Although nutrient intake and alcohol consumption are both closely associated with the incidence o... more Although nutrient intake and alcohol consumption are both closely associated with the incidence of diabetes, their interrelationships remain unclear. Therefore, we herein have investigated the interrelationships among nutrient intake, alcohol consumption, and the incidence of diabetes using longitudinal data. This study included 969 residents ≥40 years living in Japan. In 2011 and 2012, a baseline study was conducted using questionnaires on basic demographics, diabetes, nutrient intake, and lifestyle habits. In 2018 and 2019, a follow-up study was performed using questionnaires and medical records on diabetes. Two-way analysis of covariance (two-way ANCOVA) was used to test the interactions of drinking habits and diabetes incidence on nutrients intake. The prospective relationship between nutrient intake at baseline and the incidence of diabetes in the follow-up stratified by drinkers and non-drinkers was evaluated using multiple logistic regression analysis. Interactions were observed for vegetable protein intake (p = 0.023) and animal fat intake (p = 0.016) in males. Vegetable protein intake negatively correlated with the incidence of diabetes in non-drinkers (odds ratio (OR): 0.208; 95% confidence interval (95% CI): 0.046-0.935; p = 0.041). Furthermore, animal fat intake positively correlated with the incidence of diabetes in non-drinkers (OR: 1.625; 95% CI: 1.020-2.589; p = 0.041). Therefore, vegetable protein and animal fat intakes in combination with drinking habits need to be considered for the prevention of diabetes.
Selenoprotein P is a hepatokine with antioxidative properties that eliminate a physiologic burst ... more Selenoprotein P is a hepatokine with antioxidative properties that eliminate a physiologic burst of reactive oxygen species required for intracellular signal transduction. Serum levels of selenoprotein P are elevated during aging and in people with type 2 diabetes, non-alcoholic fatty liver disease, and hepatitis C. However, how serum levels of full-length selenoprotein P are regulated largely remains unknown, especially in the general population. To understand the significance of serum selenoprotein P levels in the general population, we evaluated intrinsic and environmental factors associated with serum levels of full-length selenoprotein P in 1,183 subjects participating in the Shika-health checkup cohort. Serum levels of selenium were positively correlated with liver enzymes and alcohol intake and negatively correlated with body mass index. Serum levels of selenoprotein P were positively correlated with age, liver enzymes, and alcohol intake. In multiple regression analyses, alcohol intake was positively correlated with serum levels of both selenium and selenoprotein P independently of age, gender, liver enzymes, and fatty liver on ultrasonography. In conclusion, alcohol intake is associated with elevated serum levels of selenium and selenoprotein P independently of liver enzyme levels and liver fat in the general population. Moderate alcohol intake may exert beneficial or harmful effects on health, at least partly by upregulating selenoprotein P. These findings increase our understanding of alcohol-mediated redox regulation and form the basis for the adoption of appropriate drinking guidelines.
International Journal of Environmental Research and Public Health, Aug 10, 2022
Polygenic susceptibility likely influences individual responses to air pollutants and the risk of... more Polygenic susceptibility likely influences individual responses to air pollutants and the risk of asthma. We compared the role of polygenic susceptibility on air pollution-associated asthma between German and Japanese women. We investigated women that were enrolled in the German SALIA cohort (n = 771, mean age = 73 years) and the Japanese Shika cohort (n = 847, mean age = 67 years) with known asthma status. Adjusted logistic regression models were used to assess the associations between (1) particulate matter with a median aerodynamic diameter ≤ 2.5µm (PM 2.5 ) and nitrogen dioxide (NO 2 ), (2) polygenic risk scores (PRS), and (3) gene-environment interactions (G × E) with asthma. We found an increased risk of asthma in Japanese women after exposure to low pollutant levels (PM 2.5 : median = 12.7µg/m 3 , p-value < 0.001, NO 2 : median = 8.5µg/m 3 , p-value < 0.001) and in German women protective polygenic effects (p-value = 0.008). While we found no significant G × E effects, the direction in both groups was that the PRS increased the effect of PM 2.5 and decreased the effect of NO 2 on asthma. Our study confirms that exposure to low air pollution levels increases the risk of asthma in Japanese women and indicates polygenic effects in German women; however, there was no evidence of G × E effects. Future genome-wide G × E studies should further explore the role of ethnic-specific polygenic susceptibility to asthma.
