Kazuko Nishio

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.

Dietary intakes of fat and fatty acids and risk of breast cancer: a prospective study in Japan.

To examine the possible association of dietary fat and fatty acids with breast cancer risk in a population with a low total fat intake and a high consumption of fish, we analyzed data from the Japan Collaborative Cohort (JACC) Study. From 1988 to 1990, 26 291 women aged 40–79 years completed a questionnaire on dietary and other factors. Intakes of fat or fatty acids were estimated by using a food frequency questionnaire. Rate ratios (RR) were computed by fitting proportional hazards models. During the mean follow‐up of 7.6 years, 129 breast cancer cases were documented. We found no clear association of total fat intake with breast cancer risk; the multivariate‐adjusted RR across quartiles were 1.00, 1.29, 0.95, and 0.80 (95% confidence interval [CI] 0.46–1.38). A significant decrease in the risk was detected for the highest quartile of intake compared with the lowest for fish fat and long‐chain n‐3 fatty acids; the RR were 0.56 (95% CI 0.33–0.94) and 0.50 (0.30–0.85), respectively. A decreasing trend in risk was also suggested with an increasing intake of saturated fatty acids (trend P = 0.066). Among postmenopausal women at baseline, the highest quartile of vegetable fat intake was associated with a 2.08‐fold increase in risk (95% CI 1.05–4.13). This prospective study did not support any increase in the risk of breast cancer associated with total or saturated fat intake, but it suggested the protective effects of the long‐chain n‐3 fatty acids that are abundant in fish. (Cancer Sci 2005; 96: 590 – 599)

Active Smoking, Passive Smoking, and Breast Cancer Risk: Findings from the Japan Collaborative Cohort Study for Evaluation of Cancer Risk

Background Evidence is lacking regarding the relationship between cigarette smoking and breast cancer in Japanese women. We examined the association between breast cancer incidence and active and passive smoking in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk. Methods Our study comprised 34,401 women aged 40-79 years who had not been diagnosed previously with breast cancer and who provided information on smoking status at baseline (1988-1990). The subjects were followed from enrollment until December 31, 2001. Cox proportional-hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between breast cancer incidence and tobacco smoke. Results During 271,412 person-years of follow-up, we identified 208 incident cases of breast cancer. Active smoking did not increase the risk of breast cancer, with a HR for current smokers of 0.67 (95% CI: 0.32-1.38). Furthermore, an increased risk of breast cancer was not observed in current smokers who smoked a greater number of cigarettes each day. Overall, passive smoking at home or in public spaces was also not associated with an increased risk of breast cancer among nonsmokers. Women who reported passive smoking during childhood had a statistically insignificant increase in risk (HR: 1.24; 95% CI: 0.84-1.85), compared with those who had not been exposed during this time. Conclusion Smoking may not be associated with an increased risk of breast cancer in this cohort of Japanese women.

Impact of menstrual and reproductive factors on breast cancer risk in Japan: Results of the JACC study

The incidence of breast cancer among Japanese women, a traditionally low‐risk population, has increased substantially. To evaluate the association of reproductive factors with breast cancer risk, we examined 38 159 Japanese women, aged 40–79 years, who responded to a questionnaire on reproductive and other lifestyle factors from 1988 to 1990 in the Japan Collaborative Cohort Study. During an average 7.6 years of follow‐up, we documented 151 incidents of breast cancers. Cox proportional hazards modeling was employed to estimate relative risks (RR) and 95% confidence intervals (CI). There was a significant decline in the risk of breast cancer with increasing parity among parous women (trend P = 0.01). Women with four or more parities had a 69% lower risk than uniparous women, a reduced risk was also evident among menopausal women. Breast cancer risk tended to rise with increasing age at first delivery (trend P = 0.05), the association being very apparent among menopausal women (trend P = 0.02). Compared to the women who had their first delivery before age 25, those who delayed this event until after age 34 had an RR of 2.12 (95% CI: 0.72–6.21) and 3.33 (1.07–10.3) among the overall subjects and the menopausal, respectively. There was no apparent association of breast cancer risk with age at menarche or menopause. Our study concerning reproductive risk factors suggests that breast cancer in Japan is similar to that in Western countries, and that reproductive factors, particularly the number of parity and age at first delivery, might be important in the etiology of breast cancer among Japanese women. (Cancer Sci 2005; 96: 57–63)

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.

