the intronic sequence, in 1,950 subjects recruited from the Suita study. One of the variants, an A > G polymorphism in the promoter region (Promoter 3 polymorphism), was found to be associated with hypertension. Multiple logistic analysis indicated that sex (p = 0.0223), age (p < 0.0001), body mass index (p < 0.0001), alcohol consumption (p = 0.0002), and the Promoter 3 genotype (AA = 1, AG + GG = 2) (p = 0.0090) were predictive of hypertensive status. The odds ratio of the AG + GG genotypes for hypertension was 1.35 (95% confidence interval: 1.08-1.69) over the AA genotype. SLC6A2 may be one of the genes that contribute to hypertension in Japanese. To our knowledge, this is the first report to detect associations between SLC6A2 genetic variants and blood pressure.     

Hypertension susceptibility genes on chromosome 2p24-p25 in a general Japanese population

BACKGROUND: Genome-wide scans from Italy and China suggest a hypertension-susceptible locus between D2S2278 (nucleotides 11,245,080 - 11,245,358) and D2S168 (nucleotides 11,467,214 - 11,467,422) on chromosome 2. METHODS: We performed a large association study of polymorphisms in this region with blood pressure modulation in a Japanese general population. Forty-seven polymorphisms in 14 genes between nucleotide 8,845,292 and nucleotide 11,946,689, which contains D2S2278 and D2S168, were genotyped in 1880 individuals, 796 of whom were hypertensive and 1084 normotensive. RESULTS: Multivariate logistic regression analysis with adjustment for age, body mass index, presence of hyperlipidemia, diabetes mellitus, and current smoking and drinking revealed that one single nucleotide polymorphism (SNP), IMS-JST126186, in HPCAL1 (hippocalcin-like 1) in women and two SNPs, IMS-JST149391 and IMS-JST149390, in GREB1 (gene regulated by estrogen in breast cancer 1) in men were significantly associated with both prevalence of hypertension and blood pressure levels. To examine the role of GREB1 in more detail, we identified 38 additional genetic variations in GREB1 by direct sequencing, and eight polymorphisms were genotyped. One SNP, 45718A>G, was significantly associated with hypertension and blood pressure level in men, and this SNP was in linkage disequilibrium with a SNP present at the 3' splice site of intron 11. CONCLUSION: Our study suggests that GREB1 and HPCAL1 are candidate hypertension-susceptibility genes in the Japanese general population and supports previous studies that also identified hypertension-related loci in this narrow region.     

Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project

Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10(-11)). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10(-4)). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10(-18)). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10(-7)) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension.     

Regional association-based fine-mapping for sodium-lithium countertransport on chromosome 10

BACKGROUND: Increased erythrocyte sodium-lithium countertransport (SLC) has been observed in patients with essential hypertension. Consistent evidence of genetic linkage was shown for SLC on chromosome 10, and a region of interest was localized between 26 and 56 Mb. METHODS: This study surveyed single nucleotide polymorphisms (SNPs) in 54 genes that reside in the region of interest, and investigated their association with SLC and blood pressure. These SNPs were genotyped in 1,133 non-Hispanic white individuals from 255 pedigrees comprising the second phase of the Rochester Family Heart Study. The variance-components-based genetics software package SOLAR was used for evaluating whether an SNP contributed to a significant fraction of the trait heritability. RESULTS: Of the 77 SNPs surveyed in this study across the region of interest, four SNPs were associated with SLC (P < 0.04), five SNPs were associated with blood pressure (P < 0.04), and two SNPs in mannose-binding lectin 2 (MBL2) were associated with both phenotypes. In general, the pairwise linkage disequilibrium among the genotyped SNPs was low. CONCLUSIONS: This fine-mapping survey of genetic variation in a linkage region of interest provides overall support for association-mapping for SLC on chromosome 10. Genes significantly associated with systolic blood pressure and/or SLC in these families will be prioritized for future studies.     

