Kazuya Setoh

Effects of smoking and shared epitope on the production of anti-citrullinated peptide antibody in a Japanese adult population

Anti–citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) are markers to rheumatoid arthritis (RA). Smoking and shared epitope (SE) in HLA–DRB1 are associated with the production of these autoantibodies in RA. Detailed distribution and characterization of ACPA and RF in the general population have remained unclear. We aimed to evaluate positivity of ACPA and RF in a general Japanese population and to detect correlates, including genetic components.

Descriptive epidemiology of spot urine sodium-to-potassium ratio clarified close relationship with blood pressure level: the Nagahama study.

Objectives: We undertook descriptive epidemiology of spot urine sodium-to-potassium ratio (Na/K) in a population sample to clarify the close relationship between Na/K and blood pressure level independently of potential confounding factors. Methods: Study participants consisted of 9144 apparently healthy citizens (aged 54 ± 13 years). All clinical parameters were obtained at baseline. Results: Na/K was significantly higher in hypertensive individuals irrespective of antihypertensive medication status (normotension, 3.12 ± 1.82; untreated hypertension 3.50 ± 1.96; treated hypertension, 3.72 ± 2.53). As urinary Na (&bgr; = 0.092, P < 0.001) and K (&bgr; = −0.050, P < 0.001) levels were inversely associated with BP, Na/K (&bgr; = 0.118, P < 0.001) was more closely associated with BP than Na or K alone, as well as daily salt intake estimated from urinary Na (&bgr; = 0.088, P < 0.001). Several factors were significantly associated with Na/K, namely age, sex, obesity, blood pressure, renal function, salt restriction status, serum phosphate and urinary creatinine level, and fasting period and season at urine sample collection. However, the association between Na/K and BP was independent of these factors (adjusted &bgr; = 0.112, P < 0.001). No direct association was observed between Na/K and large arterial remodeling assessed by pulse wave analysis (P = 0.496) or retinal arteriolar morphological change (P = 0.431). Further, a genome-wide association study failed to identify any particular genotype influencing urinary Na and K levels. Conclusions: Although we clarified several factors that might affect spot urine Na/K, these relationships were not substantial enough to confound the association between urinary Na/K and BP. A simple measure of Na/K might be more representative of salt loading obtained from spot urine samples than Na excretion alone.

Increased aortic wave reflection and smaller pulse pressure amplification in smokers and passive smokers confirmed by urinary cotinine levels: The Nagahama Study

BACKGROUND Central blood pressure (cSBP) is suggested to be a better predictor of cardiovascular risk than brachial BP. Although brachial BP levels among smokers have been reported to be the same or somewhat lower than those in nonsmokers, it is suggested that smoking might have a substantial impact on cSBP. METHODS We conducted a cross-sectional study to clarify the association of smoking habit with arterial tone and cSBP in a general population of 8557 participants using urinary cotinine levels as an objective marker of smoking intensity. Absolute pressure of the late systolic peak (SBP2) was obtained by calibrating the radial waveform with brachial systolic BP (bSBP) and considered to be the cSBP. RESULTS Confounding factor-adjusted mean pulse pressure amplification (PPa = bSBP-cSBP) was significantly smaller in habitual smokers (current, 9.3 ± 0.15; past, 10.2 ± 0.13; never, 10.6 ± 0.10 mmHg; p<0.001). Further, among smokers, PPa was linearly decreased with increasing urinary cotinine quartile (Q1, 10.9 ± 0.38; Q2, 10.9 ± 0.39; Q3, 10.4 ± 0.39; Q4, 9.7 ± 0.41 mmHg; p = 0.020). Multiple linear regression analysis identified both smoking habit (p = 0.003) and urinary cotinine levels (p = 0.008) as independent determinants of PPa. Urinary cotinine was also detected in a small fraction of never smokers (1.8%). These passive smokers showed a smaller PPa (passive smoker, 9.4 ± 0.4; never smoker, 10.4 ± 0.12 mmHg, p = 0.020) but not bSBP (122.7 ± 0.6, 123.1 ± 0.2 mmHg, p = 0.474). CONCLUSIONS Not only habitual smoking but also passive smoking had harmful effects on AIx and central BP. Our results strongly emphasize the importance of avoiding passive smoking to the prevention of cardiovascular risks of which the subject is likely unaware.

Gastroesophageal reflux disease symptoms and dietary behaviors are significant correlates of short sleep duration in the general population: the Nagahama Study.

