👤 Kazuko Kagawa

N-3 long-chain polyunsaturated fatty acids (n-3LCPUFAs) are crucial for child growth and development particularly for fetal growth in utero and brain development and function. This study examined the relationship between birth outcomes and FADS1 rs174547 genotypes in Japanese mothers and infants. The study included 406 mothers and 373 infants, i.e., 373 infant-mother pairs, from a supplementary survey of the Japan Environment and Children's Study. Multiple regression analysis revealed that infants with the CC genotype had significantly smaller head circumference at birth compared to those with the TT genotype. Moreover, an interaction between infant genotype and cord blood docosahexaenoic acid (DHA; 22:6n-3) composition affected head circumference at birth. The findings suggest that maternal and infant FADS1 genotypes may influence fetal growth. Furthermore, in FADS1 genotype-stratified multiple regression analysis, infants with maternal and infant CC genotypes exhibited a significant positive association between head circumference at birth and maternal erythrocyte DHA/α-linolenic acid (ALA; 18:3n-3) ratio or fish intake. We highlighted lower metabolic efficiency for endogenous long-chain polyunsaturated fatty acids synthesis in infant-mother pairs homozygous for the minor C allele of FADS1 rs174547. In conclusion, for mothers and infants with this genetic background, maternal fish intake during pregnancy may be potentially important for fetal growth and development. Show less

This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma. We retrospectively analyzed 93 patients with diffuse midline glioma (47 thalamus, 24 brainstem, 12 spinal cord and 10 other midline locations) treated at 24 affiliated hospitals in the Kansai Molecular Diagnosis Network for CNS Tumors. Considering the term "midline" areas, which had been confused in previous reports, we classified four midline locations based on previous reports and anatomical findings. Clinical and molecular characteristics of the study cohort included: age 4-78 years, female sex (41%), lower-grade histology (56%), preoperative Karnofsky performance status (KPS) scores ≥ 80 (49%), resection (36%), adjuvant radiation plus chemotherapy (83%), temozolomide therapy (76%), bevacizumab therapy (42%), HIST1H3B p.K27M mutation (2%), TERT promoter mutation (3%), MGMT promoter methylation (9%), BRAF p.V600E mutation (1%), FGFR1 mutation (14%) and EGFR mutation (3%). Median progression-free and overall survival time was 9.9 ± 1.0 (7.9-11.9, 95% CI) and 16.6 ± 1.4 (13.9-19.3, 95% CI) months, respectively. Female sex, preoperative KPS score ≥ 80, adjuvant radiation + temozolomide and radiation ≥ 50 Gy were associated with favorable prognosis. Female sex and preoperative KPS score ≥ 80 were identified as independent good prognostic factors. This study demonstrated the current state of clinical practice for patients with diffuse midline glioma and molecular analyses of diffuse midline glioma in real-world settings. Further investigation in a larger population would contribute to better understanding of the pathology of diffuse midline glioma. Show less

Mutations in a common extracellular domain of fibroblast growth factor receptor (FGFR)-2 isoforms (type IIIb and IIIc) cause craniosynostosis syndrome and chondrodysplasia syndrome. FGF10, a major ligand for FGFR2-IIIb and FGFR1-IIIb, is a key participant in the epithelial-mesenchymal interactions required for morphogenetic events. FGF10 also regulates preadipocyte differentiation and early chondrogenesis in vitro, suggesting that FGF10-FGFR signaling may be involved in craniofacial skeletogenesis in vivo. To test this hypothesis, we used a tet-on doxycycline-inducible transgenic mouse model (FGF10 Tg) to overexpress Show less

