Induced pluripotent stem cells derived renal tubular cells from a patient with pseudohypoparathyroidism and its response to parathyroid hormone stimulation.

INTRODUCTION: Creating induced pluripotent stem cells (iPSCs) from somatic cells of patients with genetic diseases offers a pathway to generate disease-specific iPSCs carrying genetic markers. Differentiating these iPSCs into renal tubular cells can aid in understanding the pathophysiology of rare inherited renal tubular diseases through cellular experiments. MATERIALS AND METHODS: Two Japanese patients with Pseudohypoparathyroidism (PHP), a 49-year-old woman and a 71-year-old man, were studied. iPSC-derived tubular cells were established from their peripheral blood mononuclear cells (PBMCs). We examined changes in intracellular and extracellular cyclic adenosine monophosphate (cAMP) levels in these cells in response to parathyroid hormone (PTH) stimulation. RESULTS: Renal tubular cells, differentiated from iPSCs of a healthy control (648A1), showed a PTH-dependent increase in both intracellular and extracellular cAMP levels. However, the renal tubular cells derived from the PHP patients' iPSCs showed inconsistent changes in cAMP levels upon PTH exposure. CONCLUSION: We successfully created disease-specific iPSCs from PHP patients' PBMCs, differentiated them into tubular cells, and replicated the distinctive response of the disease to PTH in vitro. This approach could enhance our understanding of the pathophysiology of inherited renal tubular diseases and contribute to developing effective treatments.

Lipoprotein Lipase Deficiency Arising in Type V Dyslipidemia.

A 40-year-old Japanese man presented with child-onset hypertriglyceridemia recently complicated by diabetes mellitus. The patient's diabetes mellitus was maintained, but he had persistent insulin resistance. The patient also had persistent severe hypertriglyceridemia (1,224-4,104 mg/dL), despite the administration of bezafibrate and ezetimibe. Type V dyslipidemia was revealed by agarose gel electrophoresis and the refrigerator test, and a significantly reduced post-heparin lipoprotein lipase mass of 26 ng/mL was confirmed. Genetic testing confirmed two heterozygous LPL variants, p.Tyr88X and p.Gly215Glu in trans; thus, the patient was diagnosed with lipoprotein lipase deficiency. Lipoprotein lipase deficiency typically arises in type I dyslipidemia, but is latent in type V dyslipidemia.

Adiponectin is not associated with renal function decline in community-dwelling elderly adults.

Adiponectin secreted by adipocytes plays an important role in the regulation of glucose and fatty acid metabolism. Contrary to findings in patients with chronic kidney disease (CKD), no prospective data about the association of serum adiponectin with renal function decline in the general population have yet appeared. Our objective was to analyze the relationship of total and high molecular weight (HMW) adiponectin with renal function decline as measured by cystatin C in community-dwelling elderly adults without moderate or severe CKD.In a prospective observational analysis, a total of 216 healthy elderly volunteers with eGFRcys ≥60 mL/min/1.73 m underwent anthropometric and laboratory tests at baseline and at follow-up visits. A subgroup with serum samples collected 5 years apart was further analyzed.There were no differences in either total or HMW adiponectin level between subjects subsequently undergoing rapid renal function decline and subjects with normal physiologic renal function decline (P = .71, P = .81). On univariate linear regression, neither total nor HMW adiponectin were associated with annual renal function decline (ß = -0.23; P = .71, ß = -0.057; P = .90). Multivariate analysis did not show a significant contribution of either total or HMW adiponectin to annual renal function decline (ß = -0.50; P = .46, ß = 0.01; P = .98). In the logistic regression analysis, we did not observe any statistically significant association of serum adiponectin levels with rapid renal function decline or incidence of CKD.Contrary to findings in populations with CKD, neither total nor HMW adiponectin had a substantial association with renal function decline in an elderly population with eGFRcys ≥60 mL/min/1.73 m. Our results and conclusions should not be extrapolated to subjects with other characteristics.

A case of apolipoprotein A-I deficiency due to carboxyl-terminal truncation.

Apolipoprotein A-I deficiency is a rare metabolic disease characterized by an impaired reverse cholesterol transport system resulting in excessive cholesterol accumulation. Here, we discuss a case of apolipoprotein A-I deficiency caused by a carboxyl-terminal truncation mutation p.His186ProfsX46 in APOA1, which might result in increased catabolism of the mutant protein.

