Intrauterine exposure to hypertensive disorders of pregnancy and postnatal growth in extremely and very preterm infants

Objectives: There is growing evidence regarding the association between rapid growth during infancy and metabolic and cardiovascular diseases later in life. We aimed to evaluate postnatal growth trajectories in extremely and very preterm infants exposed to hypertensive disorders of pregnancy (HDP) in utero. Study design: This multicenter retrospective study used a nationwide database of preterm infants weighing ≤1,500 g born between 22 and 31 weeks of gestation between 2003 and 2015. Main outcome measures: The Z-scores for height and weight were evaluated at three time points (at birth, corrected age of 1.5 years, and chronological age of 3 years) in 5,144 infants (HDP, n = 1,188; non-HDP, n = 3,956). Univariate and multivariate regression analyses were performed to investigate the associations between HDP exposure and accelerated postnatal growth. Results: Male and female infants in the HDP group showed increased mean Z-scores for height and weight, whereas those in the non-HDP group showed decreased mean Z-scores. Multivariate analyses showed that HDP were associated with accelerated postnatal growth (Δ Z-scores) in weight in both male and female infants (β coefficient [95% CI]; male 0.17 [0.05–0.30], female 0.27 [0.14–0.39]), but not in height (male 0.02 [−0.09 to 0.13], female 0.04 [−0.06 to 0.15]). An interaction analysis revealed no significant differences in the effects of HDP on postnatal growth between male and female infants. Conclusions: Intrauterine exposure to HDP contributes to accelerated postnatal weight growth in extremely and very preterm infants during early childhood. In addition, no sex differences were observed in postnatal growth.journal articl

Comprehensive Analysis of Risk Factors for Periodontitis Focusing on the Saliva Microbiome and Polymorphism

Few studies have exhaustively assessed relationships among polymorphisms, the microbiome, and periodontitis. The objective of the present study was to assess associations simultaneously among polymorphisms, the microbiome, and periodontitis. We used propensity score matching with a 1:1 ratio to select subjects, and then 22 individuals (mean age +/- standard deviation, 60.7 +/- 9.9 years) were analyzed. After saliva collection, V3-4 regions of the 16S rRNA gene were sequenced to investigate microbiome composition, alpha diversity (Shannon index, Simpson index, Chao1, and abundance-based coverage estimator) and beta diversity using principal coordinate analysis (PCoA) based on weighted and unweighted UniFrac distances. A total of 51 single-nucleotide polymorphisms (SNPs) related to periodontitis were identified. The frequencies of SNPs were collected from Genome-Wide Association Study data. The PCoA of unweighted UniFrac distance showed a significant difference between periodontitis and control groups (p 0.05). Two families (Lactobacillaceae and Desulfobulbaceae) and one species (Porphyromonas gingivalis) were observed only in the periodontitis group. No SNPs showed significant expression. These results suggest that periodontitis was related to the presence of P. gingivalis and the families Lactobacillaceae and Desulfobulbaceae but not SNPs

Impact of hypertensive disorders of pregnancy on respiratory outcomes in extremely and very preterm infants: A population-based study in Japan

Objectives: We aimed to evaluate the impact of hypertensive disorders of pregnancy (HDP) on short- and medium-term respiratory outcomes in extremely and very preterm infants using the Neonatal Research Network of Japan database. Study design: This was a population-based retrospective study of preterm infants weighing ≤ 1500 g born between 22 and 31 weeks of gestation between 2003 and 2017. After 1:1 stratification matching by four factors (maternal age, gestational age, parity, and year of delivery), a total of 5137 infants in each group (HDP and non-HDP groups) were selected. Main outcome measures: The association between HDP and various respiratory outcomes was evaluated using univariate and multivariate logistic regression analyses. Results: In the multivariate analyses, HDP was associated with higher odds for respiratory distress syndrome (RDS) (odds ratio 1.83, 95% confidence interval [1.65–2.03]), but reduced odds of persistent pulmonary hypertension of the newborn (PPHN) (0.34 [0.26–0.46]) and inhaled nitric oxide use (0.43 [0.33–0.55]). Although HDP was associated with an increased risk of chronic lung disease (CLD) in the univariate analysis, this association was not significant after adjustment for covariates (0.94 [0.83–1.07]). No significant association was found between HDP and home oxygen therapy (HOT) and medium-term oxygen use. Conclusion: The impact of maternal HDP largely differed depending on respiratory disorders and respiratory support. HDP was associated with higher odds of RDS but reduced odds of PPHN. The risks for CLD, HOT, and medium-term respiratory outcomes in the HDP group were comparable to those in the non-HDP group.journal articl