Increasing the amount of long-chain polyunsaturated fatty acids (LCPUFA) in human milk is an important strategy for infant growth and development. We investigated the associations of LCPUFA compositions in human milk with maternal diet (especially fish and shellfish intake), with fatty acid Δ5 desaturase gene (FADS1) polymorphisms, and with gene-diet interactions. The present study was performed as part of an adjunct study of the Japan Environment and Children’s Study. The participants were 304 lactating females, who provided human milk 6−7 months after delivery. Fatty acids in human milk were analyzed by gas chromatography, and dietary surveys were conducted using a brief self-administered diet history questionnaire. We also analyzed a single nucleotide polymorphism of FADS1 (rs174547, T/C). There was a significant difference in arachidonic acid (ARA) composition in human milk among the genotype groups, and the values were decreasing in the order of TT > TC > CC. The concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were also different between TT and CC genotype, indicating a tendency for decreasing values in the same order. The composition of ARA showed significant gene−dietary interactions in multiple regression analysis, and the positive correlation between fish and shellfish intake and ARA composition in human milk was significant only in the CC genotype. Moreover, the factor most strongly associated with EPA and DHA composition in human milk was fish and shellfish intake. Therefore, it was suggested that increasing fish and shellfish intake in mothers may increase EPA and DHA composition in human milk, while increasing fish and shellfish intake in CC genotype mothers may lead to increased ARA composition in human milk. Show less

Group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma via the robust production of type 2 cytokines. Recent studies have demonstrated that TLR7 (Toll-like receptor 7) signaling skews toward a type 1 inflammatory response in asthma, which may lead to the development of novel treatment strategies. However, the effect of TLR7 signaling on ILC2-dependent nonallergic eosinophilic inflammation remains unclear. In this study, we investigated the effects of R848, a TLR7 agonist, in a mouse model of IL-33-induced eosinophilic airway inflammation. Intranasal administration of R848 decreased infiltration of airway eosinophils and ILC2s, mucus production in epithelial cells, and type 2 cytokine production. Flow cytometric analysis identified an increased number of interstitial macrophages (IMs) expressing a high level of TLR7 in the lung upon IL-33 stimulation. IL-33-induced IMs also expressed high levels of alternatively activated (M2)-type genes and chemokines (CCL17 and CCL24). However, R848 stimulation modified these gene expressions and elicited the production of IL-27. Coculture experiments revealed that IL-33-induced IMs directly suppressed ILC2 activation in response to R848. In addition, the inhibitory effects of R848 on ILC2-induced type 2 inflammation were defective in WSX-1-deficient mice lacking the IL-27 receptor. Taken together, these findings indicate that R848 stimulates IL-33-induced IMs to suppress ILC2-mediated type 2 airway inflammation via IL-27. These findings highlight the therapeutic potential of TLR7 agonists and/or IL-27 cascades in nonallergic asthma. Show less

Long-chain polyunsaturated fatty acids (LC-PUFAs) are involved in the fetal growth in utero, and are essential for the development of visual and cognitive functions during infancy. The purpose of this study was to examine the associations of erythrocyte fatty acid compositions with FADS1 gene polymorphism in Japanese mothers and infants. The subjects were 383 mothers who participated in an adjunct birth cohort study of the Japan Environment and Children's Study (JECS). In maternal FADS1 SNP genotypes, the precursor fatty acids composition of the Δ5 desaturase in the maternal blood showed significant differences in levels among the groups, and showed increasing values in the order of TT < TC < CC genotype groups. On the other hand, many product fatty acids levels were significantly reduced in the order of TT > TC > CC genotype groups, and DHA levels were significantly lower in the CC genotype group relative to the other groups. Likewise, the relationship between fetal genotype group and fatty acid composition in cord blood was very similar to the maternal relationship. These results indicate the maternal and fetal blood fatty acid compositions are strongly influenced by the FADS1 genotypes. With respect to the cord blood DHA composition, the levels in the fetal CC genotype group showed a trend toward lower values in the maternal CC genotype group pair (p = 0.066) compared to the maternal TC genotype group pair. However, in the fetal TT and TC genotype groups (p = 0.131, p = 0.729, respectively), the maternal genotype did not have a significant effect. The DHA composition was more influenced by the maternal genotype in the fetal CC genotype group than in the fetal TT and TC genotype groups. It was shown that DHA transport via the placenta from the mother might be promoted in the fetal CC genotype compared to the other fetal genotype groups. In conclusion, differences in the FADS1 SNP genotypes of pregnant women and their children may greatly affect the supply of LC-PUFAs. Further studies on the involvement of the FADS1 polymorphisms and the fetal LC-PUFA levels in the fetal growth and development are warranted. Show less