STUDY OBJECTIVES To examine relationships among gastroesophageal reflux disease (GERD) symptoms, dietary behaviors, and sleep duration in the general population. DESIGN Cross-sectional. SETTING Community-based. PARTICIPANTS There were 9,643 participants selected from the general population (54 ± 13 y). INTERVENTIONS None. MEASUREMENTS AND RESULTS Sleep duration, sleep habits, and unfavorable dietary behaviors of each participant were assessed with a structured questionnaire. Participants were categorized into five groups according to their sleep duration: less than 5 h, 5 to less than 6 h, 6 to less than 7 h, 7 to less than 8 h, and 8 or more h per day. GERD was evaluated using the Frequency Scale for the Symptoms of GERD (FSSG) and participants having an FSSG score of 8 or more or those under treatment of GERD were defined as having GERD. Trend analysis showed that both the FSSG score and the number of unfavorable dietary habits increased with decreasing sleep duration. Further, multiple logistic regression analysis showed that both the presence of GERD (odds ratio = 1.19, 95% confidence interval (CI) = 1.07-1.32) and the number of unfavorable dietary behaviors (odds ratio = 1.19, 95% CI = 1.13-1.26) were independent and potent factors to identify participants with short sleep duration even after controlling for other confounding factors. CONCLUSION The current study showed that both GERD symptoms and unfavorable dietary behaviors were significant correlates of short sleep duration independently of each other in a large sample from the general population.

Airflow limitation in smokers is associated with arterial stiffness: The Nagahama Study

BACKGROUND Pathophysiological mechanisms of associations between airflow limitation (AL) and arterial stiffness remain unclear. One factor that might affect both AL and arterial stiffness is habitual smoking. The aim of this study is to investigate a possible interaction of smoking on the association between AL and arterial stiffness. METHODS Study subjects consisted of 8790 apparently healthy community residents. Airflow limitation was defined as a ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity of less than 70%. Brachial-to-ankle pulse wave velocity (baPWV) was used as an index of arterial stiffness. Smoking habit was investigated using a structured questionnaire. RESULTS Subjects with AL had significantly higher baPWV (AL 1381 ± 334, control 1261 ± 227 cm/s, p < 0.001). In a separate analysis by smoking habit, advanced arterial stiffness in AL was observed only in smokers (non-smokers: AL 1300 ± 220, control 1260 ± 218; smokers: AL 1436 ± 384, control 1264 ± 243 cm/s). Other clinical features of subjects with AL were older age; increased plasma hsCRP levels; and a high prevalence of male sex, hypertension, and smoking experience. Multiple linear regression analysis adjusted for these covariates identified the smoking × AL interaction as an independent determinant of baPWV (β = 0.066, p < 0.001). Conversely, baPWV was an independent determinant of AL in current and past smokers, but not in never smokers. CONCLUSIONS AL arising from cigarette smoking, but not AL in non-smokers, was associated with arterial stiffness in a general population independently of established risk factors. Measurement of subclinical arterial change in smokers may be useful in identifying persons at risk for AL.

Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels

Alpha-1 antitrypsin (AAT) encoded by SERPINA1 is an acute-phase inflammation marker, and AAT deficiency (AATD) is known as one of the common genetic disorders in European populations. However, no genetic determinants to AAT levels apart from the SERPINA gene clusters have been identified to date. Here we perform a genome-wide association study of serum AAT levels followed by a two-staged replication study recruiting a total of 9,359 Japanese community-dwelling population. Three missense variants of metabolic syndrome-related genes, namely, rs671 in ALDH2, rs1169288 in HNF1A and rs1260326 in GCKR, significantly associate with AAT levels (P≤1.5 × 10−12). Previous reports have shown the functional relevance of ALDH2 and HNF1A to AAT. We observe a significant interaction of rs671 and alcohol consumption on AAT levels. We confirm the association between AAT and rs2896268 in SERPINA1, which is independent of known causative variants of AATD. These findings would support various AAT functions including metabolic processes.

Knee Pain and Low Back Pain Additively Disturb Sleep in the General Population: A Cross-Sectional Analysis of the Nagahama Study.

Introduction Association of knee and low back pain with sleep disturbance is poorly understood. We aimed to clarify the independent and combined effects of these orthopedic symptoms on sleep in a large-scale general population. Methods Cross-sectional data about sleep and knee/low back pain were collected for 9,611 community residents (53±14 years old) by a structured questionnaire. Sleep duration less than 6 h/d was defined as short sleep. Sleep quality and the presence of knee and low back pain were evaluated by dichotomous questions. Subjects who complained about knee or low back pains were graded by tertiles of a numerical response scale (NRS) score and a Roland-Morris disability questionnaire (RDQ) score respectively. Multivariate regression analyses were performed to determine the correlates of short sleep duration and poor sleep quality. Results Frequency of participants who complained of the orthopedic symptoms was as follows; knee pain, 29.0%; low back pain, 42.0% and both knee and low back pain 17.6%. Both knee and low back pain were significantly and independently associated with short sleep duration (knee pain: odds ratio (OR) = 1.19, p<0.01; low back pain: OR = 1.13, p = 0.01) and poor sleep quality (knee pain: OR = 1.22, p<0.01; low back pain; OR = 1.57, p<0.01). The group in the highest tertile of the NRS or RDQ score had the highest risk for short sleep duration and poor sleep quality except for the relationship between the highest tertile of the RDQ score and short sleep duration.(the highest tertile of the NRS: OR for short sleep duration = 1.31, p<0.01; OR for poor sleep quality = 1.47, p<0.01; the highest tertile of the RDQ: OR for short sleep duration = 1.11, p = 0.12; OR for poor sleep quality = 1.81, p<0.01) Further, coincident knee and low back pain raised the odds ratios for short sleep duration (either of knee or low back pain: OR = 1.10, p = 0.06; both knee and low back pain: OR = 1.40, p<0.01) and poor sleep quality (either of knee or low back pain: OR = 1.61, p<0.01; both knee and low back pain: OR = 2.17, p<0.01). Conclusion Knee and low back pains were independently associated with short sleep duration and poor sleep quality. Further, they additively increased the correlation with these sleep problems in the general population.