GWAS for Japanese CSC

PURPOSE. Central serous chorioretinopathy (CSC) is a retinal disorder that often affects the vision of middle-aged people yet the molecular mechanisms of CSC remain unknown. This study was conducted to identify genetic factors influencing individual differences in susceptibility to CSC. METHODS. A two-stage genome-wide association study (GWAS) was conducted with a total of 320 unrelated Japanese idiopathic CSC cases and 3245 population-based controls. In a discovery stage, 137 unrelated Japanese idiopathic CSC cases and 1174 population-based controls were subjected to GWAS, followed by a replication study using an additional 183 individuals with idiopathic CSC and 2071 population-based volunteers. The results of the discovery and replication stages were combined to conduct a meta-analysis. RESULTS. In the two-stage GWAS, rs11865049 located at SLC7A5 in chromosome 16q24.2 was identified as a novel disease susceptibility locus for CSC, as evident from the discovery and replication results using meta-analysis (combined P = 9.71 × 10−9, odds ratio = 2.10). CONCLUSIONS. The results of the present study demonstrated that SLC7A5 might be the potential candidate gene associated with CSC, indicating a previously unidentified molecular mechanism of CSC

A SYNGAP1 Variant in ALS Causes Spine Loss

Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3′ untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the SYNGAP1 3′UTR variant rs149438267 in seven (four males and three females) out of 807 ALS patients at the FUS binding site from a multicenter cohort in Japan. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, increased isoform α1 levels, and decreased isoform γ levels, which caused dendritic spine loss. Moreover, the SYNGAP1 variant excessively recruited FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK), and antisense oligonucleotides (ASOs) blocking HNRNPK altered aberrant splicing and ameliorated dendritic spine loss. These data suggest that excessive recruitment of RNA-binding proteins, especially HNRNPK, as well as changes in SYNGAP1 isoforms, are crucial for spine formation in motor neurons

Genome-wide association study of serum prostate-specific antigen levels based on 1000 Genomes imputed data in Japanese : the Japan Multi-Institutional Collaborative Cohort Study

Prostate cancer is emerging as a significant global public health burden. The incidence and prevalence of prostate cancer has increased in Japan, as westernized lifestyles become more popular. Recent advances in genetic epidemiology, including genome-wide association studies (GWASs), have identified considerable numbers of human genetic factors associated with diseases. Several GWASs have reported significant loci associated with serum prostate-specific antigen (PSA) levels. One GWAS, which was based on classic GWAS microarray measurements, has been reported for Japanese so far. In the present study, we conducted a GWAS of serum PSA using 1000Genomes imputed GWAS data (n =1,216) from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study, to detect candidate novel genetic loci that influence serum PSA levels in Japanese. The association of SNPs/genetic variants with serum PSA as a continuous variable was tested using the linear Wald test. SNP rs10000006 in SGMS2 (sphingomyelin synthase 2) on chromosome 4 had genome-wide significance (P <5×10−8), and eight variants on three chromosomes (chromosomes 12, 14, 15) had genome-wide suggestive levels of significance (P <1×10−6). With an independent data set from the J-MICC Shizuoka Study (n = 2,447), the association of the SGMS2SNP with blood PSA levels was not replicated. Although our GWAS failed to detect novel loci associated with serum PSA levels in the Japanese cohort, it confirmed the significant effects of previously reported genetic loci on PSA levels in Japanese. Importantly, our results confirmed the significance of KLK3 SNPs also in Japanese, implying that consideration of individual genetic information in prostate cancer diagnosis may be possible in the future.departmental bulletin pape

ABCA1 gene-physical activity interaction for HDL-C

Few studies have investigated the interactions between HDL-C-related SNPs identified by genome-wide association (GWA) study and physical activity (PA) on HDL-C. First, we conducted a sex-stratified GWA study in a discovery sample (2,231 men and 2,431 women) and replication sample (2,599 men and 3,109 women) to identify SNPs influencing log-transformed HDL-C in Japanese participants in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. We also replicated previously reported HDL-C-related SNPs in a combined (discovery plus replication) sample (4,830 men and 5,540 women). We then analyzed the interactions of the HDL-C-related SNPs with PA on HDL-C. The sex-stratified GWA analyses identified 11 and 10 HDL-C-related SNPs in men and women as targets for an interaction analysis. Among these, only one interaction of ABCA1 rs1883025 with PA was statistically significant in men, after Bonferroni correction [P-interaction = 0.001 (α = 0.05/21 = 0.002)]. The per-major-allele (C allele) increase in log-transformed HDL-C was lost in men with low PA (β = 0.008) compared with those with medium (β = 0.032) or high PA (β = 0.034). These findings suggest that the benefit of carrying a C allele of ABCA1 rs1883025 on enhancing HDL-C may be attenuated in inactive men

