Combined effects of AHR, CYP1A1, and XRCC1 genotypes and prenatal maternal smoking on infant birth size : Biomarker assessment in the Hokkaido Study

Objectives: We investigated the individual and combined effects of maternal polymorphisms encoding the aromatic hydrocarbon receptor (AHR; rs2066853), cytochrome P450 (CYP) 1A1 (rs1048963), and the X-ray-complementing gene 1 (XRCC1; rs1799782) and prenatal smoking in relation to infant birth size. Methods: Totally, 3263 participants (1998 non-smokers and 1265 smokers) were included in the study between 2003 and 2007. Two groups of mothers were distinguished by plasma cotinine levels by ELISA measured during the third trimester (cut-off = 11.48 ng/mL). We conducted data analysis using multiple linear regression models. Results: Infants whose mothers smoked and had AHR-GG, CYP1A1-AG/GG, and XRCC1-CT/TT genotypes weighed, -145 g less than those born of mothers who did not smoke and had the AHR-GA/AA, CYP1A1-AA, and XRCC1-CC genotypes (95% CI: -241, -50). Conclusions: We demonstrated that infants whose mothers smoked during pregnancy with the combination of AHR, CYP1A1, and XRCC1 polymorphisms had lower birth size

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Birth cohorts in Asia : The importance, advantages, and disadvantages of different-sized cohorts

Asia contains half of the world's children, and the countries of Asia are the most rapidly industrializing nations on the globe. Environmental threats to the health of children in Asia are myriad. Several birth cohorts were started in Asia in early 2000, and currently more than 30 cohorts in 13 countries have been established for study. Cohorts can contain from approximately 100-200 to 20,000-30,000 participants. Furthermore, national cohorts targeting over 100,000 participants have been launched in Japan and Korea. The aim of this manuscript is to discuss the importance of Asian cohorts, and the advantages and disadvantages of different-sized cohorts. As for case, one small-sized (n = 514) cohort indicate that even relatively low level exposure to dioxin in utero could alter birth size, neurodevelopment, and immune and hormonal functions. Several Asian cohorts focus prenatal exposure to perfluoroalkyo substances and reported associations with birth size, thyroid hormone levels, allergies and neurodevelopment. Inconsistent findings may possibly be explained by the differences in exposure levels and target chemicals, and by possible statistical errors. In a smaller cohort, novel hypotheses or preliminary examinations are more easily verifiable. In larger cohorts, the etiology of rare diseases, such as birth defects, can be analyzed; however, they require a large cost and significant human resources. Therefore, conducting studies in only one large cohort may not always be the best strategy. International collaborations, such as the Birth Cohort Consortium of Asia, would cover the inherent limitation of sample size in addition to heterogeneity of exposure, ethnicity, and socioeconomic conditions

Prenatal di-2-ethylhexyl phthalate exposure and cord blood adipokine levels and birth size : The Hokkaido study on environment and children's health

Di-2-ethylhexyl phthalate (DEHP) is one of the most widely used phthalates. Metabolites of DEHP are detectable in majority of the population. Findings on adverse health outcomes, particularly birth weight in association with prenatal exposure to DEHP remain equivocal. Besides, there is insufficient evidence to address influence on metabolic function from epidemiological studies. Thus, our objective was to investigate cord blood adipokine levels and birth size in association with prenatal DEHP exposure in prospective birth cohort study. Mono-2-methylhexyl phthalate (MEHP), primary metabolite of DEHP was determined as exposure by using maternal blood sample of 3rd trimester. Leptin and adiponectin levels in cord blood were measured as markers of metabolic function. Birth weight and length were obtained from birth record. Association between maternal MEHP levels and cord blood adiponectin and leptin levels, birth weight and ponderal index (PI) were examined for 167 mother-child pairs who had both MEHP and cord blood adipokine measurements. The median MEHP level was 8.81 ng/ml and the detection rate was 100%. There was no sex difference in MEHP levels. Both leptin and adiponectin levels were higher in girls than in boys. MEHP level was positively associated with adiponectin level among boys and was negatively associated with leptin level among girls. MEHP level were negatively associated with PI only in girls and this could be due to decreased leptin level. This study suggested that prenatal DEHP exposure may be associated with cord blood adipokine and birth size. The influence potentially be sex-specific and could be more significant in girls

Quantifying bisphenol A in maternal and cord whole blood using isotope dilution liquid chromatography/tandem mass spectrometry and maternal characteristics associated with bisphenol A

Bisphenol A (BPA) is endocrine disrupting chemical that have been detected among general population. Exposure levels among pregnant women and their fetus are yet largely unknown among Japanese. We have developed a new method of measuring total BPA in whole blood samples by using isotopic dilution liquid chromatography-tandem mass spectrometry (ID-LC/MS/MS). For eliminating possible contaminations, we have used glass cartridge instead of polypropylene cartridge and successfully reduced background levels. Additionally gap retention technique was applied to improve sensitivity. We also confirmed no external contamination by measuring free BPA in the samples. The limit of quantification (LOQ) was 0.040 ng/ml. With this developed method, we determined total BPA concentrations of 59 maternal blood at delivery and 285 cord blood samples in prospective birth cohort study and investigated factors possibly related to total BPA levels. Total BPA levels ranged from below LOQ to 0.419 ng/ml and for maternal blood and from below LOQ to 0.217 ng/ml for cord blood, respectively. The geometric mean was 0.051 ng/ml for maternal blood and 0.046 ng/ml for cord blood, respectively. Although no correlation was observed between maternal and fetal blood levels of total BPA, our result suggested fetal exposure to BPA. We have found that younger mothers, frequent beef and pork consumption during pregnancy were positively associated with maternal total BPA levels. We confirmed in utero exposure to BPA, which highlights the importance of further studies of investing the effects of fetus BPA exposure on health outcomes