Central blood pressure relates more strongly to retinal arteriolar narrowing than brachial blood pressure: the Nagahama Study.

Objectives: Although central blood pressure (BP) is considered to be more closely associated with large arterial remodeling and cardiovascular outcomes than brachial BP, few studies have investigated these associations with changes in small arteries. As morphological changes in retinal vessels might be associated with cardiovascular outcomes, we conducted a cross-sectional study to investigate the association of central BP with retinal vessel caliber. Methods: The study included 8054 Japanese participants. Central BP was estimated by the radial arterial waveform by calibrating brachial BP. Central retinal arteriolar equivalent (CRAE) was computationally measured using fundus photography. Results: CRAE was most strongly associated with central SBP (r = −0.324, P < 0.001), followed by DBP (r = −0.292, P < 0.001) and central pulse pressure (PP; r = −0.226, P < 0.001). The correlation coefficient between SBP and CRAE was significantly greater in central SBP than in brachial SBP (r = −0.300, P < 0.001). After adjustment for possible covariates, brachial SBP (&bgr; = −0.221, P < 0.001) and central SBP (&bgr; = −0.239, P < 0.001) were independently associated with CRAE. Further, higher brachial SBP (&bgr; = −0.226, P < 0.001) and smaller PP amplification (&bgr; = 0.092, P < 0.001) were identified as independent determinants of narrowing of CRAE in the same equation, which indicated the superiority of central BP. Central BP-determined hypertensive individuals had a significantly narrower CRAE independent of brachial BP (central/brachial: hypertension/hypertension 121.4 ± 11.5, hypertension/normotension 120.9 ± 11.2, normotension/hypertension 125.1 ± 11.9, normotension/normotension 128.1 ± 11.5 &mgr;m). Conclusion: Central BP was more closely associated with the narrowing of CRAE than brachial BP. Slight increases in central BP might be involved in the morphological changes in small retinal arteries, even in individuals with optimal brachial BP.

Association of Serum–Free Fatty Acid Level With Reduced Reflection Pressure Wave Magnitude and Central Blood Pressure The Nagahama Study

Central blood pressure (BP) has been suggested to be a better predictor of cardiovascular disease risk than brachial BP. Given that central BP and arterial waveform are both influenced by insulin resistance, major initiators of insulin resistance, such as serum–free fatty acid (FFA), are suspected of potentially being involved in central hemodynamics. To confirm that insulin signaling is an important modulator of central hemodynamics, we investigated this hypothesis in a large-scale general population. Brachial BP and radial arterial waveform were measured simultaneously in 9393 middle-aged to elderly individuals. The augmentation index was calculated from the radial waveform as the ratio of the height of the late systolic peak to that of the first peak. Central systolic BP was defined as the absolute pressure of the late systolic peak of the waveform. Differences in central and brachial pulse pressure (PP) were considered to represent PP amplification. PP amplification differed significantly among serum FFA level quartiles (Q1, 7.8±5.3; Q2, 8.6±5.0; Q3, 9.3±5.7; Q4, 10.3±6.1 mm Hg; P<0.001), and the maximum difference in combination with diabetes mellitus status was 4.9 mm Hg. Multivariate analysis adjusted for major covariates indicated that higher serum FFA was an independent determinant for higher PP amplification (&bgr;=0.145, P<0.001) and lower augmentation index (&bgr;=−0.122, P<0.001) and central systolic BP (&bgr;=−0.044, P<0.001), whereas the association between FFA and PP amplification significantly decreased (&bgr;=0.022, P<0.001) after further adjustment for augmentation index. Serum FFA is an overlooked factor favorably influencing central hemodynamics. A low-magnitude reflection pressure wave might be involved in this paradoxical relationship.

Association Between Antinuclear Antibodies and the HLA Class II Locus and Heterogeneous Characteristics of Staining Patterns: The Nagahama Study

While antinuclear antibodies (ANAs) are observed in healthy populations as well as in patients with autoimmune diseases such as systemic lupus erythematosus (SLE), the detailed genetic background of ANAs has remained unclear. We undertook this study to identify the genetic determinants of ANAs in the general population in order to elucidate the underlying mechanisms of ANA production and to distinguish disease susceptibility genes from ANA production genes.