Mariko Naito

Common Defects of ABCG2, a High-Capacity Urate Exporter, Cause Gout: A Function-Based Genetic Analysis in a Japanese Population

Dysfunctional genotype combinations of polymorphic adenosine 5′-triphosphate–binding cassette transporter gene ABCG2/BCRP, which encodes a high-capacity urate secretion transporter in human gut and kidney, are major causes of gout. Gout, the “Disease of Kings” as it is often known, is a painful medical condition characterized by sharp acute pain in bone joints, due to the high deposition of uric acid crystals from the blood serum into the surrounding cartilage. It affects approximately 1% of the U.S. population and remains a significant public health concern. The prevalence of gout is much higher in certain Asian ethnic groups, and is also reportedly rising in African Americans. Current medical treatments are aimed at ameliorating pain severity, but as the underlying genetic etiology of the disease unfolds, new targets for future therapies are likely to be found. Although genome-wide association studies (GWAS) have enabled the calculation of risk predispositions for a wide variety of complex diseases, the relation of gene function to the causality of disease-related mutations has remained largely unclear. A recent U.S. population–based study supported an association between urate levels and gout in individuals carrying variants in a multifunctional transporter gene, ABCG2. This study identified Q141K as a high-risk variant in nearly 10% of gout cases in Caucasians. Now, a team led by Hirotaka Matsuo report that in a Japanese population, another risk variant in ABCG2, namely the Q126X nonfunctional mutation, confers an even higher risk associated with an increase in uric acid deposition in the blood and may cause gout in Asians. Because this gene is responsible for giving rise to a protein that transports harmful waste products and metabolites out of the kidney and gut, they extensively validate the biological activity of ABCG2 using functional assays in vitro that effectively recapitulate human data obtained from Japanese individuals afflicted with the disease. These findings lend weight to previously reported GWAS; moreover, these newly identified specific high-risk variants that block urate secretion may serve as potential intervention points for quelling the disease. Gout based on hyperuricemia is a common disease with a genetic predisposition, which causes acute arthritis. The ABCG2/BCRP gene, located in a gout-susceptibility locus on chromosome 4q, has been identified by recent genome-wide association studies of serum uric acid concentrations and gout. Urate transport assays demonstrated that ABCG2 is a high-capacity urate secretion transporter. Sequencing of the ABCG2 gene in 90 hyperuricemia patients revealed several nonfunctional ABCG2 mutations, including Q126X. Quantitative trait locus analysis of 739 individuals showed that a common dysfunctional variant of ABCG2, Q141K, increases serum uric acid. Q126X is assigned to the different disease haplotype from Q141K and increases gout risk, conferring an odds ratio of 5.97. Furthermore, 10% of gout patients (16 out of 159 cases) had genotype combinations resulting in more than 75% reduction of ABCG2 function (odds ratio, 25.8). Our findings indicate that nonfunctional variants of ABCG2 essentially block gut and renal urate excretion and cause gout.

Genetic factors involved in the development of Helicobacter pylori-related gastric cancer

Developmental process to gastric cancer by Helicobacter pylori infection consists of three steps: (1) H. pylori infection; (2) gastric atrophy development; and (3) carcinogenesis. In each step, genetic traits may influence the process, interacting with lifestyle. In the step of H. pylori infection, two lines of genetic polymorphisms were assumed: one influencing gastric acid inhibition interacting with smoking, and the other concerning innate immune response attenuation. The former includes functional polymorphisms of IL‐1B (C‐31T or tightly linked T‐511C), and TNF‐A (T‐1031C and C‐857T), and the latter possibly includes NQO1 C609T. In the step to gastric atrophy, polymorphisms pertaining to the signal transduction from cytotoxin‐associated gene A (PTPN11 A/G at intron 3) and to T‐cell responses (IL‐2 T‐330G and IL‐13 C‐1111T) were hypothesized. There are a limited number of epidemiological genotype studies on the final step of literal carcinogenesis, potentially interacting with smoking, a low vegetable and fruit intake, and salty foods, the well‐documented risk factors. In past case‐control studies on the associations between genotype and gastric cancer risk, the cases consisted of H. pylori‐related and unrelated gastric cancer patients and the controls consisted of individuals including the uninfected (H. pylori unexposed and exposed) and the infected with and without gastric atrophy. Accordingly, it was not clear whether the observed risk was for H. pylori‐related or ‐unrelated gastric cancer, nor which step was involved in the observed associations even when nearly all cases were H. pylori‐related. In order to elucidate the genetic traits of H. pylori‐related gastric cancer, stepwise evaluation will be required. (Cancer Sci 2006; 97: 1129–1138)