SNP-by-fitness and SNP-by-BMI interactions from seven candidate genes and incident hypertension after 20 years of follow-up: the CARDIA Fitness Study

The association of single nucleotide polymorphisms (SNPs) from seven candidate genes, including genotype-by-baseline fitness and genotype-by-baseline body mass index (BMI) interactions, with incident hypertension over 20 years was investigated in 2663 participants (1301 blacks, 1362 whites) of the Coronary Artery Risk Development in Young Adults Study (CARDIA). Baseline cardiorespiratory fitness was determined from duration of a modified Balke treadmill test. A total of 98 SNPs in blacks and 89 SNPs in whites from seven candidate genes were genotyped. Participants that became hypertensive (295 blacks and 146 whites) had significantly higher blood pressure and BMI (both races), and lower fitness (blacks only) at baseline than those who remained normotensive. Markers at the peroxisome proliferative activated receptor gamma coactivator 1α (PPARGC1A) and bradykinin β2 receptor (BDKRB2) genes were nominally associated with greater risk of hypertension, although one marker each at the BDKRB2 and endothelial nitric oxide synthase-3 (NOS3) genes were nominally associated with lower risk. The association of baseline fitness with risk of hypertension was nominally modified by genotype at markers within the angiotensin converting enzyme, angiotensinogen, BDKRB2 and NOS3 genes in blacks and the BDKRB2, endothelin-1 and PPARGC1A genes in whites. BDKRB2 rs4900318 showed nominal interactions with baseline fitness on the risk of hypertension in both races. The association of baseline BMI with risk of hypertension was nominally modified by GNB3 rs2301339 genotype in whites. None of the above associations were statistically significant after correcting for multiple testing. We found that SNPs in these candidate genes did not modify the association between baseline fitness or BMI and risk of hypertension in CARDIA participants.     

The combined impact of 12 common variants on hypertension in Japanese men, considering GWAS results

Genome-wide association studies have identified several polymorphisms that appear to be on hypertension-susceptible regions. We performed the current replication study in order to evaluate the association of these loci with hypertension in healthy Japanese males and then examined the combined effect of 12 independent variants. Overall, 735 Japanese men from two independent cohorts were recruited. Association with hypertension was assessed in 16 polymorphisms on 12 genes and 12 were chosen to evaluate the combined impact. Polymorphisms on the COMT, ATP2B1, CYP11A1 and the CSK genes were confirmed to be associated with hypertension and blood pressure (BP). Current findings also replicated previous results for the CYP11B2 and PTGIS genes. Although there were no significant associations found for other variants, our results suggested there was a combined impact for 12 loci. Individuals carrying more risk alleles had a higher risk of hypertension (P for the slope=0.002). Blood pressures also increased in conjunction with an increasing risk allele score (P for trend=7.84 × 10(-6) and 1.85 × 10(-5) for SBP and DBP, respectively). Our results confirmed the associations between hypertension or blood pressure and four gene variants. We also found a significant combined effect of the 12 gene loci.     

The thiazide-sensitive Na(+)-Cl(-) cotransporter gene, C1784T, and adrenergic receptor-beta3 gene, T727C, may be gene polymorphisms susceptible to the antihypertensive effect of thiazide diuretics.

The response of blood pressure to thiazide diuretics (TZDs) differs among individuals. The prediction of the antihypertensive effect of TZDs is important for realizing individualized therapy in the management of hypertension. The aim of this study was to identify the single nucleotide polymorphisms (SNPs) susceptible to the antihypertensive effect of TZDs, particularly focusing on genes related to water-electrolyte absorption in the kidney. Seventy-six outpatients (mean age, 65.4+/-9.0 years) with essential hypertension (EHT) taking TZDs were retrospectively assessed. We defined as responders (R) those whose mean blood pressure was lowered by more than 5 mmHg after the use of TZDs. Forty-eight SNPs in 17 genes (ADD1, GNB3, TSC [SLC12A3], MLR [NR3C2], NCX1 [SLC8A1], WNK1, WNK4, AGT, ACE, AT1 [AGTR1], CYP11B2, ADRB1, ADRB2, ADRB3, ADRA1A, ADRA1B, ADRA2A) were genotyped in the 76 patients. The SNPs in TSC, MLR, NCX1, WNK1, and WNK4 were identified by direct sequencing and those with minor frequencies of greater than 5% were genotyped in this study. The comparison of polymorphism prevalence between R and non-responders (NR) showed significant differences in TSC C1784T (C allele vs. T allele, odds ratio (OR)=3.81, p =0.016, confidence interval (CI): 1.25-11.63) and ADRB3 T727C (Trp64Arg) (T allele vs. C allele, OR=4.59, p =0.005, CI: 1.54-13.68). The blood pressure (BP) in patients homozygous for the major alleles of both TSC C1784T and ADRB3 T727C were significantly reduced by TZD treatment; however, the BP in those homozygous for the minor allele and heterozygous (TSC C1784T: TT+CT; ADRB3 T727C: CC+CT) for both SNPs were not significantly changed after TZD treatment. Both newly detected TSC C1784T and ADRB3 T727C are gene polymorphisms susceptible to the antihypertensive effect of TZDs in patients with EHT. Thus, the prediction of BP reduction by TZDs may be possible by evaluating these two SNPs.     