We investigated whether the single nucleotide polymorphism rs174547 (T/C) of the fatty acid desaturase-1 gene, FADS1, is associated with changes in erythrocyte membrane and plasma phospholipid (PL) long-chain polyunsaturated fatty acid (LCPUFA) composition in elderly Japanese participants (n=124; 65 years or older; self-feeding and oral intake). The rs174547 C-allele carriers had significantly lower arachidonic acid (ARA; n-6 PUFA) and higher linoleic acid (LA, n-6 PUFA precursor) levels in erythrocyte membrane and plasma PL (15% and 6% ARA reduction, respectively, per C-allele), suggesting a low LA to ARA conversion rate in erythrocyte membrane and plasma PL of C-allele carriers. α-linolenic acid (n-3 PUFA precursor) levels were higher in the plasma PL of C-allele carriers, whereas levels of the n-3 LCPUFAs eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) were unchanged in erythrocyte membrane and plasma PL. Thus, rs174547 genotypes were significantly associated with different ARA compositions of the blood of elderly Japanese. Show less

MLXIPL is a transcription factor integral to the regulation of glycolysis and lipogenesis in the liver. Common variants of the MLXIPL gene (MLXIPL) are known to influence plasma triglyceride levels in people of European descent. As MLXIPL has a key role in energy storage, genetic variations of the MLXIPL may be relevant to physiological adaptations to nutritional stresses that have occurred during the evolution of modern humans. In the present study, we assessed the phenotypic consequences of the Q241H variant of MLXIPL in populations of Asian and Oceanian origin and also surveyed the prevalence of Q241H variant in populations worldwide. Multiple linear regression models based on 2373 individuals of Asian origin showed that the H allele was significantly associated with decreased concentrations of plasma triglycerides (P=0.0003). Direct genotyping of 1455 individuals from Africa, Asia and Oceania showed that the triglyceride-lowering H allele was found at quite low frequencies (0.00-0.16) in most of the populations examined. The exceptions were some Central Asian populations, including Mongolians, Tibetans and Uyghurs, which exhibited much higher frequencies of the H allele (0.21-0.26). The high prevalence of the H allele in Central Asia implies that the Q241H variant of MLXIPL might have been significant for utilization of carbohydrates and fats in the common ancestors of these populations, who successfully adapted to the environment of Central Asia by relying on nomadic livestock herding. Show less

Recent genome-wide association studies (GWASs) showed that single nucleotide polymorphisms (SNPs) in FADS1/FADS2 were associated with plasma lipid concentrations in populations with European ancestry. We investigated the associations between the SNPs in FADS1/FADS2 and plasma concentrations of triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in two Asian groups, i.e., Japanese and Mongolians. The genotype of rs174547 (T/C), found to be associated with triglyceride and HDL-C concentrations in the GWAS, was determined in 21,004 Japanese and 1,203 Mongolian individuals. Genotype-phenotype association was assessed by using multiple linear regression models, assuming an additive model of inheritance. The copy number of the rs174547 C allele was significantly associated with increased triglyceride levels (P = 1.5 x 10(-6)) and decreased HDL-C levels (P = 0.03) in the Japanese population. On the other hand, in the Mongolian population, the rs174547 C allele copy number was strongly associated with decreased LDL-C levels (P = 2.6 x 10(-6)), but was not associated with triglyceride and HDL-C levels. The linkage disequilibrium pattern and haplotype structures of SNPs around the FADS1/FADS2 locus showed no marked dissimilarity between Japanese and Mongolian individuals. The present data indicate that the FADS1/FADS2 locus can be added to the growing list of loci involved in polygenic dyslipidemia in Asians. Furthermore, the variable effects of FADS1/FADS2 on plasma lipid profiles in Asians may result from differences in the dietary intake of polyunsaturated fatty acids, which serve as substrates for enzymes encoded by FADS1/FADS2. Show less