Marked alteration of glycemic profile surrounding lanreotide administration in acromegaly: A case report.

Whether somatostatin analogs for acromegaly improve or worsen a patient's glycemic profile is controversial. A risk of hypoglycemia should be presumed, especially when patients receive insulin therapy, as the package inserts caution. However, a detailed clinical course of such a case has never been reported in research articles. An 80-year-old Japanese female diabetes patient treated with insulin therapy was diagnosed with acromegaly, and the somatostatin analog, lanreotide, was given. On day 4 of lanreotide treatment, repeated hypoglycemia as a result of exogenous insulin arose and the patient required inpatient care. After lanreotide treatment, the total daily insulin dose could be reduced, but her fasting C-peptide level decreased from 1.6 to 0.4 ng/mL, implying improved insulin resistance and impaired endogenous insulin secretion. In the present case, marked alteration surrounding lanreotide administration was observed; careful co-administration with insulin therapy is required, as the package insert cautions.

High-molecular-weight adiponectin levels in healthy, community-dwelling, elderly Japanese volunteers: a 5-year prospective observational study.

BACKGROUND: Serum adiponectin levels are associated with frailty and cardiovascular diseases. Longitudinal changes in adiponectin levels might enhance our understanding of age-related conditions and diseases. AIMS: This prospective observational study aimed to: (1) elucidate age-related changes in high-molecular-weight (HMW) adiponectin levels; and (2) identify variables predictive of elevated HMW adiponectin levels and the association with well-known adiponectin single-nucleotide polymorphisms (SNPs) in healthy, elderly Japanese participants. METHODS: Healthy elderly volunteers (n = 196; 55 men and 141 women; median age 72.0 years; range 69.0-75.0 years) underwent anthropometric and physical function measurements, as well as laboratory tests at baseline and the 5-year follow-up. RESULTS: HMW adiponectin levels were significantly higher in women than in men (8.4, 5.3-11.9 vs. 5.7, 3.1-9.0 µg/mL; p < 0.001) at baseline and decreased significantly at follow-up in women (7.7, 4.8-11.2 µg/mL; p < 0.001), but not in men. In the multiple regression analysis, high-density lipoprotein cholesterol levels and body weight were independent predictors of HMW adiponectin levels. The rate of change in HMW adiponectin levels was inversely correlated with the rates of change in body weight, body mass index, and knee leg extension strengths, and positively correlated with rates of change in high-density lipoprotein cholesterol and one-leg standing time. There were no significant differences in HMW adiponectin levels among SNPs. DISCUSSION: Decreasing HMW adiponectin levels might lead to an increased risk of cardiovascular diseases in elderly women. CONCLUSION: HMW adiponectin levels significantly decreased over a 5-year period in community-dwelling elderly Japanese women.

Plasma adrenocorticotropic hormone but not aldosterone is correlated with blood pressure in patients with aldosterone-producing adenomas.

Although plasma aldosterone concentration (PAC) varies depending on primary aldosteronism (PA) subtypes, patients with different subtypes may have similar blood pressure (BP). The authors hypothesized that hormones other than aldosterone might influence BP in PA patients. A total of 73 PA cases, including 30 cases of aldosterone-producing adenomas (APAs), 29 cases of bilateral hyperaldosteronism, and 24 control cases of essential hypertension were enrolled retrospectively. The authors examined the levels of aldosterone, cortisol, renin, and adrenocorticotropic hormone (ACTH) measured at 12 am, 6 am, 12 pm, and 6 pm and BP in the early morning (6 am to 7 am), late morning (9 am to 11 am), and early evening (5 pm to 7 pm). Results showed no statistically significant correlation between PAC and BP in the patients with PA; however, early and late morning systolic BP strongly correlated with ACTH at 6 am in patients with APA. These results suggest that hormones other than aldosterone, such as ACTH, may affect BP in patients with APA.

Scoring system for the diagnosis of bilateral primary aldosteronism in the outpatient setting before adrenal venous sampling.