Association of angiotensin II type 2 receptor gene variant with hypertension.

The renin-angiotensin system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. Angiotensin II, the major biologically active component of this system, exerts its effect via two pharmacologically distinct subtypes of angiotensin II receptors, the angiotensin II type 1 receptor (AT1-R) and the angiotensin II type 2 receptor (AT2-R). Thus, the AT2-R gene may be involved in hypertension. Accordingly, our objective was to examine whether polymorphisms of the AT2-R gene are involved in hypertension. The entire AT2-R gene including the promoter region was screened to find polymorphisms. As a result, two novel single nucleotide polymorphisms (SNPs), A1818T in intron 2 and G4303A in exon 3, as well as two known SNPs, A1675G in intron 1 and C4599A in exon 3, were identified. These four SNPs had similar allele frequencies, and the A1675G and C4599A polymorphisms were in almost complete linkage disequilibrium. Because the AT2-R gene is located on the X chromosome, we analyzed the possible association between the C4599A polymorphism and hypertension in men and in women separately in two large Japanese populations. This analysis showed that the C4599A polymorphism was associated with hypertension in women (p=0.0058), but not in men. Moreover, this female-specific association was pronounced in premenopausal women. The female-specific association may be helpful in conducting further molecular and biological studies on the relationship among sex, the renin-angiotensin system, and hypertension.     

Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals

We previously conducted genome-wide association meta-analysis of systolic blood pressure, diastolic blood pressure, and hypertension in 29,136 people from 6 cohort studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Here we examine associations of these traits with 30 gene regions encoding known antihypertensive drug targets. We find nominal evidence of association of ADRB1, ADRB2, AGT, CACNA1A, CACNA1C, and SLC12A3 polymorphisms with 1 or more BP traits in the Cohorts for Heart and Aging Research in Genomic Epidemiology genome-wide association meta-analysis. We attempted replication of the top meta-analysis single nucleotide polymorphisms for these genes in the Global BPgen Consortium (n=34,433) and the Women's Genome Health Study (n=23,019) and found significant results for rs1801253 in ADRB1 (Arg389Gly), with the Gly allele associated with a lower mean systolic blood pressure (β: 0.57 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=4.7×10(-10)), diastolic blood pressure (β: 0.36 mm Hg; SE: 0.06 mm Hg; meta-analysis: P=9.5×10(-10)), and prevalence of hypertension (β: 0.06 mm Hg; SE: 0.02 mm Hg; meta-analysis: P=3.3×10(-4)). Variation in AGT (rs2004776) was associated with systolic blood pressure (β: 0.42 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=3.8×10(-6)), as well as diastolic blood pressure (P=5.0×10(-8)) and hypertension (P=3.7×10(-7)). A polymorphism in ACE (rs4305) showed modest replication of association with increased hypertension (β: 0.06 mm Hg; SE: 0.01 mm Hg; meta-analysis: P=3.0×10(-5)). Two loci, ADRB1 and AGT, contain single nucleotide polymorphisms that reached a genome-wide significance threshold in meta-analysis for the first time. Our findings suggest that these genes warrant further studies of their genetic effects on blood pressure, including pharmacogenetic interactions.     

