Hiroko Nakagawa

ABCG2 dysfunction causes hyperuricemia due to both renal urate underexcretion and renal urate overload

Gout is a common disease which results from hyperuricemia. We have reported that the dysfunction of urate exporter ABCG2 is the major cause of renal overload (ROL) hyperuricemia, but its involvement in renal underexcretion (RUE) hyperuricemia, the most prevalent subtype, is not clearly explained so far. In this study, the association analysis with 644 hyperuricemia patients and 1,623 controls in male Japanese revealed that ABCG2 dysfunction significantly increased the risk of RUE hyperuricemia as well as overall and ROL hyperuricemia, according to the severity of impairment. ABCG2 dysfunction caused renal urate underexcretion and induced hyperuricemia even if the renal urate overload was not remarkable. These results show that ABCG2 plays physiologically important roles in both renal and extra-renal urate excretion mechanisms. Our findings indicate the importance of ABCG2 as a promising therapeutic and screening target of hyperuricemia and gout.

Significant Association between Serum Interleukin-6 and Helicobacter pylori Antibody Levels among H. pylori-Positive Japanese Adults

Background. Interleukin-6 (IL-6) is a multifunctional cytokine produced by many types of cells. Inflammation plays a key role in the pathogenesis of atherosclerosis that is an underlying cause of coronary heart disease (CHD). Since the 1990s, some studies have shown an association between H. pylori infection and CHD, which may be mediated by inflammation. Therefore, this study aimed to evaluate the association between serum anti-H. pylori IgG levels and serum IL-6 levels in H. pylori-infected adults. Methods. We enrolled 158 subjects who visited a clinic located in an urban area to be tested for H. pylori infection, using the 13C-urea breath test, and who were found to be infected and subsequently received eradication. Results. The geometric mean serum IL-6 level was 1.78 pg/mL for men, 1.57 pg/mL for women, and 1.64 pg/mL overall. Logarithms of serum IL-6 levels were positively correlated with logarithms of serum H. pylori IgG levels (r = 0.24, P = 0.002). In multiple linear regression analysis adjusting for sex and age, the serum IL-6 level was still significantly associated with the IgG level in all subjects (β = 0.18, P = 0.012). Conclusion. Higher H. pylori IgG levels were significantly associated with higher serum IL-6 levels among H. pylori-infected individuals.

Significant interaction between LRP2 rs2544390 in intron 1 and alcohol drinking for serum uric acid levels among a Japanese population

A genome-wide association study identified that LRP2 rs2544390 in intron 1 was associated with serum uric acid (SUA) levels among Japanese, as well as polymorphisms of SLC22A12, ABCG2, and SLC2A9. This study aimed to confirm the association of rs2544390 C/T with SUA, as well as another LRP2 polymorphism (rs3755166 G/A) in the promoter. Subjects were 5016 health checkup examinees (3409 males and 1607 females) aged 35 to 69years with creatinine<2.0mg/dL. The subjects with SLC22A12 258WW, SLC2A9 rs11722228C allele, ABCG2 126QQ and 141Q allele (2546 males and 1199 females) were selected for analysis. Mean SUA was 6.03mg/dL for CC, 6.18mg/dL for CT, and 6.19mg/dL for TT among males (p=0.012), and 4.49mg/dL, 4.45mg/dL, and 4.42mg/dL among females (not significant), respectively. No association was observed for rs3755166. The association with rs2544390 was stronger among male drinkers. The odds ratio of drinking ≥5/week relative to no drinking for hyperuricemia (SUA≥7mg/dL and/or under medication for hyperuricemia) was 1.11 (95% confidence interval, 0.67-1.84) among CC males, 1.75 (1.22-2.51) among CT males, and 3.13 (1.80-5.43) among TT males. The interaction terms with drinking ≥5/week were 1.56 (p=0.156) for CT and 2.87 (p=0.005) for TT. This was the first report on the interaction between LRP2 genotype and alcohol drinking for SUA. Since the low density lipoprotein-related protein 2 (megalin) encoded by LRP2 is a multi-ligand endocytic receptor expressed in many tissues including the kidney proximal tubules, the association/interaction remained to be confirmed both epidemiologically and biologically.