OBJECTIVE: The only reliable method for subtyping primary aldosteronism (PA) is adrenal venous sampling (AVS), which is costly and time-consuming. Considering the limited availability of AVS, it would be helpful to obtain information on the diagnosis of bilateral hyperaldosteronism (BHA) from routine tests. We aimed to establish new, simple criteria for outpatients to diagnose BHA from PA before AVS. DESIGN: We retrospectively analysed 82 patients who were diagnosed with PA and underwent AVS. Thirty-seven patients were diagnosed with unilateral hyperaldosteronism (UHA), and 36 with BHA and nine were undetermined. Among the variables that were significantly different between UHA and BHA in the univariate analysis, we chose three variables to be included in multivariate logistic regression models and constructed a subtype prediction score. RESULTS: The subtype prediction score was calculated as follows: 3 points for no adrenal nodules on computed tomography imaging, 2 for serum potassium of ≥3·5 mmol/l and 2 for aldosterone-to-renin ratio of <490 after a captopril challenge test. Receiver operating characteristic curve analysis for the ability to discriminate BHA from UHA showed that a score of 7 points had 50% sensitivity and 100% specificity and a score of 5 points had 67% sensitivity and 94% specificity (area under the curve: 0·922; 95% CI: 0·863-0·980). CONCLUSIONS: Our new, simple criteria specifically distinguished BHA from UHA in the outpatient setting before AVS. Furthermore, not only endocrinologists but also general internists can use this convenient, safe scoring system.

Subtype prediction in primary aldosteronism: measurement of circadian variation of adrenocortical hormones and 24-h urinary aldosterone.

OBJECTIVE: Currently, adrenal venous sampling (AVS) is the only reliable method to distinguish unilateral from bilateral hyperaldosteronism in primary aldosteronism (PA). However, AVS is costly and time-consuming compared with simple blood tests. In this study, we conducted a retrospective study to determine whether circadian variation in plasma adrenocortical hormone levels (i.e. aldosterone, cortisol and ACTH) and a 24-h urinary aldosterone could contribute to the clinical differentiation between unilateral hyperaldosteronism (UHA) and bilateral hyperaldosteronism (BHA). DESIGN: In 64 patients who were diagnosed with PA and underwent AVS, 32 and 22 patients were diagnosed with UHA and BHA, respectively. Plasma adrenocortical hormone levels at 0:00, 6:00, 12:00 and 18:00 and 24-h urinary aldosterone under a condition of 6 g daily dietary sodium chloride intake were measured. RESULTS: Baseline plasma aldosterone concentration (PAC) and 24-h urinary aldosterone level in patients with UHA were significantly higher than in patients with BHA, particularly at 6:00. The area under the ROC curve for PAC at 0:00, 6:00, 12:00 and 18:00 and 24-h urinary aldosterone to discriminate UHA and BHA was 0·839 [95% confidence interval (CI); 0·73-0·95], 0·922 (95% CI; 0·85-1·00), 0·875 (95% CI; 0·78-0·97), 0·811 (95% CI; 0·69-0·93), 0·898 (95% CI; 0·81-0·99), respectively. CONCLUSIONS: PAC at different blood sampling times and 24-h urinary aldosterone level may be diagnostically helpful in discriminating between UHA and BHA. We believe that these tests could reduce the number of unnecessary AVS procedures.

Unusual Manifestation of Graves' Disease: Ventricular Fibrillation.

BACKGROUND: It is well known that thyrotoxicosis causes rhythm disorders including sinus tachycardia, atrial fibrillation, and atrial flutter. Atrial fibrillation is the most common arrhythmia in thyrotoxicosis, occurring in 5-15% of patients over 60 years of age, whereas ventricular arrhythmia is an unusual manifestation. CASE REPORT: An 18-year-old Japanese woman was admitted to our emergency department because of loss of consciousness caused by ventricular fibrillation. She had been diagnosed with Graves' disease only 5 days earlier and had no other past medical history. Blood examination showed no obvious abnormality except thyrotoxicosis, and coronary angiography revealed patent coronary arteries. She was diagnosed with thyroid storm due to Graves' disease and is currently healthy during outpatient follow-up. CONCLUSION: This case highlights that thyrotoxicosis can, albeit extremely rarely, cause ventricular fibrillation even in the absence of hypokalemia or underlying cardiovascular disease.

A novel gene regulator, pyrrole-imidazole polyamide targeting ABCA1 gene increases cholesterol efflux from macrophages and plasma HDL concentration.