Polymorphisms in four genes related to triglyceride and HDL-cholesterol levels in the general Japanese population in 2000

We studied the association of six common polymorphisms of four genes related to lipid metabolism with serum lipid levels. We selected single-nucleotide polymorphisms (SNPs) in the genes for cholesteryl ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic lipase (LIPC), and apolipoprotein CIII (APOC3), and studied 2267 individuals randomly selected from the participants of Serum Lipid Survey 2000. There was a significant association of CETP polymorphism (D442G, Int14 +1 G --> A, and TaqIB), LPL polymorphism (S447X), and LIPC polymorphism (-514 --> CT) with HDL-cholesterol levels. We also found a significant association of LPL polymorphism (S447X) and APOC3 polymorphism (SstI) with triglyceride levels. This is the largest database showing the association of common genetic variants in lipid metabolism with serum lipid levels in the general Japanese population. Further study is necessary to elucidate the role of these gene polymorphisms in cardiovascular events.     

Identification of hypertension-susceptibility genes and pathways by a systemic multiple candidate gene approach: the millennium genome project for hypertension.

A multiple candidate-gene approach was used to investigate not only candidate genes, but also candidate pathways involved in the regulation of blood pressure. We evaluated 307 single nucleotide polymorphisms (SNPs) in 307 genes and performed an association study between 758 cases and 726 controls. Genes were selected from among those encoding components of signal transduction pathways, including receptors, soluble carrier proteins, binding proteins, channels, enzymes, and G-proteins, that are potentially related to blood pressure regulation. In total, 38 SNPs were positively (p<0.05) associated with hypertension. Replication of the findings and possible polygenic interaction was evaluated in five G-protein-related positive genes (GNI2, GNA14, RGS2, RGS19, RGS20) in a large cohort population (total n=9,700, 3,305 hypertensives and 3,827 normotensive controls). In RGS20 and GNA14, dominant models for the minor allele were significantly associated with hypertension. Multiple dimension reduction (MDR) analysis revealed the presence of gene-gene interaction between GNA14 and RGS20. The MDR-proved combination of two genotypes showed a significant association with hypertension (chi2=9.93, p=0.0016) with an odds ratio of the high-risk genotype of 1.168 (95% confidence interval [CI] [1.061-1.287]). After correction for all possible confounding parameters, the MDR-proved high-risk genotype was still a risk for hypertension (p=0.0052). Furthermore, the high-risk genotype was associated with a significantly higher systolic blood pressure (133.08+/-19.46 vs. 132.25+/-19.19 mmHg, p=0.04) and diastolic blood pressure (79.65+/-11.49 vs. 79.01+/-11.32 mmHg, p=0.019) in the total population. In conclusion, a systemic multiple candidate gene approach can be used to identify not only hypertension-susceptibility genes but also hypertension-susceptibility pathways in which related genes may synergistically collaborate through gene-gene interactions to predispose to hypertension.     

溶质载体家族22A4和5基因多态性与中国汉族人群克罗恩病的关联分析

目的 探讨中国汉族人群中溶质载体家族22A4(SLC22A4)和SLC22A5基因单核苷酸多态性(SNP)与克罗恩病(CD)的相关性.方法 采用直接测序方法测定80例汉族CD患者和80名健康对照者的SLC22A4和SLC22A5基因所有外显子区序列,检测其SNP位点,并进行统计学分析.结果 ①C1672T位点和G-207C位点在汉族人群中不存在多态性.发现SLC22A4和SLC22A5基因全编码区分别有2个和3个SNP.②病例一对照关联分析显示,SLC22A4和SLC22A5基因的SNP在基因型和等位基因型频率方面,CD患者和对照者间差异无统计学意义(P>0.05).结论 在中国汉族人群中,SLC22A4和SLC22A5基因多态性和CD易感性无相关性.     

Prediction of genetic risk for hypertension

Although genetic epidemiological studies have suggested that several genetic variants increase the risk for hypertension, the genes that underlie genetic susceptibility to this condition remain to be identified definitively. Large-scale association studies that examine many gene polymorphisms simultaneously are required to predict genetic risk for hypertension. The population of the present study comprised 1940 unrelated Japanese individuals, including 1067 subjects with hypertension (574 men, 493 women) and 873 controls (533 men, 340 women). The genotypes for 33 single nucleotide polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that 2 polymorphisms (825C-->T in the G protein beta3 subunit gene and 190G-->A in the CC chemokine receptor 2 gene) were significantly associated with hypertension in men and that one polymorphism (-238G-->A in the tumor necrosis factor alpha gene) was significantly associated with hypertension in women. These results suggest that 2 and 1 genes may be susceptibility loci for hypertension in Japanese men and women, respectively, and that genotyping of these polymorphisms may prove informative for prediction of the genetic risk for hypertension.     

