Akira Haketa

Two medium-chain acyl-coenzyme A synthetase genes, SAH and MACS1, are associated with plasma high-density lipoprotein cholesterol levels, but they are not associated with essential hypertension.

Background and objectives SAH has been proposed as a candidate gene for essential hypertension (EH) because elevated expression of SAH was observed in the kidneys of spontaneously hypertensive rats. Recently, a homology search of SAH in the human genome revealed the presence of the SAH gene family, which includes SAH, MACS1, MACS2, and MACS3. SAH and MACS1 are located within a 150-kb region on human chromosome 16p13.11. SAH and MACS1 are thought to function as acyl-coenzyme A synthetases, which are involved in fatty acid metabolism. In the present study, we analyzed six single nucleotide polymorphisms (SNPs) in the SAH and MACS1 genes in a Japanese population, and examined whether these SNPs contribute to EH and multiple risk factors. Methods and results We performed association studies of six SNPs in 287 EH patients and 259 normotensive subjects. Multiple logistic linear regression analysis revealed that the allele frequencies of these six SNPs in SAH and MACS1 genes were not significantly different between EH patients and normotensives. SNP in exon 8 of the A/G polymorphism of the MACS1 gene and the G/T SNP in intron 3 of the SAH gene were associated with plasma levels of plasma high-density lipoprotein cholesterol. Conclusions SNPs in the MACS1 and SAH genes contribute to plasma levels of high-density lipoprotein cholesterol.

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 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 between SIRT2 gene polymorphism and height in healthy, elderly Japanese subjects

T he silent information regulator factor 2 (SIR2; a nicotinamide adenine dinucleotide–dependent histone deacetylase) protein is related to life span extension in a diverse range of species. In mammals there are 7 sirtuins, all possessing a highly conserved central nicotinamide adenine dinucleotide–binding site and common catalytic domain. Sirtuin 2 (SIRT2) is the mammalian ortholog of the yeast HST2, one of the four SIR2 paralogs. Similar to SIR2, HST2 is upregulated by caloric restriction and oxidative stress and extends life span. SITR2 acts as an important regulator of cell differentiation through modulation of forkhead transcription factor 1 acetylation/phosphorylation. Forkhead transcription factor 1 is a homolog of daf-16, a key regulator of the insulin-like growth factor 1 signaling pathway, and is necessary for increasing life span. An association between chronic obstructive pulmonary disease and SIRT2 single nucleotide polymorphisms (SNPs) has been reported, but an association of the SIRT2 gene with longevity and other phenotypes has not been reported. We focused on the biological pleiotropic roles of SIRT2 and investigated their association with various laboratory and anthropometric data in elderly Japanese subjects.

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

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).

Scoring System for the Diagnosis of Bilateral Primary Aldosteronism in the Outpatient Setting before Adrenal Venous Sampling

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.

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.

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.

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 patients 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.

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

Whether somatostatin analogs for acromegaly improve or worsen a patients 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.