UNLABELLED: Pyrrole-imidazole (PI) polyamides are nuclease-resistant novel compounds that inhibit transcription factors by binding to the minor groove of DNA. A PI polyamide that targets mouse ABCA1 and increases ABCA1 gene expression was designed and evaluated as an agent to increase plasma HDL concentration. A PI polyamide was designed to bind the activator protein-2 binding site of the mouse ABCA1 promoter. The effect of this PI polyamide on ABCA1 expression was evaluated by real-time RT-PCR and Western blotting using RAW264 cells. In vivo effects of this polyamide on ABCA1 gene expression and plasma HDL level were examined in C57B6 mice. One milligram per kilogram of body weight of PI polyamide was injected via the tail veins every 2 days for 1 week, and plasma lipid profiles were evaluated. PI polyamide showed a specific binding to the target DNA in gel mobility shift assay. Treatment of RAW264 cells with 1.0 µM PI polyamide significantly increased ABCA1 mRNA expression. PI polyamide also significantly increased apolipoprotein AI-mediated HDL biogenesis in RAW264 cells. Cellular cholesterol efflux mediated by apolipoprotein AI was significantly increased by the PI polyamide treatment. PI polyamide significantly increased expression of ABCA1 mRNA in the liver of C57B6 mice. Plasma HDL concentration was increased by PI polyamide administration. All of the HDL sub-fractions showed a tendency to increase after PI polyamide administration. The designed PI polyamide that targeted ABCA1 successfully increased ABCA1 expression and HDL biogenesis. This novel gene-regulating agent is promising as a useful compound to increase plasma HDL concentration. KEY MESSAGES: A novel pyrrole-imidazole (PI) polyamide binds to ABCA1. PI polyamide interfered with binding of AP-2ɑ protein to the ABCA1 gene promoter. PI polyamide inhibited the AP-2ɑ-mediated reduction of ABCA1 gene and protein expression. PI polyamide increased ABCA1 protein and apolipoprotein AI mediated HDL biogenesis. PI polyamide is a new gene regulator for the prevention of atherosclerotic diseases.

The insulin-like growth factor-1 gene is associated with cerebral infarction in Japanese subjects.

Atherosclerosis leads to cerebral infarction (CI) and the insulin/insulin-like growth factor-1 (IGF1) signaling pathway plays an important role in this process during adult life. The purpose of this study was to investigate the relationship between the human IGF1 gene and CI in the Japanese population via a case-control study that also included a separate analysis of the two gender groups. A total of 155 CI patients and 316 controls were genotyped for six single nucleotide polymorphisms (SNPs) of the human IGF1 gene (rs2162679, rs7956547, rs2288378, rs2072592, rs978458 and rs6218). All data were analyzed for three separate groups: the total subjects, men and women. The logistic regression analysis revealed that the GG + AG variant of rs2162679 (P = 0.047), the AA + GA variant of rs2072592 (P = 0.005) and the CC + TC variant of rs6218 (P = 0.015) exhibited a protective effect for CI in the total subject group. For the women and the total subjects groups, the overall distribution of the haplotype established by rs7956547-rs978458 was significantly different between the CI patients and the non-CI subjects. For the total subjects, the frequency of the T-G haplotype (rs7956547-rs978458) was also significantly higher (P = 0.034), whereas the frequency of the T-A haplotype (rs7956547-rs978458) was significantly lower (P = 0.008) in the CI patients versus the non-CI subjects. For women, the frequency of the T-A haplotype (rs7956547-rs978458) was significantly lower (P = 0.021) in the CI patients as compared with the non-CI subjects. The specific SNPs and haplotypes can be utilized as genetic markers for CI resistance or CI risk.

Association of the insulin-like growth factor1 gene with myocardial infarction in Japanese subjects.

During adult life, the insulin/insulin-like growth factor1 (IGF1) signaling pathway plays an important role in cardiovascular function. Several reports have suggested that low baseline levels of IGF1 increase the risk of fatal ischemic heart disease. Thus, IGF1 may be involved in cardiovascular disease. The aim of the present study was to investigate the relationship between the human IGF1 gene and myocardial infarction (MI) in the Japanese population via the use of single nucleotide polymorphisms (SNPs). After selecting six SNPs in the human IGF1 gene (rs2162679, rs7956547, rs2288378, rs2072592, rs978458 and rs6218), we performed a case-control study using each of the SNPs and haplotypes in 320 MI patients and 307 non-MI controls. Multiple logistic regression analysis demonstrated that the GG+GA variant of rs2162679 (p=0.009) and the AA+GA variant of rs2072592 (p=0.026) exhibited a resistant effect for MI. The haplotype-based case-control study revealed that the frequency of the A-T-G-G haplotype for rs2162679-rs7956547-rs2072592-rs978458 was significantly higher in the MI group (47.3%) as compared to the non-MI group (41.4%) (p=0.037, odds ratio=1.270). The frequency of the A-T-G-T haplotype for rs2162679-rs7956547-rs978458-rs6218 was also significantly higher in the MI group (47.3%) as compared to the non-MI group (41.3%) (p=0.033, odds ratio=1.276). The current results suggest that specific SNPs and haplotypes can be utilized as genetic markers for MI risk or MI resistance. In addition, IGF1 or a neighboring gene might be associated with increased or decreased susceptibility to MI.