Toll-Like Receptor 4 +3725 G/C Polymorphism, Helicobacter pylori Seropositivity, and the Risk of Gastric Atrophy and Gastric Cancer in Japanese

Background:  Toll‐like receptor 4 (TLR4) Asp299Gly and Thr399Ile polymorphisms were reported to be a risk factor of gastric carcinoma or its precursors in Caucasian and Indian population, but these polymorphisms are absent in Japanese. We investigated the associations of TLR4+3725 G/C polymorphism, another functional polymorphism of TLR4, with risk of gastric cancer and gastric atrophy in Japanese.

Common dysfunctional variants in ABCG2 are a major cause of early-onset gout

Gout is a common disease which mostly occurs after middle age, but more people nowadays develop it before the age of thirty. We investigated whether common dysfunction of ABCG2, a high-capacity urate transporter which regulates serum uric acid levels, causes early-onset gout. 705 Japanese male gout cases with onset age data and 1,887 male controls were genotyped, and the ABCG2 functions which are estimated by its genotype combination were determined. The onset age was 6.5 years earlier with severe ABCG2 dysfunction than with normal ABCG2 function (P = 6.14 × 10−3). Patients with mild to severe ABCG2 dysfunction accounted for 88.2% of early-onset cases (twenties or younger). Severe ABCG2 dysfunction particularly increased the risk of early-onset gout (odds ratio 22.2, P = 4.66 × 10−6). Our finding that common dysfunction of ABCG2 is a major cause of early-onset gout will serve to improve earlier prevention and therapy for high-risk individuals.

Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes

Objective Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. Methods A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. Results Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10−8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10−12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10−23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10−9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case–control ORs for two distinct types of gout (r=0.96 [p=4.8×10−4] for urate clearance and r=0.96 [p=5.0×10−4] for urinary urate excretion). Conclusions Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.

Internet Use for Health-Related Information via Personal Computers and Cell Phones in Japan: A Cross-Sectional Population-Based Survey

Background The Internet is known to be used for health purposes by the general public all over the world. However, little is known about the use of, attitudes toward, and activities regarding eHealth among the Japanese population. Objectives This study aimed to measure the prevalence of Internet use for health-related information compared with other sources, and to examine the effects on user knowledge, attitudes, and activities with regard to Internet use for health-related information in Japan. We examined the extent of use via personal computers and cell phones. Methods We conducted a cross-sectional survey of a quasi-representative sample (N = 1200) of the Japanese general population aged 15–79 years in September 2007. The main outcome measures were (1) self-reported rates of Internet use in the past year to acquire health-related information and to contact health professionals, family, friends, and peers specifically for health-related purposes, and (2) perceived effects of Internet use on health care. Results The prevalence of Internet use via personal computer for acquiring health-related information was 23.8% (286/1200) among those surveyed, whereas the prevalence via cell phone was 6% (77). Internet use via both personal computer and cell phone for communicating with health professionals, family, friends, or peers was not common. The Internet was used via personal computer for acquiring health-related information primarily by younger people, people with higher education levels, and people with higher household incomes. The majority of those who used the Internet for health care purposes responded that the Internet improved their knowledge or affected their lifestyle attitude, and that they felt confident in the health-related information they obtained from the Internet. However, less than one-quarter thought it improved their ability to manage their health or affected their health-related activities. Conclusions Japanese moderately used the Internet via personal computers for health purposes, and rarely used the Internet via cell phones. Older people, people with lower education levels, and people with lower household incomes were less likely to access the Internet via cell phone. The Internet moderately improved users’ health-related knowledge and attitudes but seldom changed their health-related abilities and activities. To encourage communication between health providers and consumers, it is important to improve eHealth literacy, especially in middle-aged people. It is also important to make adequate amendments to the reimbursement payment system and nationwide eHealth privacy and security framework, and to develop a collaborative relationship among industry, government, and academia.

Tooth loss and intakes of nutrients and foods: a nationwide survey of Japanese dentists.