Glucokinase has an important role in regulating glycolysis as a glucose sensor in liver and pancr... more Glucokinase has an important role in regulating glycolysis as a glucose sensor in liver and pancreatic β cells. Glucokinase-maturity onset diabetes in young (GCK-MODY also known as MODY2) is caused by autosomal dominant gene mutation of the GCK gene; it is characterized by mild fasting hyperglycemia and small 2-h glucose increment during 75 g-oral glucose tolerance test (OGTT) as well as near-normal postprandial glucose variabilities. A 10-year-old girl with family history of diabetes visited her physician after being found positive for urinary glucose by school medical checkup. She received a diagnosis of diabetes based on the laboratory data: 75 g-OGTT (mild fasting hyperglycemia and small 2-h glucose increment) and factory-calibrated glucose monitoring (mild elevation of average glucose level and near-normal glycemic variability), which raised suspicion of GCK-MODY. She was then referred to our institution for genetic examination, which revealed a GCK heterozygous mutation (NM_000162: exon10: c.1324G>T: p.E442X) in the proband as well as in her mother and maternal grandmother, who had been receiving anti-diabetes medications without knowing that they had GCK-MODY specifically. GCK-MODY cases show incidence of microvascular and macrovascular diseases similar to that of normal subjects, and their glucose levels are adequately controlled without anti-diabetes drug use. Thus, early and definitive diagnosis of MODY2 by genetic testing is important to avoid unnecessary medication.
Background: Few epidemiological studies have been performed to clarify the association between gl... more Background: Few epidemiological studies have been performed to clarify the association between glucose metabolism disorders in early adults (20 years old) and physiological and environmental factors, including body mass index (BMI) in junior high school days. Therefore, we examined the association between hemoglobin A1c (HbA1c) level and body size (BMI) in early adulthood and lifestyles, including sleep habits and BMI in junior high school days in Shika town, a small town in Japan, by conducting a retrospective cohort study. We examined the HbA1c levels and body size (BMI) of 99 early adults who turned 20 years old between 2016 and 2020 and were residing in Shika town, Ishikawa Prefecture. We obtained the information on lifestyles and living environment factors, including BMI, from a questionnaire survey conducted among the subjects during their junior high school days (13-15 years old) from 2009 to 2013. No correlations were observed between the HbA1c levels and the BMI values of the early adults. A two-way analysis of covariance (with the HbA1c levels and BMI values of the early adults as main factors) of the body size and lifestyle habits of the junior high school students revealed that "sleep quality in junior high school" was significantly poorer in the high HbA1c group than in the low HbA1c group in the early adults with high BMI values only. This result was also supported by the logistic regression analysis result. The present results indicate that poor sleep quality in junior high school was associated with the high HbA1c levels of the early adults with higher BMI values, which suggests that good sleep quality in junior high school
Dens evaginatus (DE) is a dental abnormality characterized by tubercles on the occlusal surfaces ... more Dens evaginatus (DE) is a dental abnormality characterized by tubercles on the occlusal surfaces of teeth and is associated with the risk of pulpal inflammation due to fractures. The cause of DE remains unclear, as limited data are available to determine its etiology. The aim of this study was to investigate the genetic background of DE using whole-exome sequencing (WES). Saliva samples were collected from two patients of Family A and three patients of Family B, including an incident case of DE, and analyzed using WES. Rare variants were extracted from the WES data and filtered by family to extract candidate variants. Gene variants of TLR3 and MDC1 were identified as etiologic factors for DE. The variant MDC1 (c.3908C>T) was identified to be damaging, according to the scores from Polymorphism Phenotyping v2. Our findings contribute towards an understanding of the etiology of DE, which would facilitate improved treatment to prevent the risk of DE fractures and pulpal inflammation. Understanding the mechanism of DE development may also be helpful for developing regenerative medicine and gene therapy strategies.
In cancer patients, circulating cell-free DNA (cfDNA) includes tumor-derived DNA (tDNA). cfDNA ha... more In cancer patients, circulating cell-free DNA (cfDNA) includes tumor-derived DNA (tDNA). cfDNA has been used clinically for non-invasive gene mutation testing. The aim of this study was to characterize the features of the genetic alterations detected in cfDNA. This study included 6 patients with primary lung cancer who died due to cancer progression. Tumors were biopsied at autopsy. Genetic alteration profiles were obtained using next generation sequencing. The features of the tDNA genetic alterations detected in cfDNA included a higher frequency of being present in multiple tumors (67% truncal mutations, 36% shared mutations, and 4% individual mutations) and a higher variant allele frequency (VAF; 47.6% versus 4.1% for tDNA alterations detected in cfDNA versus not detected in cfDNA, respectively). The data revealed that the tumor-derived genetic alterations most easily detected in cfDNA were truncal mutations with a high VAF. These results showed that essential genetic alterations enriched in cfDNA could help to characterize cancer cells and that genetic testing using cfDNA has advantages in the detection of fundamental regulatory aberrations occurring during tumorigenesis. Circulating cell-free DNA (cfDNA) is present at very low levels as fragments in the bloodstream. cfDNA includes circulating tumor-derived DNA (ctDNA) in patients