Association of SLC6A9 gene variants with human essential hypertension.

AIM: We previously identified a quantitative trait locus (QTL) on rat chromosome 5 that appeared to be primarily controlled by the sympathetic nervous system. Because sympathetic overactivity is related to hypertension, solute carrier family 6, member 9 (SLC6A9) is a candidate gene for the connection of this QTL with blood pressure regulation. In the present study, we therefore explored the role of SLC6A9 genetic variations in human essential hypertension (EH). METHODS: We evaluated three single nucleotide polymorphisms (SNPs) (rs2286245, rs3791124 and rs2486001) in 758 essential hypertension patients and 726 controls. Polymorphism-related genotypes were determined with TaqMan assays. RESULTS: The allelic frequency of rs2286245 (C versus T, p=0.032) showed significant differences between EH and normotensive controls (NT) groups. The genotypic distribution of rs3791124 in its dominant model (AA+GA versus GG, p=0.027) also showed significant differences between EH and NT groups. The genotype and allele distributions of rs2486001 did not exhibit any significant differences. CONCLUSION: We found an association between SLC6A9 gene polymorphisms and essential hypertension in a Japanese population, suggesting that SLC6A9 is a susceptibility locus for essential hypertension.

Human uncoupling protein 2 and 3 genes are associated with obesity in Japanese.

Human uncoupling proteins (UCPs) are mitochondrial proteins that are involved in the control of energy metabolism and the pathophysiology of obesity. Although there have been several reports on the association between the UCP2/UCP3 locus and the obesity, there have been no haplotype-based case-control studies with gender-specific analysis. The aim of this study was to examine whether there is an association between the UCP2/UCP3 locus and the obesity in the Japanese population when using a single nucleotide polymorphism (SNP)-based and haplotype-based case-control study with gender-specific analysis. We examined a group consisting of 551 subjects, of which 369 were non-obese and 182 were overweight and/or obese. We selected one nonsynonymous SNP (rs660339: Ala55Val) as a genetic marker. Genotyping for all subjects was performed by the TaqMan polymerase chain reaction (PCR) method. Although the overall distributions of genotype and allele were not significantly different between the non-obese and the obese groups, the overall distributions of the genotype were significantly different in men (P = 0.030). In the obese group, male subjects with the Val allele were significantly more frequent in both association studies. There was a significant difference in the overall distribution of the haplotype (UCP3 rs180049, UCP3 rs2075577, UCP2 rs660339) between the weight groups (P = 0.010), and in women, there was a significant difference (P = 0.042) in the overall distribution of the haplotype (UCP3 rs2075577, UCP2 rs660339). Nonsynonymous rs660339 in the human UCP2 gene in men, and the haplotype (UCP3 rs2075577-UCP2 rs660339) in women might be good obesity markers.

Case-control study of the role of the Gitelman's syndrome gene in essential hypertension.

BACKGROUND: Gitelman's syndrome is an inherited tubular disorder characterized by sodium wasting, low blood pressure, secondary hyperaldosteronism, metabolic alkalosis, hypokalemia, hypomagnesemia of renal origin, and hypocalciuria. The majority of patients with this syndrome carry inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive Na (+)-Cl (-) cotransporter (NCC) located in the distal convoluted tubule, which is involved in renal sodium reabsorption. This suggests that the SLC12A3 gene is involved in mediation of blood pressure levels. The aim of the present study was to investigate relationships between single nucleotide polymorphisms (SNPs) in the human SLC12A3 gene and essential hypertension (EH) in Japanese. METHOD: We selected 3 SNPs in the human SLC12A3 gene (T180K, A569V, L849H), and performed a case-control study of 315 EH patients and 305 normotensive (NT) individuals. RESULTS: There was no significant difference in overall distribution of genotypes or alleles of any of the SNPs between the EH and NT groups. CONCLUSION: We conclude that the causal gene of Gitelman's syndrome is not involved in determining blood pressure levels.