OBJECTIVES To clarify the association of tooth loss with dietary intakes among dentists, for whom sufficient dental care is available. METHODS We analyzed the data from 20 366 Japanese dentists (mean age +/- SD, 52.2 +/- 12.1 years; women 8.0%) who participated in a nationwide cohort study from 2001 to 2006. The baseline questionnaire included a validated food-frequency questionnaire to estimate intakes of foods and nutrients. We computed the geometric means of daily intakes by the number of teeth, adjusting for age, sex, smoking, physical activity, and history of diabetes. RESULTS The mean intakes of some key nutrients and food groups, such as carotene, vitamins A and C, milk and dairy products, and vegetables including green-yellow vegetables, decreased with the increasing number of teeth lost (P for trend <0.05). On the contrary, mean intakes of carbohydrate, rice, and confectioneries were increased among those with fewer teeth (P for trend <0.05). The difference in the geometric mean (%) between totally edentulous subjects and those with > or =25 teeth, that is [(Geometric mean for > or =25 teeth) - (Geometric mean for 0 teeth)]/(Geometric mean for > or =25 teeth) x 100, was 14.3%, 8.6%, 6.1%, and -6.1% for carotene, vitamin C, vitamin A, and carbohydrate, respectively. For food groups, it was 26.3%, 11.9%, 5.6%, -9.5%, and -29.6% for milk and dairy products, green-yellow vegetables, total vegetables, rice, and confectioneries, respectively. CONCLUSIONS Tooth loss was linked with poorer nutrition even among dentists.

Liver cancer risk, coffee, and hepatitis C virus infection: a nested case–control study in Japan

We examined hepatocellular carcinoma mortality in relation to coffee consumption and anti-hepatitis C virus (HCV) antibody seropositivity in a nested case–control study involving 96 cases. The multivariate-adjusted odds ratios (95% confidence interval) for daily coffee drinkers vs non-drinkers were 0.49 (0.25–0.96), 0.31 (0.11–0.85), and 0.75 (0.29–1.92) in all cases, in HCV-positive and in HCV-negative individuals, respectively.

Intensive Smoking-cessation Intervention in the Dental Setting

Smoking exerts detrimental effects on dental treatment and oral health. Our goal was to evaluate effectiveness in terms of the abstinence rate in smoking-cessation intervention delivered by dental professionals. Individuals who were willing to quit smoking were randomly assigned to either an intervention or a non-intervention group. Intensive intervention was provided, consisting of 5 counseling sessions, including an additional nicotine replacement regimen. Reported abstinence was verified by the salivary cotinine level. Thirty-three persons in the intervention and 23 in the non-intervention group started the trial. On an intent-to-treat basis, 3-, 6- and 12-month continuous abstinence rates in the intervention group were 51.5%, 39.4%, and 36.4%, respectively, while the rates in the non-intervention group were consistent at 13.0%. Adjusted odds ratios (95% confidence interval) by logistic stepwise regression analyses were 7.1 (1.8, 28.5), 8.9 (1.7, 47.2), and 6.4 (1.3, 30.7), respectively. Intensive smoking-cessation intervention in the dental setting was therefore effective.

Serum Folate and Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism Adjusted for Folate Intake

Background Serum folate concentration is lower in individuals with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype than in those with the MTHFR 677CC or 677CT genotypes. Since studies considering folate intake are limited, we examined the association between folate intake and serum folate levels, according to the genotype. Methods The subjects comprised 170 Japanese persons (74 males and 96 females) aged 20-75 years who visited a clinic to test for Helicobacter pylori infection. Folate intake was estimated using a semiquantitative food-frequency questionnaire, and serum folate was measured in the residual fasting blood samples of the subjects. MTHFR C677T was genotyped using polymerase chain reaction. Results The geometric means of serum folate level were 6.19, 6.20, and 5.17 ng/mL among the 60 participants with the 677CC genotype, 90 participants with the 677CT genotype, and 20 participants with the 677TT genotype, respectively. No difference was noted in the mean folate intake estimated using the food-frequency questionnaire. Regression analysis showed that loge(serum folate) adjusted for age, sex, and loge(folate intake) was significantly lower among those with the 677TT genotype than among those with the 677CT or 677CC genotypes (p = 0.01). The adjusted reduction in serum folate was 20.2% (95% confidence interval, 5.4-32.6%) in the case of the 677TT genotype relative to the levels in the case of the 677CC/677CT genotypes. When folate intake was adjusted for total energy intake, using the residual method, the slope of the regression line for 677TT was smaller than those of the regression lines for 677CC and 677CT. Conclusion Individuals with the 677TT genotype may need to consume more folate to maintain serum folate levels similar to those found in individuals with the 677CC/677CT genotypes.