Associations between polymorphisms of interleukin-6 and related cytokine genes and serum liver damage markers: a cross-sectional study in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study

Cytokines, including interleukin-6 (IL-6), play an important role in the liver. The aim of this study was to investigate associations between common polymorphisms in potential functional promoters of cytokine genes and liver damage markers among enrollees of a large Japanese cohort study. Subjects included 3257 Japanese individuals (1608 men and 1649 women, aged 35-69 years). Six single nucleotide polymorphisms (SNPs) in the promoter regions of five cytokine genes, IL1B (T-31C), IL6 (C-634G), IL8 (T-251A), IL10 (T-819C), tumor necrosis factor-A (TNFA) (T-1031C), and TNFA (C-857T), were genotyped by polymerase chain reaction. Information regarding alcohol intake, smoking habits, height, and weight was collected by a self-administered questionnaire. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured during a routine health check-up. Of the six SNPs genotyped, an IL6 polymorphism (rs1800796, C-634G) was most strongly associated with a liver damage marker, AST. Mean serum AST was significantly different among the three genotypes (mean ± SD, 22.7 ± 7.3 IU/L for CC, 22.8 ± 7.7 IU/L for CG, and 24.3 ± 8.6 IU/L for GG, p=0.011 by analysis of variance). The differences remained significant after adjustment for potential confounders by general linear models. The variations in mean serum AST and ALT levels were marked especially among men. Thus, the functional polymorphism IL6 C-634G may affect serum AST and ALT levels, possibly through different IL-6 production.

Changes in trends in colorectal cancer incidence rate by anatomic site between 1978 and 2004 in Japan

Although colorectal cancer (CRC), a major type of cancer worldwide, has shown a proximal or right-sided shift in subsite distribution in western countries, trends in subsite incidence in Asian countries remain unclear. Here, we evaluated subsite-specific trends in CRC incidence rate between 1978 and 2004 in Japan using large data from 10 population-based cancer registries. The colorectal sites (C18–C20) were categorized into three groups: proximal colon (C18.0–C18.5), distal colon (C18.6–C18.7), and rectum (C19.9 and C20.9). Trends in age-standardized incidence rates (ASRs) were characterized by joinpoint regression analysis. A total of 303 802 CRC cases were analyzed. Overall, ASRs increased remarkably until 1993, with an annual percentage change (APC) of 4.9%, and then stabilized thereafter. By subsite, however, ASRs of proximal colon significantly increased, with APCs of 7.1% (1978–1991), 3.8% (1991–1996), and 0.9% (1996–2004); distal colon showed an initial significant increase, with an APC of 7.6%, but stabilized from 1991 until the end of observation; and rectal cancer showed an initial significant increase, with APCs of 1.9% (1978–1988) and 5.6% (1988–1992), but then decreased abruptly in 1992, the year CRC screening was introduced nationwide, with an APC of −1.0%. Thus, we revealed that changes in incidence trends for the three anatomic sites apparently began to differ in the 1990s. Careful monitoring is necessary to confirm whether these trends are changing in the Japanese population.

Association Between Helicobacter pylori Infection Detected by the 13C-Urea Breath Test and Low Serum Ferritin Levels among Japanese Adults

Helicobacter pylori infection is a major risk factor for chronic gastritis, digestive ulcers, and gastric cancer. Previous studies have shown associations between H. pylori infection and decreased iron storage. Therefore, this study aimed to examine the associations between H. pylori infection and serum iron and ferritin levels in Japan.

Effects of IL6 C-634G polymorphism on tooth loss and their interaction with smoking habits.