with malignancies. Cancer-related genetic alterations can be detected in cfDNA from patients with malignancies 1-6 . Therefore, cfDNA has been clinically examined as a liquid biopsy source in oncogene testing. Liquid biopsies are advantageous because they can be performed safely and repeatedly, and they are less invasive than tumor biopsies. Recently, cfDNA-based mutation tests of the epidermal growth factor receptor (EGFR) gene have been approved as in vitro diagnostic tests in clinical settings worldwide, including in Japan. They are used in treatment decision-making for patients with advanced non-small cell lung cancer (NSCLC). One drawback of cfDNA-based genetic testing is that the detection sensitivity is not always satisfactory . The hope is that cfDNA can provide an alternative sample source for genetic testing. Efforts to improve the sensitivity of mutation detection in cfDNA are actively underway. Simultaneously, clarifying the characteristics of genetic alterations detectable in cfDNA will provide useful information for understanding the results of cfDNA genetic testing and effectively using this method in clinical practice. Although tumor biopsies are essential for pathological diagnosis, and tumor tissue is the first choice for genetic tests conducted in patients with NSCLC, it is unclear whether tissue biopsy specimens are representative of the genetic characteristics of the whole tumor burden of a patient. That is, the biopsy sample is collected from only a small part of the tumor. Samples obtained from transbronchial biopsy, which is one of the most widely used methods of tumor collection in advanced NSCLC, are very limited and represent a small fraction of the tumor lesion. Tumor cells in advanced malignancies exhibit inter-or intratumoral heterogeneity that limits the response to targeted treatments 1 . Low-volume specimens, such as those from transbronchial biopsies, are likely to contain only a small portion of the genetic alterations present; thus, clinicians evaluating these specimens may miss important alterations critical for treatment decision-making because of intra-and intertumoral heterogeneity. In contrast, ctDNA may contain genetic alterations derived from multiple tumor lesions, and ctDNA analyses have the potential to provide an overall picture of all tumor-derived genetic alterations in patients with
Chronic nonbacterial osteomyelitis is a rare bone disorder that can be found in the jaw. It is of... more Chronic nonbacterial osteomyelitis is a rare bone disorder that can be found in the jaw. It is often associated with systemic conditions, including autoimmune deficiencies. However, little is known about how the genetic and immunologic background of patients influences the disease. Here, we focus on human leukocyte antigen (HLA), killer cell immunoglobulin-like receptors (KIRs), and their specific combinations that have been difficult to analyze owing to their high diversity. We employed a recently developed technology of simultaneous typing of HLA alleles and KIR haplotype and investigated alleles of the 35 HLA loci and KIR haplotypes composed of centromeric and telomeric motifs in 18 cases and 18 controls for discovery and 472 independent controls for validation. We identified an amino acid substitution of threonine at position 94 of HLA-C in combination with the telomeric KIR genotype of haplotype tA01/tB01 that had significantly higher frequency (>20%) in the case population than in both control populations. Multiple logistic regression analysis based on a dominant model with adjustments for age and sex revealed and validated its statistical significance and high predictive accuracy (C-statistic ≥0.85). Structure-based analysis revealed that the combination of the amino acid change in HLA-C and the telomeric genotype tA01/tB01 could be associated with lower stability of HLA-C. This is the first case-control study of a rare disease that employed the latest sequencing technology enabling simultaneous typing and investigated amino acid polymorphisms at HLA loci in combination with KIR haplotype.
Aims/Introduction: Risk factors of type 2 diabetes mellitus in Japanese women with recent gestati... more Aims/Introduction: Risk factors of type 2 diabetes mellitus in Japanese women with recent gestational diabetes mellitus are unknown. The objective of the present study was to investigate the clinical and genetic characteristics associated with postpartum abnormal glucose tolerance in Japanese women with gestational diabetes mellitus. Materials and Methods: A total of 213 Japanese women with recent gestational diabetes mellitus who underwent a postpartum 2-h oral glucose tolerance test were investigated. The association between antepartum clinical characteristics and postpartum abnormal glucose tolerance (diabetes or prediabetes based on the Japan Diabetes Society criteria) was examined. Frequencies of 45 known type 2 diabetes mellitus-associated genetic variants were also compared between women with and without postpartum abnormal glucose tolerance. Results: A total of 59 women showed postpartum abnormal glucose tolerance (prediabetes, n = 51; diabetes, n = 8). Plasma glucose levels at 1 or 2 h, the insulinogenic index and the insulin secretion-sensitivity index-2 of the antepartum oral glucose tolerance test were independent of postpartum abnormal glucose tolerance risk factors (P = 0.006, P = 0.00002, P = 0.01 and P = 0.006, respectively). Four genetic variants (rs266729 [ADI-POQ], rs6017317 [HNF4A], rs5215 [KCNJ11] and rs7177055 [HMG20A]) showed a nominally significant association with postpartum abnormal glucose tolerance (P < 0.05, respectively). Among these, three were related to insulin secretion. Postpartum abnormal glucose tolerance risk significantly increased with increasing risk-allele number (P = 0.0005; odds ratio 1.91). Conclusions: Clinical features and genetic variants related to impaired insulin secretion are risk factors of postpartum abnormal glucose tolerance in Japanese women with recent gestational diabetes mellitus.
