Kouichi Yoshimasu

EPHX1 polymorphisms and the risk of lung cancer: a HuGE review.

Background: Microsomal epoxide hydrolase 1 (EPHX1) plays an important role in both the activation and detoxification of tobacco-derived carcinogens. Polymorphisms at exons 3 and 4 of the EPHX1 gene have been reported to be associated with variations in EPHX1 activity. The aim of this study is to review and summarize the available molecular epidemiologic studies of lung cancer and EPHX1. Methods: We searched MEDLINE, Current Contents, and Web of Science databases for studies published before August 2004. We conducted a systematic review and meta-analysis of 13 case–control studies. Summary odds ratios and summary prevalence of the variant allele (genotype) of both polymorphisms in the EPHX1 gene were calculated using the DerSimonian and Laird method. Results: The low-activity (variant) genotype of EPHX1 polymorphism at exon 3 was associated with decreased risk of lung cancer (odds ratio = 0.65; 95% confidence interval = 0.44–0.96) in lung cancer risk among whites. In white populations, the high-activity (variant) genotype of EPHX1 polymorphism at exon 4 was associated with a modest increase in risk of lung cancer (1.22; 0.79–1.90) and the predicted low activity was associated with a modest decrease in risk (0.72; 0.43–1.22). Conclusions: EPHX1 enzyme may act as a phase I enzyme in lung carcinogenesis. The low-activity genotype of EPHX1 gene is associated with decreased risk of lung cancer among whites.

Association between major depressive disorder and a functional polymorphism of the 5-hydroxytryptamine (serotonin) transporter gene: a meta-analysis

Objectives A functional polymorphism in the promoter region of the 5-hydroxytryptamine (serotonin) transporter (5-HTT) gene, termed 5-HTTLPR, alters transcription of the 5-HTT gene. The short variation (S allele) produces less transcriptional efficiency of serotonin, which can partly account for psychiatric disorders. Despite strong biological plausibility, the relationship between 5-HTTLPR and the risk of major depressive disorder (MDD) is unclear. To elucidate the relationship, we applied meta-analysis techniques to molecular studies of 5-HTTLPR and MDD. Methods A total of 22 articles were identified from MEDLINE through March 2008, using the search keywords ‘depression,’ ‘5-HTTLPR’, and ‘polymorphism.’ The authors assessed the evidence of genotypic association using STATA Version 8.2. Results Summary frequencies of the S allele of 5-HTTLPR among Caucasians and Asians based on the random effects model were 42.1% [95% confidence interval (CI) = 40.5–43.6] and 76.8% (95% CI = 73.9–79.7), respectively. The distribution of the S allele was significantly different between Asians and Caucasians (P<0.001). The SS genotype was significantly associated with an increased risk of MDD among Caucasian populations (odds ratio = 1.41, 95% CI = 1.15–1.72), although there was no significant association among Asians. Conclusion Although the summary risk for developing MDD in individuals with the ‘at-risk’ SS genotype of 5-HTTLPR may be small, MDD is such a common disease that even a small increase in risk translates to a large number of excess MDD cases in the population. Thus, 5-HTT may be a candidate MDD susceptibility gene.

A meta-analysis of the evidence on the impact of prenatal and early infancy exposures to mercury on autism and attention deficit/hyperactivity disorder in the childhood

Although a measurable number of epidemiological studies have been conducted to clarify the associations between mercury exposure during embryo or early infancy and later incidences of autism spectrum disorders (ASD) or attention-deficit hyperactivity disorder (ADHD), the conclusion still remains unclear. Meta-analysis was conducted for two major exposure sources; i.e., thimerosal vaccines that contain ethylmercury (clinical exposure), and environmental sources, using relevant literature published before April 2014. While thimerosal exposures did not show any material associations with an increased risk of ASD or ADHD (the summary odds ratio (OR) 0.99, 95% confidence interval (CI) 0.80-1.24 for ASD; OR 0.91, 95% CI 0.70-1.13 for ADHD/ADD), significant associations were observed for environmental exposures in both ASD (OR 1.66, 95% CI 1.14-2.17) and ADHD (OR 1.60, 95% CI 1.10-2.33). The summary ORs were similar after excluding studies not adjusted for confounders. Moderate adverse effects were observed only between environmental inorganic or organic mercury exposures and ASD/ADHD. However, these results should be interpreted with caution since the number of epidemiological studies on this issue was limited and still at an early stage. Further studies focused on subjects with genetic vulnerabilities of developmental disorders are warranted for better understanding of the effects of such environmental exposures.

Genetic polymorphisms and environmental risk of lung cancer: a review.

