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For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

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Osteoporosis is a multifactorial trait with low bone mineral density (BMD). We report results of an association study between BMD and nine candidate genes (TGFB1, TGFBR2, SMAD2, SMAD3, SMAD4, IFNB1, IFNAR1, FOS and LRP5), as well as of a case-control study of osteoporosis. Samples for the former association study included 481 general Japanese women. Among the nine candidate genes examined, only LRP5 showed a significant association with BMD. We identified a strong linkage disequilibrium (LD) block within LRP5. Of five LPR5 single nucleotide polymorphisms (SNPs) that are located in the LD block, three gave relatively significant results: Women with the C/C genotype at the c.2220C>T SNP site had higher adjusted BMD (AdjBMD) value compared to those with C/T and T/T (p=0.022); and likewise, G/G at IVS17-30G>A and C/C women at c.3989C>T showed higher AdjBMD than those with G/ A or A/A (p=0.039) and with C/T or T/T (p=0.053), respectively. The case-control study in another series of samples consisting of 126 osteoporotic patients and 131 normal controls also gave a significant difference in allele frequency at c.2220C>T (, 2 =6.737, p=0.009). These results suggest that LRP5 is a BMD determinant and also contributes to a risk of osteoporosis.

Usefulness of complex demodulation (CDM) in assessing the frequency components of cardiovascular variability was assessed and, subsequently, this technique was utilized to determine the time-dependent responses of the low-frequency (LF) and high-frequency (HF) amplitudes of heart rate and blood pressure variabilities during postural tilt. CDM provides the time-dependent changes in amplitude of a particular frequency component on a continuous basis. Analysis of simulated data showed that CDM has sufficient frequency resolution to separately measure LF and HF amplitudes with a time resolution < 15 s and that CDM is robust to alterations in the frequency of the components. Analysis of actual data during postural tilt test in 23 young healthy subjects demonstrated that the HF amplitude of heart rate, an index of cardiac parasympathetic tone, rapidly decayed with head-up tilt (P < 0.01) and increased quickly showing an overshoot with tilt back to the supine position (P < 0.01). The LF amplitude of blood pressure, an index of vasomotor sympathetic activity, showed marked rhythmic fluctuation at an interval of 48-100 s during head-up tilt (P < 0.01), synchronizing with similar fluctuation in the LF amplitude of heart rate (P < 0.01). These results suggest that CDM can be used to provide a continuous assessment of cardiovascular variability components and that the dynamic responses of autonomic circulatory control to upright posture result in a phasic modulation of LF amplitude.

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To investigate the diurnal variation in autonomic cardiac control, the magnitudes of the power spectral components of supine and standing heart rate variability were measured during controlled respiration (15 breaths/min). Examination was performed hourly between 0700 and 2300 h in eight male subjects whose activities and food intake were controlled for 24 h in the laboratory. The respiratory component (0.25 Hz) was greater in the morning than in the late afternoon (P less than 0.05) and decreased 30 min after food intake (P less than 0.01) in the supine position, but it was unaffected by the time of day or food intake while in the standing position. The Mayer wave component (0.03-0.15 Hz) did not change with the time of day, but it increased 90 min after food intake in both supine and standing positions (P less than 0.01 and P less than 0.05, respectively). These data suggest that supine vagal cardiac control during the waking period increases in the morning and decreases 30 min after food intake and that sympathetic cardiac control increases 90 min after food intake.