Although chronic pain (CP) is classified as inflammatory or non-inflammatory, the involvement of ... more Although chronic pain (CP) is classified as inflammatory or non-inflammatory, the involvement of fatty acid intake in this process has not yet been examined in detail. Therefore, the present study investigated whether the relationship between CP and fatty acid intake differs between high and low C-reactive protein (CRP) levels in middle-aged and elderly individuals in the Shika study. One-thousand and seven males and 1216 females with mean ages of 68⋅78 and 69⋅65 years, respectively, participated in the present study. CRP was quantified by blood sampling from participants who responded to a CP questionnaire. The brief-type self-administered diet history questionnaire (BDHQ) was used to assess fatty acid intake. Interactions were observed between CP and CRP on monounsaturated fatty acids (MUFA) and eicosadienoic acid in a two-way analysis of covariance adjusted for sex, age, lack of exercise, lack of sleep, current smoking and drinking status, and BMI. MUFA (OR 1⋅359) and eicosadienoic acid (OR 1⋅072) were identified as significant independent variables for CP in a multiple logistic regression analysis, but only in the low CRP group. Only a high intake of MUFA and eicosadienoic acid was associated with chronic neck/shoulder/upper limb pain without elevated CRP. In psychogenic and neuropathic pain without elevated CRP,
L eukocytes that lack expression of HLA alleles are frequently detected in patients with acquired... more L eukocytes that lack expression of HLA alleles are frequently detected in patients with acquired aplastic anemia (AA) who respond to immunosuppressive therapy, although the exact mechanisms underlying the HLA loss and HLA allele repertoire likely to acquire loss-of-function mutations are unknown. We identified a common nonsense mutation at codon 19 (c.19C>T, p.R7X) in exon 1 (Exon1 mut ) of different HLA-A and -B alleles in HLA-lacking granulocytes from AA patients. A droplet digital polymerase chain reaction assay capable of detecting as few as 0.07% Exon1 mut HLA alleles in total DNA revealed that the mutation was present in 29% (101/353) of AA patients, with a median allele frequency of 0.42% (range, 0.071% to 21.3%). Exon1 mut occurred in only 12 different HLA-A (n=4) and HLA-B (n=8) alleles, including B*40:02 (n=31) and A*02:06 (n=15), which correspond to four HLA class I supertypes (A02, A03, B07, and B44). The percentages of patients who possessed at least one of these 12 HLA alleles were significantly higher in the 353 AA patients (92%, P<0.001) and in 83 AA patients with copy number neutral loss of heterozygosity in chromosome 6p (100%, P<0.001) than the percentage (81%) in 18,604 Japanese healthy individuals. Eighty-two percent (37/45) of AA patients with Exon1 mut responded to immunosuppressive therapy. Small populations of leukocytes that lack particular HLA-A or B alleles due to Exon1 mut are common in AA patients. The detection of Exon1 mut using a droplet digital polymerase chain reaction assay without the need for HLA typing may serve as a powerful tool for diagnosing the immune pathophysiology of patients with bone marrow failure.
Recent archaeogenomic studies in Mongolia have elucidated the genetic origins of people from the ... more Recent archaeogenomic studies in Mongolia have elucidated the genetic origins of people from the Xiongnu and Mongol eras, but left the Medieval period between them only tangentially explored. Due to this dearth of ancient genomes, the dynamic history of Medieval Mongolia with the rise and fall of numerous polities still lacks a genomic perspective. To fill in this knowledge gap, here we report whole-genome sequences of nine ancient individuals from eastern Mongolia, who were excavated from two nearby cemeteries, Gurvan Dov and Tavan Khailaast. They are distributed from the Xiongnu-Xianbei period (ca. 200 CE) to the Mongol era (ca. 1,400 CE), forming a local time transect encompassing nearly 1,200 years. Remarkably, despite the long-time span, all nine individuals derive most of their ancestry (85-100%) from the eastern Eurasian lineages and show low
Mitochondrial DNA (mtDNA) mutations are found in many types of cancers and suspected to be involv... more Mitochondrial DNA (mtDNA) mutations are found in many types of cancers and suspected to be involved in carcinogenesis, although the mechanism has not been elucidated. In this study, we report that consecutive C-to-T mutations (hypermutations), a unique feature of mutations induced by APOBECs, are found in mtDNA from cervical dysplasia and oropharyngeal cancers. In vitro, we found that APOBEC3A (A3A) and 3B (A3B) expression, as well as mtDNA hypermutation, were induced in a cervical dysplastic cell line W12 when cultured in a differentiating condition. The ectopic expression of A3A or A3B was sufficient to hypermutate mtDNA. Fractionation of W12 cell lysates and immunocytochemical analysis revealed that A3A and A3B could be contained in mitochondrion. These results suggest that mtDNA hypermutation is induced upon keratinocyte differentiation, and shed light on its molecular mechanism, which involves A3s. The possible involvement of mtDNA hypermutations in carcinogenesis is also discu...