OBJECTIVE To examine the association between an IL6 (Interleukin-6) polymorphism (C-634G or rs1800796) and tooth loss, and an interaction between the polymorphism and smoking habits for the loss. MATERIAL AND METHODS Our subjects were 4917 check-up examinees ages 35-69. They reported tooth loss and lifestyle in a questionnaire. We regressed the number of teeth on the IL6 genotype, gender, age, smoking, drinking, diabetes, hypertension, physical activity, energy intake, education, and brushing. We further estimated multivariate-adjusted odds ratios (ORs) for having <20 teeth. RESULTS Participants with a GG genotype tended to have less teeth than those with CC; β = -0.798 (95% confidence interval [CI] = -1.501--0.096). Subjects with a GG genotype were more likely to have <20 teeth than those with CC; OR was 1.56 (95% CI = 1.08-2.25). Association between current smoking and tooth loss was stronger among those with GG than among those with CC. In a multiple regression analysis, a significant interaction was found between GG genotype and current smoking in the prediction of tooth loss (P = 0.018). CONCLUSION The IL6 C-634G polymorphism was significantly associated with tooth loss. Our results suggest greater effects of smoking on tooth loss in GG genotype individuals.

Associations of smoking status with other lifestyle behaviors are modified by sex and occupational category among urban civil servants in Japan

ObjectivesThe aim of the present study was to examine the associations of current smoking with five other unhealthy lifestyle behaviors among urban civil servants in Japan according to sex and occupational category.MethodsThe study included 10,232 urban civil servants in Japan who presented for a health check-up in 2011. We analyzed data on anthropometric measurements and self-reported lifestyle factors.ResultsCurrent smokers had a higher BMI than never smokers in white-collar workers, but not in blue-collar workers of both sexes. There were strong associations of current smoking with irregular breakfasting regardless of sex and occupational category. In males, current smokers were less likely to take exercise than ex-smokers in both occupational categories.ConclusionsThe associations of current smoking with other unhealthy behaviors were modified by sex and occupational category. These results are useful for understanding the health risks among smokers according to sex and occupational category.

Abstract 5205: Changes in trends in colorectal cancer incidence rate by anatomic site between 1978 and 2004 in Japan

Although colorectal cancer (CRC), a major cancer worldwide, has shown a proximal or right-sided shift in subsite distribution in western countries, trends in subsite incidence in Asian countries remain unclear. Here, we evaluated subsite-specific trends in CRC incidence rate between 1978 and 2004 in Japan using large data from 10 population-based cancer registries. The colorectal sites (C18-20) were categorized into three groups, proximal colon (C18.0-18.5), distal colon (C18.6-C18.7) and rectum (C19.9 and C20.9). Trends in age-standardized incidence rates (ASRs) were characterized by Joinpoint regression analysis. A total of 474,651 colorectal cancer cases were analyzed. Overall, ASRs increased remarkably until 1993, with an annual percent change (APC) of 4.9%, and then stabilized thereafter. By subsite, however, ASRs of proximal colon significantly increased, with APCs of 7.1% (1978∼1991), 3.8% (1991∼96) and 0.9% (1996∼2004); distal colon showed an initial significant increase, with an APC of 7.6%, but stabilized from 1991 until the end of observation; and rectal cancer showed an initial significant increase, with APCs of 1.9% (1978∼88) and 5.6% (1988∼92), but then decreased abruptly in 1992, the year colorectal cancer screening was introduced nationwide, with an APC of -1.0%. Thus, we revealed that changes in incidence trends for the three anatomic sites apparently began to differ in the 1990s, and this is a first report to our knowledge. We also discuss factors that could explain these changes in Japanese. Careful monitoring is necessary to confirm whether these trends are changing in the Japanese population. Citation Format: Hiroko Nakagawa, Hidemi Ito, Satoyo Hosono, Isao Oze, Haruo Mikami, Masakazu Hattori, Yoshikazu Nishino, Hiromi Sugiyama, Kayo Nakata, Hideo Tanaka. Changes in trends in colorectal cancer incidence rate by anatomic site between 1978 and 2004 in Japan. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5205.