Association between the calcitonin-related peptide alpha (CALCA) gene and essential hypertension in Japanese subjects

BACKGROUND: Calcitonin-related peptide alpha (CALCA) is a neuropeptide that is a very potent vasodilator. It has been reported that CALCA knockout mice have a significantly elevated systolic blood pressure (BP). The aims of this study were to discover novel polymorphisms or mutations in the 5' flanking region of the human CALCA gene in Japanese subjects and to assess the association between this gene and essential hypertension (EH). METHODS: Japanese patients with EH (50.1 +/- 6.6 years old, n = 274) and age-matched Japanese subjects without EH (51.1 +/- 6.6 years old, n = 225) were recruited. The 5' flanking region of the human CALCA gene was searched to identify novel polymorphisms in the 20 EH patients using polymerase chain reaction (PCR) and a direct sequencing method. These novel polymorphisms, as well as the known single nucleotide polymorphisms (SNPs), were used for genotyping. RESULTS: We discovered a novel 2-bp microdeletion polymorphism in intron 1. The only three participants with 2-bp microdeletion polymorphism were found in the EH group. None of the subjects without EH had a 2-bp microdeletion polymorphism. The genotype and allele distribution of the 4 SNPs were not significantly different between the groups. All five polymorphisms were located in one haplotype block. The haplotype was constructed using, in order, rs1553005, 2-bp microdeletion polymorphism, and rs5241. There was a significant association between EH and the C-AGins-A haplotype (P = .00031). CONCLUSIONS: A novel 2-bp microdeletion polymorphism was discovered in the CALCA gene. Based on the results of the haplotype-based case control study, the CALCA gene could be the susceptibility gene for EH.     

Hunting for genes for hypertension: the Millennium Genome Project for Hypertension

The Millennium Genome Project for Hypertension was started in 2000 to identify genetic variants conferring susceptibility to hypertension, with the aim of furthering the understanding of the pathogenesis of this condition and realizing genome-based personalized medical care. Two different approaches were launched, genome-wide association analysis using single-nucleotide polymorphisms (SNPs) and microsatellite markers, and systematic candidate gene analysis, under the hypothesis that common variants have an important role in the etiology of common diseases. These multilateral approaches identified ATP2B1 as a gene responsible for hypertension in not only Japanese but also Caucasians. The high blood pressure susceptibility conferred by certain alleles of ATP2B1 has been widely replicated in various populations. Ex vivo mRNA expression analysis in umbilical artery smooth muscle cells indicated that reduced expression of this gene associated with the risk allele may be an underlying mechanism relating the ATP2B1 variant to hypertension. However, the effect size of a SNP was too small to clarify the entire picture of the genetic basis of hypertension. Further, dense genome analysis with accurate phenotype data may be required.     

Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis

In a recent genome-wide association study, variants in 8 genes were associated with VWF level, a risk factor for venous thrombosis (VT). In an independent, population-based, case-control study of incident VT, we tested hypotheses that variants in these genes would be associated with risk. Cases were 656 women who experienced an incident VT, and controls comprised 710 women without a history of VT. DNA was obtained from whole blood. Logistic regression was used to test associations between incident VT and single nucleotide polymorphisms (SNPs) in 7 genes not previously shown to be associated with VT. Associations with P < .05 were candidates for replication in an independent case-control study of VT in both sexes. Two of the 7 SNPs tested yielded P < .05: rs1039084 (P = .005) in STXBP5, a novel candidate gene for VT, and rs1063856 (P = .04) in VWF, a gene whose protein level is associated with VT risk. Association results for the remaining 5 variants in SCARA5, STAB2, STX2, TC2N, and CLEC4M were not significant. Both STXBP5 and VWF findings were replicated successfully. Variation in genes associated with VWF levels in the genome-wide association study was found to be independently associated with incident VT.