Although nutrient intake and alcohol consumption are both closely associated with the incidence o... more Although nutrient intake and alcohol consumption are both closely associated with the incidence of diabetes, their interrelationships remain unclear. Therefore, we herein have investigated the interrelationships among nutrient intake, alcohol consumption, and the incidence of diabetes using longitudinal data. This study included 969 residents ≥40 years living in Japan. In 2011 and 2012, a baseline study was conducted using questionnaires on basic demographics, diabetes, nutrient intake, and lifestyle habits. In 2018 and 2019, a follow-up study was performed using questionnaires and medical records on diabetes. Two-way analysis of covariance (two-way ANCOVA) was used to test the interactions of drinking habits and diabetes incidence on nutrients intake. The prospective relationship between nutrient intake at baseline and the incidence of diabetes in the follow-up stratified by drinkers and non-drinkers was evaluated using multiple logistic regression analysis. Interactions were observed for vegetable protein intake (p = 0.023) and animal fat intake (p = 0.016) in males. Vegetable protein intake negatively correlated with the incidence of diabetes in non-drinkers (odds ratio (OR): 0.208; 95% confidence interval (95% CI): 0.046-0.935; p = 0.041). Furthermore, animal fat intake positively correlated with the incidence of diabetes in non-drinkers (OR: 1.625; 95% CI: 1.020-2.589; p = 0.041). Therefore, vegetable protein and animal fat intakes in combination with drinking habits need to be considered for the prevention of diabetes.
Selenoprotein P is a hepatokine with antioxidative properties that eliminate a physiologic burst ... more Selenoprotein P is a hepatokine with antioxidative properties that eliminate a physiologic burst of reactive oxygen species required for intracellular signal transduction. Serum levels of selenoprotein P are elevated during aging and in people with type 2 diabetes, non-alcoholic fatty liver disease, and hepatitis C. However, how serum levels of full-length selenoprotein P are regulated largely remains unknown, especially in the general population. To understand the significance of serum selenoprotein P levels in the general population, we evaluated intrinsic and environmental factors associated with serum levels of full-length selenoprotein P in 1,183 subjects participating in the Shika-health checkup cohort. Serum levels of selenium were positively correlated with liver enzymes and alcohol intake and negatively correlated with body mass index. Serum levels of selenoprotein P were positively correlated with age, liver enzymes, and alcohol intake. In multiple regression analyses, alcohol intake was positively correlated with serum levels of both selenium and selenoprotein P independently of age, gender, liver enzymes, and fatty liver on ultrasonography. In conclusion, alcohol intake is associated with elevated serum levels of selenium and selenoprotein P independently of liver enzyme levels and liver fat in the general population. Moderate alcohol intake may exert beneficial or harmful effects on health, at least partly by upregulating selenoprotein P. These findings increase our understanding of alcohol-mediated redox regulation and form the basis for the adoption of appropriate drinking guidelines.
International Journal of Environmental Research and Public Health, Aug 10, 2022
Polygenic susceptibility likely influences individual responses to air pollutants and the risk of... more Polygenic susceptibility likely influences individual responses to air pollutants and the risk of asthma. We compared the role of polygenic susceptibility on air pollution-associated asthma between German and Japanese women. We investigated women that were enrolled in the German SALIA cohort (n = 771, mean age = 73 years) and the Japanese Shika cohort (n = 847, mean age = 67 years) with known asthma status. Adjusted logistic regression models were used to assess the associations between (1) particulate matter with a median aerodynamic diameter ≤ 2.5µm (PM 2.5 ) and nitrogen dioxide (NO 2 ), (2) polygenic risk scores (PRS), and (3) gene-environment interactions (G × E) with asthma. We found an increased risk of asthma in Japanese women after exposure to low pollutant levels (PM 2.5 : median = 12.7µg/m 3 , p-value < 0.001, NO 2 : median = 8.5µg/m 3 , p-value < 0.001) and in German women protective polygenic effects (p-value = 0.008). While we found no significant G × E effects, the direction in both groups was that the PRS increased the effect of PM 2.5 and decreased the effect of NO 2 on asthma. Our study confirms that exposure to low air pollution levels increases the risk of asthma in Japanese women and indicates polygenic effects in German women; however, there was no evidence of G × E effects. Future genome-wide G × E studies should further explore the role of ethnic-specific polygenic susceptibility to asthma.