Sex-specific differences in effect of prenatal exposure to dioxin-like compounds on neurodevelopment in Japanese children : Sapporo cohort study

BACKGROUND: Consistent reports are not available on the effects of dioxin-like polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDD)/ polychlorinated dibenzofurans (PCDF) (dioxin-like compounds [DLCs]) on child neurodevelopment. Further, the effect of background-level exposure to individual DLC isomers is not known. OBJECTIVES: We carried out the Sapporo cohort study to evaluate the effect of prenatal exposure to each DLC isomer on child neurodevelopment at 6 and 18 months of age, and assessed sex-specific differences in these effects. METHODS: The levels of all and each individual DLC isomers were estimated in maternal peripheral blood. Neurodevelopment was evaluated using the Bayley Scales of Infant Development-2nd Edition for 6-month-old infants (n = 190) and 18-month-old children (n = 121). RESULTS: In male children, levels of 10 DLC isomers were significantly negatively associated with the Psychomotor Developmental Index (PDI) at 6 months of age after adjustment for potential confounding variables. However, at 18 months of age, these associations were absent. In female children, the level of only one DLC isomer was significantly negatively associated with PDI at 6 months of age. However, in contrast to the male children, the levels of six DLC isomers in 18-month-old female children were significantly positively associated with the Mental Developmental Index. CONCLUSIONS: These findings indicate that adverse neurodevelopmental effects of prenatal background-level exposure to DLCs may be stronger in male children

Association between Fetal Adipokines and Child Behavioral Problems at Preschool Age : The Hokkaido Study on Environment and Children's Health

Studies have suggested associations between maternal obesity and mental health problems of their children. However, the underlying mechanism is largely unknown. A possible mechanism can be via inflammatory states and the other possible mechanism is metabolic hormone-induced programming. Cross-talk between adipokines, including inflammatory cytokines and metabolic hormones secreted from adipose tissue and the central nervous system needs to be further investigated to elucidate the mechanism. Thus, the aim of this study was to investigate the association between fetal adipokine levels and child behavioral problems at preschool age. Cord blood adiponectin, leptin, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels were measured and child behavioral problems were assessed using the Strengths and Difficulties Questionnaire at preschool age. Logistic regression models adjusted by related maternal factors were performed to examine the association between cord blood adipokines and child behavioral problems. Three hundred and sixty-one children were included in the final analysis. A significant association between decreased hyperactivity/inattention and increased leptin was found (OR = 0.22, 95% CI: 0.06-0.89). Cord blood adiponectin, TNF-α and IL-6 levels were not associated with child behavioral problems. Our findings suggested that cord blood adipokines, particularly, leptin level, may be a predictor of hyperactivity/inattention problems at preschool age

Associations between maternal mono-(2-ethylhexyl) phthalate levels, nuclear receptor gene polymorphisms, and fatty acid levels in pregnant Japanese women in the Hokkaido study

We assessed how the interaction between mono-(2-ethylhexyl) phthalate (MEHP) in maternal sera and the maternal genotypes associated with nuclear receptors affect fatty acid levels in a prospective birth cohort study of pregnant Japanese individuals (n = 437) recruited in Sapporo between 2002 and 2005. We analyzed MEHP and fatty acids using gas chromatography-mass spectrometry. Thirteen single nucleotide polymorphisms of peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma (PPARG), PPARG coactivator 1A (PPARGC1A), PPAR delta, constitutive androstane receptor, liver X receptor (LXR) alpha, and LXR beta (LXRB) were analyzed using real-time PCR. Multiple linear regression models were used to confirm the influence of log(10)-transformed MEHP levels and maternal genotypes on log(10)-transformed fatty acid levels. When the effects of the interaction between MEHP levels and the maternal PPARGC1A (rs8192678) genotype on oleic acid levels were evaluated, the estimated changes (95 % confidence intervals) in oleic acid levels against MEHP levels, maternal PPARGC1A (rs8192678)-GA/AA genotype, and the interaction between them showed a mean reduction of 0.200 (0.079, 0.322), mean reduction of 0.141 (0.000, 0.283), and mean increase of 0.145 (0.010, 0.281), respectively, after adjusting for the perfluorooctanesulfonate level. The effects of the interaction between MEHP levels and maternal LXRB (rs2303044) genotype on linoleic acid levels was also significant (p(int) = 0.010). In conclusion, the interaction between MEHP and the maternal genotypes PPARGC1A (rs8192678) and LXRB (rs2303044) decreased fatty acid levels. Further, the interaction between MEHP and PPARGC1A (rs8192678) may have a greater effect on fatty acid levels than the interaction between PFOS and PPARGC1A