A at Single Nucleotide Polymorphism-358 Is Required for G at -420 to Confer the Highest Plasma Resistin in the General Japanese Population

Insulin resistance is a feature of type 2 diabetes. Resistin, secreted from adipocytes, causes insulin resistance in mice. We previously reported that the G/G genotype of single nucleotide polymorphism (SNP) at −420 (rs1862513) in the human resistin gene (RETN) increased susceptibility to type 2 diabetes by enhancing its promoter activity. Plasma resistin was highest in Japanese subjects with G/G genotype, followed by C/G, and C/C. In this study, we cross-sectionally analyzed plasma resistin and SNPs in the RETN region in 2,019 community-dwelling Japanese subjects. Plasma resistin was associated with SNP-638 (rs34861192), SNP-537 (rs34124816), SNP-420, SNP-358 (rs3219175), SNP+299 (rs3745367), and SNP+1263 (rs3745369) (P<10−13 in all cases). SNP-638, SNP -420, SNP-358, and SNP+157 were in the same linkage disequilibrium (LD) block. SNP-358 and SNP-638 were nearly in complete LD (r2 = 0.98), and were tightly correlated with SNP-420 (r2 = 0.50, and 0.51, respectively). The correlation between either SNP-358 (or SNP-638) or SNP-420 and plasma resistin appeared to be strong (risk alleles for high plasma resistin; A at SNP-358, r2 = 0.5224, P = 4.94×10−324; G at SNP-420, r2 = 0.2616, P = 1.71×10−133). In haplotypes determined by SNP-420 and SNP-358, the estimated frequencies for C-G, G-A, and G-G were 0.6700, 0.2005, and 0.1284, respectively, and C-A was rare (0.0011), suggesting that subjects with A at −358, generally had G at −420. This G-A haplotype conferred the highest plasma resistin (8.24 ng/ml difference/allele compared to C-G, P<0.0001). In THP-1 cells, the RETN promoter with the G-A haplotype showed the highest activity. Nuclear proteins specifically recognized one base difference at SNP-358, but not at SNP-638. Therefore, A at -358 is required for G at −420 to confer the highest plasma resistin in the general Japanese population. In Caucasians, the association between SNP-420 and plasma resistin is not strong, and A at −358 may not exist, suggesting that SNP-358 could explain this ethnic difference

Transient Creatine Kinase Elevation Followed by Hypocomplementemia in a Case of Rotavirus Myositis

We report an infant case of rotavirus myositis, a rare complication of rotavirus infection. Complement levels of the patient were normal when serum creatine kinase (CK) level was at its peak and then decreased when the CK level became normalized. In a previous case report of rotavirus myositis, transient decrease of serum albumin, immunoglobulin, and complement levels was reported. The authors speculated that intravascular complement activation was caused by rotavirus and resulted in the pathogenesis of myositis, although complement levels at onset were not measured by the authors. In this report, however, we demonstrate that the complement activation of our patient is a result of, rather than the cause of, skeletal muscle damage

Case Report Transient Creatine Kinase Elevation Followed by Hypocomplementemia in a Case of Rotavirus Myositis

We report an infant case of rotavirus myositis, a rare complication of rotavirus infection. Complement levels of the patient were normal when serum creatine kinase (CK) level was at its peak and then decreased when the CK level became normalized. In a previous case report of rotavirus myositis, transient decrease of serum albumin, immunoglobulin, and complement levels was reported. The authors speculated that intravascular complement activation was caused by rotavirus and resulted in the pathogenesis of myositis, although complement levels at onset were not measured by the authors. In this report, however, we demonstrate that the complement activation of our patient is a result of, rather than the cause of, skeletal muscle damage

Hoarseness as the first symptom in a patient with acute suppurative thyroiditis secondary to a pyriform sinus fistula: a case report

Abstract Background Pyriform sinus fistulas (PSFs) are rare congenital anomalies of the third or fourth brachial pouch. Dyspnea is reportedly secondary to compression by a neck mass. However, hoarseness, as the first symptom of PSF, has not yet been reported. Case presentation This report describes an 11-year-old girl presenting with hoarseness as the first symptom of PSF. Hoarseness occurred 2 days prior to admission. On admission, she had fever, hoarseness, and an elastic soft mass on her left anterior neck. Contrast-enhanced computed tomography of the cervical region demonstrated an abscess partially infiltrating the thyroid gland and an air pocket near the pyriform sinus. Pharyngoscopy revealed swelling of the left arytenoid region, with purulent retention. The left vocal cord was swollen but not paralyzed. Additionally, the laboratory data indicated thyrotoxicosis. Suspecting a PSF infection, parenteral treatment with cefotaxime and dexamethasone was initiated. On the following day, the hoarseness disappeared, and the fever resolved. Four weeks after onset, the thyroid hormone levels returned to the normal range, and a barium esophagogram revealed residual contrast in the left pyriform sinus, leading to a diagnosis of PSF. Conclusion PSF presenting with hoarseness as the first symptom in patients should be considered

Heart Rate Variability, Insulin Resistance, and Insulin Sensitivity in Japanese Adults: The Toon Health Study