Glucokinase has an important role in regulating glycolysis as a glucose sensor in liver and pancr... more Glucokinase has an important role in regulating glycolysis as a glucose sensor in liver and pancreatic β cells. Glucokinase-maturity onset diabetes in young (GCK-MODY also known as MODY2) is caused by autosomal dominant gene mutation of the GCK gene; it is characterized by mild fasting hyperglycemia and small 2-h glucose increment during 75 g-oral glucose tolerance test (OGTT) as well as near-normal postprandial glucose variabilities. A 10-year-old girl with family history of diabetes visited her physician after being found positive for urinary glucose by school medical checkup. She received a diagnosis of diabetes based on the laboratory data: 75 g-OGTT (mild fasting hyperglycemia and small 2-h glucose increment) and factory-calibrated glucose monitoring (mild elevation of average glucose level and near-normal glycemic variability), which raised suspicion of GCK-MODY. She was then referred to our institution for genetic examination, which revealed a GCK heterozygous mutation (NM_000162: exon10: c.1324G>T: p.E442X) in the proband as well as in her mother and maternal grandmother, who had been receiving anti-diabetes medications without knowing that they had GCK-MODY specifically. GCK-MODY cases show incidence of microvascular and macrovascular diseases similar to that of normal subjects, and their glucose levels are adequately controlled without anti-diabetes drug use. Thus, early and definitive diagnosis of MODY2 by genetic testing is important to avoid unnecessary medication.
Background: Few epidemiological studies have been performed to clarify the association between gl... more Background: Few epidemiological studies have been performed to clarify the association between glucose metabolism disorders in early adults (20 years old) and physiological and environmental factors, including body mass index (BMI) in junior high school days. Therefore, we examined the association between hemoglobin A1c (HbA1c) level and body size (BMI) in early adulthood and lifestyles, including sleep habits and BMI in junior high school days in Shika town, a small town in Japan, by conducting a retrospective cohort study. We examined the HbA1c levels and body size (BMI) of 99 early adults who turned 20 years old between 2016 and 2020 and were residing in Shika town, Ishikawa Prefecture. We obtained the information on lifestyles and living environment factors, including BMI, from a questionnaire survey conducted among the subjects during their junior high school days (13-15 years old) from 2009 to 2013. No correlations were observed between the HbA1c levels and the BMI values of the early adults. A two-way analysis of covariance (with the HbA1c levels and BMI values of the early adults as main factors) of the body size and lifestyle habits of the junior high school students revealed that "sleep quality in junior high school" was significantly poorer in the high HbA1c group than in the low HbA1c group in the early adults with high BMI values only. This result was also supported by the logistic regression analysis result. The present results indicate that poor sleep quality in junior high school was associated with the high HbA1c levels of the early adults with higher BMI values, which suggests that good sleep quality in junior high school
Dens evaginatus (DE) is a dental abnormality characterized by tubercles on the occlusal surfaces ... more Dens evaginatus (DE) is a dental abnormality characterized by tubercles on the occlusal surfaces of teeth and is associated with the risk of pulpal inflammation due to fractures. The cause of DE remains unclear, as limited data are available to determine its etiology. The aim of this study was to investigate the genetic background of DE using whole-exome sequencing (WES). Saliva samples were collected from two patients of Family A and three patients of Family B, including an incident case of DE, and analyzed using WES. Rare variants were extracted from the WES data and filtered by family to extract candidate variants. Gene variants of TLR3 and MDC1 were identified as etiologic factors for DE. The variant MDC1 (c.3908C>T) was identified to be damaging, according to the scores from Polymorphism Phenotyping v2. Our findings contribute towards an understanding of the etiology of DE, which would facilitate improved treatment to prevent the risk of DE fractures and pulpal inflammation. Understanding the mechanism of DE development may also be helpful for developing regenerative medicine and gene therapy strategies.
In cancer patients, circulating cell-free DNA (cfDNA) includes tumor-derived DNA (tDNA). cfDNA ha... more In cancer patients, circulating cell-free DNA (cfDNA) includes tumor-derived DNA (tDNA). cfDNA has been used clinically for non-invasive gene mutation testing. The aim of this study was to characterize the features of the genetic alterations detected in cfDNA. This study included 6 patients with primary lung cancer who died due to cancer progression. Tumors were biopsied at autopsy. Genetic alteration profiles were obtained using next generation sequencing. The features of the tDNA genetic alterations detected in cfDNA included a higher frequency of being present in multiple tumors (67% truncal mutations, 36% shared mutations, and 4% individual mutations) and a higher variant allele frequency (VAF; 47.6% versus 4.1% for tDNA alterations detected in cfDNA versus not detected in cfDNA, respectively). The data revealed that the tumor-derived genetic alterations most easily detected in cfDNA were truncal mutations with a high VAF. These results showed that essential genetic alterations enriched in cfDNA could help to characterize cancer cells and that genetic testing using cfDNA has advantages in the detection of fundamental regulatory aberrations occurring during tumorigenesis. Circulating cell-free DNA (cfDNA) is present at very low levels as fragments in the bloodstream. cfDNA includes circulating tumor-derived DNA (ctDNA) in patients