KLOTHO gene polymorphisms G-395A and C1818T are associated with lipid and glucose metabolism, bone mineral density and systolic blood pressure in Japanese healthy subjects.

BACKGROUND We investigated the association of KLOTHO gene single nucleotide polymorphisms (SNPs) with various laboratory data in 476 Japanese healthy subjects. METHODS The genotyping of G-395A in the promoter region and C1818T in exon 4 was performed using PCR with confronting 2-pair primers assay. RESULTS Multivariate analysis adjusted for age demonstrated that in men, body-fat ratio was high, and HDL cholesterol level was low in A allele carriers of G-395A compared with GG. In women, glucose was high in A allele carriers of G-395A compared with GG, and also in T allele carriers of C1818T compared with CC. When divided into 2 groups according to age, in men <60 y, body mass index, body-fat ratio and waist circumference were high in A carriers of G-395A compared with GG. In women <60 y, bone mineral density was high in A allele carriers of G-395A compared with GG, and systolic blood pressure and glucose were high in T carriers of C1818T compared with CC. CONCLUSIONS KLOTHO gene SNPs G-395A and C1818T are associated with lipid metabolism in men, and glucose metabolism, bone mineral density and systolic blood pressure in women.

Relationship between body mass index and the risk of ovarian cancer in the Japanese population: Findings from the Japanese Collaborate Cohort (JACC) study

Aim: The incidence of ovarian cancer in Japan has increased since the 1970s. The many studies that have assessed the relationship between body mass index (BMI) and the risk of ovarian cancer have produced contradictory results. Here we investigated this relation using data from the Japan Collaborative Cohort Study for the Evaluation of Cancer Risk, which was initiated in 1988.

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.

Smoking and serum CA19-9 levels according to Lewis and secretor genotypes.

CA19‐9, a marker for cancers of biliary tract, pancreas and colorectum, is not synthesized in those with no enzyme activity genotype (le/le) of Lewis (Le) gene. No enzyme activity genotype (se/se) of secretor (Se) gene is known to have an association with high serum CA19‐9 levels. There are also variations in serum CA19‐9 levels independent of the genotypes. This study aimed to examine the associations of serum CA19‐9 levels with smoking, alcohol drinking and body mass index (BMI; kg/m2), after the adjustments of Le and Se genotypes. Subjects were 486 health check‐up examinees (158 males and 328 females) aged from 39 to 90 years in Hokkaido, Japan. Genotyping was conducted for 3 polymorphisms; Le T59G (59T for Le allele and 59G for le allele), Se A385T (385A for Se allele and 385T for sej allele), and Se pseudogene (se5 allele). The genotypes of Le and Se were deterministic factors of serum CA19‐9. Those with Le/Le & se/se had the highest mean, while CA19‐9 was not detected or very low in those with le/le. Although no associations were observed with alcohol drinking and BMI, a significant association was observed with smoking. Among those with Le/Le, the geometric mean of CA19‐9 was significantly lower for current smokers than for noncurrent smokers (p = 0.011 in 4‐way ANOVA with age, sex and Se genotype). When hemoglobin A1c was further adjusted, the association became stronger (p = 0.0027). In addition to polymorphic variations, some components of cigarette smoke may influence the production or destruction of CA19‐9.

Prospective study of alcohol consumption and breast cancer risk in Japanese women

Epidemiologic evidence is lacking for the association between alcohol consumption and the risk of breast cancer in Japanese women. We addressed this association in a prospective cohort study with an average follow‐up of 7.6 years. At baseline (1988–1990), cohort participants completed a self‐administered questionnaire that included alcohol use, reproductive history and hormone use. The women were followed up for breast cancer incidence through December 31, 1997. Cox proportional hazards models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs) for breast cancer incidence and any association with alcohol consumption. During a follow‐up of 271,412 person‐years, we identified 151 women with breast cancer, of whom 45 were current drinkers and 11 drank ≥15 g of alcohol/day. After adjustment for age and other potential risk factors for breast cancer, the RR for current drinkers was 1.27 (95% CI 0.87–1.84) compared to nondrinkers. Average alcohol intake of <15 g/day did not significantly increase the risk for breast cancer. However, risk was significantly increased for women who consumed ≥15 g/day of alcohol (RR = 2.93, 95% CI 1.55–5.54). Age at starting drinking and frequency of consumption per week were not significantly associated with breast cancer risk. Our cohort study demonstrated that Japanese women who consume at least a moderate amount of alcohol have an increased risk of breast cancer.