Lung cancer results from man-made and natural environmental exposures acting in concert with both genetic and acquired characteristics. Chronic inhalation of cigarette smoke is a major risk factor, and environmental tobacco exposure can cause lung cancer in life-long neversmokers. Air pollution, indoor-radon exposure, occupational exposures, dietary, physical activity, and reproductive history have been identified as independent or contributing risk factors for lung cancer. Because only a small portion of smokers develops the disease, genetic susceptibility can contribute to the risk. Developments in molecular biology have led to the discovery of biological markers that increase predisposition to lung carcinogenesis. Therefore, the high-risk genotype of an individual can be determined easily. Because of the great number of carcinogen-activating and -detoxifying enzymes, the variation in their expression, the complexity of exposures to tobacco carcinogens, and the existence of multiple alleles at loci of those enzymes results in differential susceptibilities of individuals. As lung cancer is a multifactorial disease, an improved understanding of the interplay of environmental and genetic polymorphisms at multiple loci can help identify individuals who are at increased risk for lung cancer. Hopefully, in the future we will be able to screen for lung cancer susceptibility by using specific biomarkers.

Molecular epidemiology of major depressive disorder

Major depressive disorder causes significant morbidity, affecting people’s ability to work, function in relationships, and engage in social activities. Moreover, major depressive disorder increases the risk of suicidal ideation, attempted suicide and death by completed suicide. There is evidence that chronic stress can cause major depressive disorder. As for genetic factors, only minor susceptibility genes have been reliably identified. The serotonin system provides a logical source of susceptibility genes for depression, because this system is the target of selective serotonin reuptake-inhibitor drugs that are effective in treating depression. The 5-hydroxytryptamine (serotonin) transporter (5-HTT) has received particular attention because it is involved in the reuptake of serotonin at brain synapses. One common polymorphic variant of the 5-HTT-linked polymorphic region (5-HTTLPR), which affects the promoter of the 5-HTT gene, causes reduced uptake of the neurotransmitter serotonin into the presynaptic cells in the brain. The authors discussed the relationship between genetic polymorphisms and major depressive disorder, with special emphasis on the 5-HTTTLPR polymorphism. As the 5-HTTLPR polymorphism was significantly associated with an increased risk of major depressive disorder, the 5-HTT gene may be a candidate for a major depressive disorder susceptibility gene. As major depressive disorder is a multifactorial disease, an improved understanding of the interplay of environmental and genetic polymorphisms at multiple loci may help identify individuals who are at increased risk for major depressive disorder. Hopefully, in the future we will be able to screen for major depressive disorder susceptibility by using specific biomarkers.

Gender differences in psychiatric symptoms related to suicidal ideation in Japanese patients with depression

Abstract  Recent figures show that more than 30 000 people suicide each year in Japan, and that many of them are considered to suffer from depression. In addition, the suicide rate among Japanese women has been shown to be higher than in other countries. However, it is not clear whether the psychiatric symptoms leading to suicide differ by gender. The authors examined gender differences in psychiatric symptoms related to suicidal ideation (SI) in Japanese patients with depression. Study subjects were 199 new patients (66 men and 133 women) who were diagnosed with a major depressive disorder. SI and psychiatric symptoms were assessed by several psychological tests using questionnaires. Logistic regression analysis was used to calculate the odds ratio (OR) and 95% confidence interval (CI) with an adjustment for all relevant factors simultaneously. The stepwise method was also used for selecting variables. In univariate analysis, several psychosocial factors such as self‐reproach, derealization, depressive moods, depersonalization, and anxiety traits were statistically significantly associated with SI in both men and women. However, multivariate analysis using the stepwise method distinguished gender differences. Low social/family support and depersonalization were statistically significantly associated with SI in men, while depressive moods and an anxiety state were significantly associated with SI in women. The relation between derealization and SI was statistically significant in women but not significant in men.

Epidemiological aspects of intermittent explosive disorder in Japan; prevalence and psychosocial comorbidity: Findings from the World Mental Health Japan Survey 2002-2006

The purpose of the present study is to evaluate the prevalence of intermittent explosive disorder (IED) as well as its comorbidity with other mental disorders in a Japanese community sample. Subjects were 4,134 residents in selected sites in Japan. Diagnoses of mental disorders are based on the World Mental Health Survey Initiative Version of the World Health Organization Composite International Diagnostic Interview. Lifetime and 12-month prevalence of IED were 2.1% and 0.7%, respectively, whereas those of narrow IED were 1.2% and 0.6%, respectively. Male gender and young age were positively associated with an increased prevalence of IED. Mood and anxiety disorders as well as suicidal ideation were shown to be associated with IED in both genders. The overall association between anxiety disorders and IED was stronger in women than in men. Positive association of substance use problems with IED was also observed. Similar findings were observed between those psychosocial factors and narrow IED. These results suggest that people having those mixed complications might have a high suicidal risk. Further research using psychological measures for anger suppression will lead to more thorough understanding of the effects of IED on psychosocial comorbidity and suicidal risk.