with malignancies. Cancer-related genetic alterations can be detected in cfDNA from patients with malignancies 1-6 . Therefore, cfDNA has been clinically examined as a liquid biopsy source in oncogene testing. Liquid biopsies are advantageous because they can be performed safely and repeatedly, and they are less invasive than tumor biopsies. Recently, cfDNA-based mutation tests of the epidermal growth factor receptor (EGFR) gene have been approved as in vitro diagnostic tests in clinical settings worldwide, including in Japan. They are used in treatment decision-making for patients with advanced non-small cell lung cancer (NSCLC). One drawback of cfDNA-based genetic testing is that the detection sensitivity is not always satisfactory . The hope is that cfDNA can provide an alternative sample source for genetic testing. Efforts to improve the sensitivity of mutation detection in cfDNA are actively underway. Simultaneously, clarifying the characteristics of genetic alterations detectable in cfDNA will provide useful information for understanding the results of cfDNA genetic testing and effectively using this method in clinical practice. Although tumor biopsies are essential for pathological diagnosis, and tumor tissue is the first choice for genetic tests conducted in patients with NSCLC, it is unclear whether tissue biopsy specimens are representative of the genetic characteristics of the whole tumor burden of a patient. That is, the biopsy sample is collected from only a small part of the tumor. Samples obtained from transbronchial biopsy, which is one of the most widely used methods of tumor collection in advanced NSCLC, are very limited and represent a small fraction of the tumor lesion. Tumor cells in advanced malignancies exhibit inter-or intratumoral heterogeneity that limits the response to targeted treatments 1 . Low-volume specimens, such as those from transbronchial biopsies, are likely to contain only a small portion of the genetic alterations present; thus, clinicians evaluating these specimens may miss important alterations critical for treatment decision-making because of intra-and intertumoral heterogeneity. In contrast, ctDNA may contain genetic alterations derived from multiple tumor lesions, and ctDNA analyses have the potential to provide an overall picture of all tumor-derived genetic alterations in patients with
Chronic nonbacterial osteomyelitis is a rare bone disorder that can be found in the jaw. It is of... more Chronic nonbacterial osteomyelitis is a rare bone disorder that can be found in the jaw. It is often associated with systemic conditions, including autoimmune deficiencies. However, little is known about how the genetic and immunologic background of patients influences the disease. Here, we focus on human leukocyte antigen (HLA), killer cell immunoglobulin-like receptors (KIRs), and their specific combinations that have been difficult to analyze owing to their high diversity. We employed a recently developed technology of simultaneous typing of HLA alleles and KIR haplotype and investigated alleles of the 35 HLA loci and KIR haplotypes composed of centromeric and telomeric motifs in 18 cases and 18 controls for discovery and 472 independent controls for validation. We identified an amino acid substitution of threonine at position 94 of HLA-C in combination with the telomeric KIR genotype of haplotype tA01/tB01 that had significantly higher frequency (>20%) in the case population than in both control populations. Multiple logistic regression analysis based on a dominant model with adjustments for age and sex revealed and validated its statistical significance and high predictive accuracy (C-statistic ≥0.85). Structure-based analysis revealed that the combination of the amino acid change in HLA-C and the telomeric genotype tA01/tB01 could be associated with lower stability of HLA-C. This is the first case-control study of a rare disease that employed the latest sequencing technology enabling simultaneous typing and investigated amino acid polymorphisms at HLA loci in combination with KIR haplotype.
Aims/Introduction: Risk factors of type 2 diabetes mellitus in Japanese women with recent gestati... more Aims/Introduction: Risk factors of type 2 diabetes mellitus in Japanese women with recent gestational diabetes mellitus are unknown. The objective of the present study was to investigate the clinical and genetic characteristics associated with postpartum abnormal glucose tolerance in Japanese women with gestational diabetes mellitus. Materials and Methods: A total of 213 Japanese women with recent gestational diabetes mellitus who underwent a postpartum 2-h oral glucose tolerance test were investigated. The association between antepartum clinical characteristics and postpartum abnormal glucose tolerance (diabetes or prediabetes based on the Japan Diabetes Society criteria) was examined. Frequencies of 45 known type 2 diabetes mellitus-associated genetic variants were also compared between women with and without postpartum abnormal glucose tolerance. Results: A total of 59 women showed postpartum abnormal glucose tolerance (prediabetes, n = 51; diabetes, n = 8). Plasma glucose levels at 1 or 2 h, the insulinogenic index and the insulin secretion-sensitivity index-2 of the antepartum oral glucose tolerance test were independent of postpartum abnormal glucose tolerance risk factors (P = 0.006, P = 0.00002, P = 0.01 and P = 0.006, respectively). Four genetic variants (rs266729 [ADI-POQ], rs6017317 [HNF4A], rs5215 [KCNJ11] and rs7177055 [HMG20A]) showed a nominally significant association with postpartum abnormal glucose tolerance (P < 0.05, respectively). Among these, three were related to insulin secretion. Postpartum abnormal glucose tolerance risk significantly increased with increasing risk-allele number (P = 0.0005; odds ratio 1.91). Conclusions: Clinical features and genetic variants related to impaired insulin secretion are risk factors of postpartum abnormal glucose tolerance in Japanese women with recent gestational diabetes mellitus.