Background: Although impaired cardiac autonomic function is associated with an increased risk of type 2 diabetes in Caucasians, evidence in Asian populations with a lower body mass index is limited. Methods: Between 2009–2012, the Toon Health Study recruited 1899 individuals aged 30–79 years who were not taking medication for diabetes. A 75-g oral glucose tolerance test was used to diagnose type 2 diabetes, and fasting and 2-h-postload glucose and insulin concentrations were measured. We assessed the homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt’s insulin sensitivity index (ISI). Pulse was recorded for 5 min, and time-domain heart rate variability (HRV) indices were calculated: the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive difference (RMSSD). Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power, and the LF:HF ratio. Results: Multivariate-adjusted logistic regression models showed decreased SDNN, RMSSD, and HF, and increased LF:HF ratio were associated significantly with increased HOMA-IR and decreased ISI. When stratified by overweight status, the association of RMSSD, HF, and LF:HF ratio with decreased ISI was also apparent in non-overweight individuals. The interaction between LF:HF ratio and decreased ISI in overweight individuals was significant, with the odds ratio for decreased ISI in the highest quartile of LF:HF ratio in non-overweight individuals being 2.09 (95% confidence interval, 1.41–3.10). Conclusions: Reduced HRV was associated with insulin resistance and lower insulin sensitivity. Decreased ISI was linked with parasympathetic dysfunction, primarily in non-overweight individuals

Association of hematological parameters with insulin resistance, insulin sensitivity, and asymptomatic cerebrovascular damage: The J-SHIP and Toon Health Study.

BACKGROUND: Elevated hematocrit levels have been suggested to be an independent determinant of insulin resistance and type 2 diabetes. To clarify the diagnostic significance of hematocrit level, we investigated the association with hemodynamic profiles, insulin resistance and insulin sensitivity, arterial properties, and asymptomatic cerebrovascular damage in a general Japanese population. METHODS: This study included 1, 978 participants from two independent cohorts. Insulin sensitivity was assessed by the oral 75 g glucose tolerance test. Carotid ultrasonography was performed to evaluate atherosclerosis and wall shear stress. Periventricular hyperintensity and lacunar infarction were assessed by brain magnetic resonance imaging. RESULTS: Hematocrit quartile showed a stepwise association with insulin sensitivity (Q1: 2.2 ± 0.7, Q2: 2.0 ± 0.7, Q3: 1.9 ± 0.7, Q4: 1.8 ± 0.6, p < 0.001) and insulin resistance (1.0 ± 0.6, 1.2 ± 0.7, 1.3 ± 0.8, 1.5 ± 1.0, p < 0.001). Multiple linear regression analysis adjusted for possible covariates identified hematocrit as an independent determinant of insulin sensitivity (β = −0.074, p = 0.019) and insulin resistance (β = 0.115, p < 0.001). However, this association was lost after further adjustment for visceral fat area and plasma alanine aminotransferase level. Further, no significant association was observed between hematocrit and carotid intima-media thickness (p = 0.306) where as wall shear stress was inversely associated with the carotid atherosclerosis (r = −0.250, p < 0.001). In contrast, a low hematocrit level was independently associated with periventricular hyperintensity (odds ratio 0.87 (95% CI 0.80–0.95), p = 0.001). CONCLUSION: Hematocrit was positively associated with insulin resistance and insulin sensitivity. This association was epiphenomenon of visceral and hepatic adiposity. Conversely, low hematocrit was a significant risk factor for periventricular hyperintensity independent of insulin resistance

SNP-358, and SNP-638 were nearly in complete LD, and were tightly correlated with SNP-420 in the general Japanese population.

<p>The 8 SNPs around <i>RETN</i> were genotyped in 2,019 subjects in the general Japanese population, and LD between each pair of these SNPs were analyzed by Haploview <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009718#pone.0009718-Barrett1" target="_blank">[28]</a>. One LD block consisting of SNP-638, SNP -420, SNP-358, and SNP+157 was defined by the confidence interval analysis. Each square represents a pairwise value of <i>D</i>', with the standard gradation (black indicates LOD> = 2 and <i>D</i>' = 1; none indicates, LOD<2 and <i>D</i>' = 1; white indicates LOD<2 and D' <1, gray indicates LOD> = 2 and <i>D</i>'<1). The <i>r²</i> between SNP-638 and SNP-358 was 0.98. The <i>r²</i> between SNP-420 and SNP-358 or SNP-638 was 0.50, and 0.51, respectively.</p

Estimated frequency and plasma resistin in each haplotype defined by <i>RETN</i> SNP-420, and SNP-358 genotypes.

<p>Frequency and plasma resistin for each haplotype defined by <i>RETN</i> SNP-420 and SNP-358 genotypes were estimated by SNPstats <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009718#pone.0009718-Sole1" target="_blank">[29]</a>. Estimated differences of plasma resistin compared to a reference haplotype, C-G, are shown in each haplotype.</p

Characteristics of the population studied (<i>n</i> = 2,019).

<p>Values are means±SD, or <i>n</i> (%). Number of subjects who measured immunoreactive insulin was 1,958. HOMA-IR (homeostasis model assessment insulin resistance index) was calculated as glucose (mg/dl) x insulin (µU/ml)/405. CVD indicates cardiovascular disease, including stroke, myocardial infarction, and angina pectoris.</p

Nuclear proteins specifically recognized a difference in one base at SNP-358 but not at SNP-638.

<p>EMSA was performed as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009718#s4" target="_blank"><i>Methods</i></a>. A labeled probe representing <i>RETN</i> promoter sequences around SNP-358 contained G (major allele) or A (minor allele) at SNP-358 (<b>³²</b>P-358G or <b>³²</b>P-358A, respectively), and that around SNP-638 contained G (major allele) or A (minor allele) at SNP-638 (<b>³²</b>P-638G or <b>³²</b>P-638A, respectively). Each probe was incubated with a nuclear extract of THP-1 cells in the absence (−) or presence of a 200-fold molar excess of unlabeled competitor double-stranded oligonucleotides indicated (−358G, −358A, −638G, or −638A). The arrow points to the band that specifically bound to the probe with G at SNP-358.</p