Smoking, Drinking, and Genetic Factors Affect HDL-cholesterol

Background: Environmental and genetic factors are suggested to exhibit factor-based association with HDL-cholesterol (HDL-C) levels. However, the population-based effects of environmental and genetic factors have not been compared clearly. We conducted a cross- sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study to evaluate the population-based impact of smoking, drinking, and genetic factors on low HDL-C. Methods: Data from 11,498 men and women aged 35–69 years were collected for a genome-wide association study (GWAS). Sixty-five HDL-C-related SNPs with genome-wide significance (P <5 × 10−8) were selected from the GWAS catalog, of which seven representative SNPs were defined, and the population-based impact was estimated using population attributable fraction (PAF). Results: We found that smoking, drinking, daily activity, habitual exercise, egg intake, BMI, age, sex, and the SNPs CETP rs3764261, APOA5 rs662799, LIPC rs1800588, LPL rs328, ABCA1 rs2575876, LIPG rs3786247, and APOE rs429358 were associated with HDL-C levels. The gene-environmental interactions on smoking and drinking were not statistically significant. The PAF for low HDL-C was the highest in men (63.2%) and in rs3764261 (31.5%) of the genetic factors, and the PAFs of smoking and drinking were 23.1% and 41.8%, respectively. Conclusion: The present study showed that the population-based impact of genomic factor CETP rs3764261 for low HDL-C was higher than that of smoking and lower than that of drinking

Polymorphisms and Body Mass Index Across Life Course

Background: Obesity is a reported risk factor for various health problems. Genome-wide association studies (GWASs) have identified numerous independent loci associated with body mass index (BMI). However, most of these have been focused on Europeans, and little evidence is available on the genetic effects across the life course of other ethnicities. Methods: We conducted a cross-sectional study to examine the associations of 282 GWAS-identified single nucleotide polymorphisms with three BMI-related traits, current BMI, BMI at 20 years old (BMI at 20), and change in BMI (BMI change), among 11,586 Japanese individuals enrolled in the Japan Multi-Institutional Collaborative Cohort study. Associations were examined using multivariable linear regression models. Results: We found a significant association (P < 0.05/282 = 1.77 × 10−4) between BMI and 11 polymorphisms in or near FTO, BDNF, TMEM18, HS6ST3, and BORCS7. The trend was similar between current BMI and BMI change, but differed from that of the BMI at 20. Among the significant variants, those on FTO were associated with all BMI traits, whereas those on TMEM18 and HS6SR3 were only associated with BMI at 20. The association of FTO loci with BMI remained, even after additional adjustment for dietary energy intake. Conclusions: Previously reported BMI-associated loci discovered in Europeans were also identified in the Japanese population. Additionally, our results suggest that the effects of each loci on BMI may vary across the life course and that this variation may be caused by the differential effects of individual genes on BMI via different pathways

Mendelian Randomization on hs-CRP and eGFR

Background: Inflammation is thought to be a risk factor for kidney disease. However, whether inflammatory status is either a cause or an outcome of chronic kidney disease remains controversial. We aimed to investigate the causal relationship between high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) using Mendelian randomization (MR) approaches. Methods: A total of 10,521 participants of the Japan Multi-institutional Collaborative Cohort Study was analyzed in this study. We used two-sample MR approaches (the inverse-variance weighted (IVW), the weighted median (WM), and the MR-Egger method) to estimate the effect of genetically determined hs-CRP on kidney function. We selected four and three hs-CRP associated single nucleotide polymorphisms (SNPs) as two instrumental variables (IV): IVCRP and IVAsian, based on SNPs previously identified in European and Asian populations. IVCRP and IVAsian explained 3.4% and 3.9% of the variation in hs-CRP, respectively. Results: Using the IVCRP, genetically determined hs-CRP was not significantly associated with eGFR in the IVW and the WM methods (estimate per 1 unit increase in ln(hs-CRP), 0.000; 95% confidence interval [CI], −0.019 to 0.020 and −0.003; 95% CI, −0.019 to 0.014, respectively). For IVAsian, we found similar results using the IVW and the WM methods (estimate, 0.005; 95% CI, −0.020 to 0.010 and −0.004; 95% CI, −0.020 to 0.012, respectively). The MR-Egger method also showed no causal relationships between hs-CRP and eGFR (IVCRP: −0.008; 95% CI, −0.058 to 0.042; IVAsian: 0.001; 95% CI, −0.036 to 0.036). Conclusion: Our two-sample MR analyses with different IVs did not support a causal effect of hs-CRP on eGFR