Although chronic pain (CP) is classified as inflammatory or non-inflammatory, the involvement of ... more Although chronic pain (CP) is classified as inflammatory or non-inflammatory, the involvement of fatty acid intake in this process has not yet been examined in detail. Therefore, the present study investigated whether the relationship between CP and fatty acid intake differs between high and low C-reactive protein (CRP) levels in middle-aged and elderly individuals in the Shika study. One-thousand and seven males and 1216 females with mean ages of 68⋅78 and 69⋅65 years, respectively, participated in the present study. CRP was quantified by blood sampling from participants who responded to a CP questionnaire. The brief-type self-administered diet history questionnaire (BDHQ) was used to assess fatty acid intake. Interactions were observed between CP and CRP on monounsaturated fatty acids (MUFA) and eicosadienoic acid in a two-way analysis of covariance adjusted for sex, age, lack of exercise, lack of sleep, current smoking and drinking status, and BMI. MUFA (OR 1⋅359) and eicosadienoic acid (OR 1⋅072) were identified as significant independent variables for CP in a multiple logistic regression analysis, but only in the low CRP group. Only a high intake of MUFA and eicosadienoic acid was associated with chronic neck/shoulder/upper limb pain without elevated CRP. In psychogenic and neuropathic pain without elevated CRP,
L eukocytes that lack expression of HLA alleles are frequently detected in patients with acquired... more L eukocytes that lack expression of HLA alleles are frequently detected in patients with acquired aplastic anemia (AA) who respond to immunosuppressive therapy, although the exact mechanisms underlying the HLA loss and HLA allele repertoire likely to acquire loss-of-function mutations are unknown. We identified a common nonsense mutation at codon 19 (c.19C>T, p.R7X) in exon 1 (Exon1 mut ) of different HLA-A and -B alleles in HLA-lacking granulocytes from AA patients. A droplet digital polymerase chain reaction assay capable of detecting as few as 0.07% Exon1 mut HLA alleles in total DNA revealed that the mutation was present in 29% (101/353) of AA patients, with a median allele frequency of 0.42% (range, 0.071% to 21.3%). Exon1 mut occurred in only 12 different HLA-A (n=4) and HLA-B (n=8) alleles, including B*40:02 (n=31) and A*02:06 (n=15), which correspond to four HLA class I supertypes (A02, A03, B07, and B44). The percentages of patients who possessed at least one of these 12 HLA alleles were significantly higher in the 353 AA patients (92%, P<0.001) and in 83 AA patients with copy number neutral loss of heterozygosity in chromosome 6p (100%, P<0.001) than the percentage (81%) in 18,604 Japanese healthy individuals. Eighty-two percent (37/45) of AA patients with Exon1 mut responded to immunosuppressive therapy. Small populations of leukocytes that lack particular HLA-A or B alleles due to Exon1 mut are common in AA patients. The detection of Exon1 mut using a droplet digital polymerase chain reaction assay without the need for HLA typing may serve as a powerful tool for diagnosing the immune pathophysiology of patients with bone marrow failure.
Recent archaeogenomic studies in Mongolia have elucidated the genetic origins of people from the ... more Recent archaeogenomic studies in Mongolia have elucidated the genetic origins of people from the Xiongnu and Mongol eras, but left the Medieval period between them only tangentially explored. Due to this dearth of ancient genomes, the dynamic history of Medieval Mongolia with the rise and fall of numerous polities still lacks a genomic perspective. To fill in this knowledge gap, here we report whole-genome sequences of nine ancient individuals from eastern Mongolia, who were excavated from two nearby cemeteries, Gurvan Dov and Tavan Khailaast. They are distributed from the Xiongnu-Xianbei period (ca. 200 CE) to the Mongol era (ca. 1,400 CE), forming a local time transect encompassing nearly 1,200 years. Remarkably, despite the long-time span, all nine individuals derive most of their ancestry (85-100%) from the eastern Eurasian lineages and show low
Mitochondrial DNA (mtDNA) mutations are found in many types of cancers and suspected to be involv... more Mitochondrial DNA (mtDNA) mutations are found in many types of cancers and suspected to be involved in carcinogenesis, although the mechanism has not been elucidated. In this study, we report that consecutive C-to-T mutations (hypermutations), a unique feature of mutations induced by APOBECs, are found in mtDNA from cervical dysplasia and oropharyngeal cancers. In vitro, we found that APOBEC3A (A3A) and 3B (A3B) expression, as well as mtDNA hypermutation, were induced in a cervical dysplastic cell line W12 when cultured in a differentiating condition. The ectopic expression of A3A or A3B was sufficient to hypermutate mtDNA. Fractionation of W12 cell lysates and immunocytochemical analysis revealed that A3A and A3B could be contained in mitochondrion. These results suggest that mtDNA hypermutation is induced upon keratinocyte differentiation, and shed light on its molecular mechanism, which involves A3s. The possible involvement of mtDNA hypermutations in carcinogenesis is also discu...
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Papers by Atsushi Tajima