Lung cancer susceptibility: are we on our way to identifying a high-risk group?

Many studies have investigated lung cancer susceptibility based on the presence of low-penetrance, high-frequency single nucleotide polymorphisms. Identifying such susceptibility polymorphisms may lead to the development of tests that allow a more focused follow-up of a high-risk group. Genetic polymorphisms of xenobiotic metabolism, DNA repair, cell-cycle control, immunity, addiction and nutritional status have been described as promising candidates. Genetic polymorphisms in both metabolic activation (Phase I) and detoxification (Phase II) enzymes influence DNA damage. The DNA repair system is a critical cellular response that counteracts the carcinogenic effects of DNA. Thus, genetically determined susceptibility to carcinogens depends on the balance between metabolic and DNA repair enzymes. This review evaluates whether or not a specific polymorphism or a combination of such polymorphisms can effectively predict high-risk groups.

Suicidal behavior and psychological distress in university students: a 12-nation study

This study investigated the prevalence of suicidal behavior and psychological distress in university students across 12 nations. A total of 5,572 university students from 12 countries were surveyed about suicide ideation, suicide attempts, and psychological distress by means of a self-administered questionnaire. Almost 29% of the samples reported having contemplated suicide and 7% reported attempting suicide. Of the total sample, 51.1% scored above the General Health Questionnaire-12 ≥ 3 cut-off points, 41.6% above the GHQ-12 ≥ 4 cut-off points, and 33.8% scored above the GHQ-12 ≥ 5 cut-off points. While odds of suicide ideation were elevated in Austria and the UK, reduced ORs were detected for China, Italy, Saudi Arabia, Tunisia, and Turkey. Similarly, while odds of suicide attempt were high in Jordan, Palestine, Saudi Arabia, and to some extent in Turkey, reduced ORs were observed for Austria, China, Italy, Japan and the United States. Elevated ORs for psychological distress were seen in Japan, Jordan, Palestine, Saudi Arabia, Tunisia, and Turkey but reduced ORs were noted in Austria, China, Iran, Italy, and the United States. Psychological distress was strongly associated with reports of suicide ideation and attempts. Suicide ideation, suicide attempt, and psychological distress are common in university students but their rates vary depending on the sociocultural context. Due attention should be devoted to the mental health needs of young adults enrolled in higher educational institutions and more cross-cultural research is warranted to better understand the etiology of the observed intersocietal variations in suicidal behavior and psychological distress.

Genetic alcohol sensitivity regulated by ALDH2 and ADH1B polymorphisms is strongly associated with depression and anxiety in Japanese employees

BACKGROUND Although alcohol-related disorders (ARD) have been shown to be accompanied by comorbid depressive and anxiety disorders, and alcohol metabolic enzyme genes, ADH1B and ALDH2 polymorphisms, have been associated with an increased risk of ARD, no studies have been conducted to evaluate the associations between these genetic polymorphisms and anxiety or depression. METHOD A total of 1944 Japanese workers were interviewed regarding their depressive and anxiety disorders, including suicidality, by a brief psychiatric structured interview (MINI). We investigated the relationship of ADH1B rs1229984 and ALDH2 rs671 polymorphism combinations with mental disorder risks. Logistic regression analysis was used to evaluate the associations between those polymorphisms and anxiety/depressive disorders, adjusting for sex, age, and job rank. The degree of alcohol sensitivity was classified into five groups according to the combination of two enzyme genotypes (Group I-V, in order from the lowest alcohol sensitivity). RESULTS Those with ALDH2(*)1/(*)1 and ADH1B(*)1/(*)1 were likely to be at an increased risk of depressive and anxiety disorders as well as ARD. This tendency was more apparent among non-drinkers (OR 9.20, 95% CI 1.66-50.89). No adverse effects of ALDH2 or ADH1B alone were observed with mental disorder risks. Likewise, analyses conducted combining job rank and genetic alcohol sensitivity showed no material associations with such risks. CONCLUSIONS Genetic alcohol sensitivity, especially that with the genotype combination of ALDH2(*)1/(*)1 and ADH1B(*)1/(*)1, was significantly associated with an increased risk of depressive and anxiety disorders as well as ARD.