Two novel genotypes of the thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene in patients with Gitelman's syndrome.

Gitelman's syndrome is an autosomal recessive disorder marked by salt wasting and hypokalaemia resulting from loss-of-function mutations in the SLC12A3 gene that codes for the thiazide-sensitive Na-Cl cotransporter. Gitelman's syndrome is usually distinguished from Bartter's syndrome by the presence of both hypomagnesaemia and hypocalciuria. Although recent advances in molecular genetics may make it possible to both diagnose and differentiate these diseases, the phenotypes sometimes overlap. Here we report two sporadic cases of Gitelman's syndrome and two novel genotypes of SLC12A3. Patient 1 was a compound heterozygote with a known missense mutation, L849H, and a novel mutation, R852H in exon 22. Patient 2 was homozygous for the missense mutation L849H. To our knowledge, this is the first report of a patient homozygous for 849H. Interestingly, both patients were affected with autoimmune thyroid disease. Patient 1 was affected with Hashimoto's disease, and Patient 2 was affected with Graves' disease. The symptoms of Patient 2 were more serious than those of Patient 1. Although the patients both carried the 849H allele (Patient 1 as a heterozygote and Patient 2 as a homozygous), their clinical symptoms differed. The difference in the clinical features may have been due both to phenotypic differences and the fact that Gitelman's syndrome is a complicated disorder.

Association between prostaglandin E2 receptor gene and essential hypertension.

BACKGROUND: Essential hypertension (EH) is a complex multifactorial polygenic disorder that is thought to result from an interaction between an individual's genetic makeup and various environmental factors. In the kidney, prostaglandins (PGs) are important mediators of vascular tone and salt and water homeostasis, and are involved in the mediation and/or modulation of hormonal action. In previous studies, mice deficient in the prostaglandin E2 (PGE(2)) EP2 receptor had resting systolic blood pressure (BP) that was significantly lower than that of wild-type controls. The BP of those mice increased when they were put on a high-salt diet, suggesting that the EP2 receptor is involved in sodium handling by the kidney. In the present study, we investigated the association between EH and nucleotide polymorphisms in the gene encoding the prostaglandin E2 receptor subtype EP2 (PTGER2). METHODS: We selected three single-nucleotide polymorphisms (SNP) in the human PTGER2 gene (rs1254601, rs2075797, and rs17197), and we performed a genetic association study of 266 EH patients and 253 age-matched normotensive (NT) controls. RESULTS: There was no significant difference in overall distribution of genotypes or alleles of any of the SNP between the EH and NT groups. However, among men, the A/A type of the SNP rs17197 (rs17197, A/G in 3'UTR) was significantly more frequent in EH subjects than in NT subjects (P=0.041). CONCLUSION: The present findings suggest that rs17197 is useful as a genetic marker of EH in men.

An association study in essential hypertension using functional polymorphisms in lymphotoxin-alpha gene.

BACKGROUND: Lymphotoxin-alpha (LTA), a member of the tumor necrosis factor family, is a cytokine produced by lymphocytes. The substance LTA mediates a wide variety of inflammatory, immunostimulatory, and antiviral responses. In 2002, LTA was identified as a major risk factor for myocardial infarction (MI) in Japanese individuals, in a large-scale case-control study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers in the whole human genome. Essential hypertension (EH) is thought to be a multifactorial disorder involved in endothelial dysfunction and atherosclerosis. Although hypertension is one of the greatest risk factors for MI, there have been no reports estimating the association between EH and LTA. The aim of the present study was to evaluate the association between EH and the LTA gene. METHODS: In the present study, we assessed the association between EH and SNP and haplotypes of the LTA gene in a case-control study of 202 EH patients and 217 age-matched normotensive control subjects. RESULTS: The overall distribution of genotypes for each SNP did not significantly differ between the two groups. Furthermore, the haplotype analysis revealed no association between the EH and normotensive groups. CONCLUSIONS: Polymorphisms of the LTA gene were not associated with EH. This finding suggests differences in genetic backgrounds between EH and MI.