Association of Pooled Fecal Microbiota on Height Growth in Children According to Enterotypes.

OBJECTIVES: The association between fecal microbiota and height in children has yielded conflicting findings, warranting further investigation into potential differences in fecal bacterial composition between children with short stature and those of standard height based on enterotypes (ETs). METHODS: According to the height z score for age and gender, the children were categorized into normal-stature (NS; n = 335) and short-stature (SS; n = 152) groups using a z score of -1.15 as a separator value. The human fecal bacterial FASTA/Q files (n = 487) were pooled and analyzed with the QIIME 2 platform with the National Center for Biotechnology Information alignment search tool. According to ETs, the prediction models by the machine learning algorithms were used for explaining SS, and their quality was validated. RESULTS: The proportion of SS was 16.4% in ET Enterobacteriaceae (ET-E) and 68.1% in Prevotellaceae (ET-P). The Chao1 and Shannon indexes were significantly lower in the SS than in the NS groups only in ET-P. The fecal bacteria related to SS from the prediction models were similar regardless of ETs. However, in network analysis, the negative correlations between fecal bacteria in the NS and SS groups were much higher in the ET-P than in the ET-E. In the metagenome function, fecal bacteria showed an inverse association of biotin and secondary bile acid synthesis and downregulation of insulin/insulin-like growth factor-1-driven phosphoinositide 3-kinase Akt signaling and AMP-kinase signaling in the SS group compared with the NS group in both ETs. CONCLUSION: The gut microbial compositions in children were associated with height. Strategies to modify and optimize the gut microbiota composition should be investigated for any potential in promoting height in children.

Air pollution and mortality in patients with chronic obstructive pulmonary disease: a cohort study in South Korea.

Background: Evidence on whether long-term exposure to air pollution increases the mortality risk in patients with chronic obstructive pulmonary disease (COPD) is limited. Objectives: We aimed to investigate the associations of long-term exposure to particulate matter with diameter <10 µm (PM10) and nitrogen dioxide (NO2) with overall and disease-specific mortality in COPD patients. Design: We conducted a nationwide retrospective cohort study of 121,423 adults ⩾40 years diagnosed with COPD during 1 January to 31 December 2009. Methods: Exposure to PM10 and NO2 was estimated for residential location using the ordinary kriging method. We estimated the risk of overall mortality associated with 1-, 3-, and 5-years average concentrations of PM10 and NO2 using Cox proportional hazards models and disease-specific mortality using the Fine and Gray method adjusted for age, sex, income, body mass index, smoking, comorbidities, and exacerbation history. Results: The adjusted hazard ratios (HRs) for overall mortality associated with a 10 µg/m3 increase in 1-year PM10 and NO2 exposures were 1.004 [95% confidence interval (CI) = 0.985, 1.023] and 0.993 (95% CI = 0.984, 1.002), respectively. The results were similar for 3- and 5-year exposures. For a 10-µg/m3 increase in 1-year PM10 and NO2 exposures, the adjusted HRs for chronic lower airway disease mortality were 1.068 (95% CI = 1.024, 1.113) and 1.029 (95% CI = 1.009, 1.050), respectively. In stratified analyses, exposures to PM10 and NO2 were associated with overall mortality in patients who were underweight and had a history of severe exacerbation. Conclusion: In this large population-based study of patients with COPD, long-term PM10 and NO2 exposures were not associated with overall mortality but were associated with chronic lower airway disease mortality. PM10 and NO2 exposures were both associated with an increased risk of overall mortality, and with overall mortality in underweight individuals and those with a history of severe exacerbation.

Fecal Microbiota Composition, Their Interactions, and Metagenome Function in US Adults with Type 2 Diabetes According to Enterotypes.

T2DM etiology differs among Asians and Caucasians and may be associated with gut microbiota influenced by different diet patterns. However, the association between fecal bacterial composition, enterotypes, and T2DM susceptibility remained controversial. We investigated the fecal bacterial composition, co-abundance network, and metagenome function in US adults with T2DM compared to healthy adults based on enterotypes. We analyzed 1911 fecal bacterial files of 1039 T2DM and 872 healthy US adults from the Human Microbiome Projects. Operational taxonomic units were obtained after filtering and cleaning the files using Qiime2 tools. Machine learning and network analysis identified primary bacteria and their interactions influencing T2DM incidence, clustered into enterotypes, Bacteroidaceae (ET-B), Lachnospiraceae (ET-L), and Prevotellaceae (ET-P). ET-B showed higher T2DM incidence. Alpha-diversity was significantly lower in T2DM in ET-L and ET-P (p < 0.0001), but not in ET-B. Beta-diversity revealed a distinct separation between T2DM and healthy groups across all enterotypes (p < 0.0001). The XGBoost model exhibited high accuracy and sensitivity. Enterocloster bolteae, Facalicatena fissicatena, Clostridium symbiosum, and Facalibacterium prausnitizii were more abundant in the T2DM group than in the healthy group. Bacteroides koreensis, Oscillibacter ruminantium, Bacteroides uniformis, and Blautia wexlerae were lower in the T2DM than in the healthy group regardless of the enterotypes in the XGBoost model (p < 0.0001). However, the patterns of microbial interactions varied among different enterotypes affecting T2DM risk. The interaction between fecal bacteria was more tightly regulated in the ET-L than in the ET-B and ET-P groups (p < 0.001). Metagenomic analysis revealed an inverse association between bacteria abundance in T2DM, energy utility, butanoate and propanoate metabolism, and the insulin signaling pathway (p < 0.0001). In conclusion, fecal bacteria play a role in T2DM pathogenesis, particularly within different enterotypes, providing valuable insights into the link between gut microbiota and T2DM in the US population.

Interaction of polygenetic variants related to inflammation with carbohydrate and vitamin D intakes in middle-aged and older adults in a large hospital-based cohort.

Low-grade subclinical inflammation is interrelated with metabolic diseases, and its susceptibility interacts with genetic and environmental factors. We aimed to examine genetic variants related to a high risk for inflammation using serum C-reactive protein (CRP) concentration, interactions among the genetic variants and the genetic variant interaction with dietary and lifestyle factors in adults. The participants were divided into case and control by serum CRP concentrations: ≥ 0·5 mg/dl (case; n 2018) and < 0·5 mg/dl (control; n 47 185). Genetic variants contributing to high inflammation risk were selected using GWAS after adjusting covariates to influence inflammation, and genetic variant-genetic variant interactions were identified by generalised multifactor dimensionality reduction analysis. Polygenetic-risk scores (PRS) were constructed from the selected genetic variants, and PRS-nutrient interactions for the high inflammation risk were determined. The PRS included CRP_rs1205, OASL_rs3213545, APOE_rs429358, HNF1A_rs1169286, APOC1_rs7256200 and SLC13A3_rs424697. The PRS was positively associated with serum CRP concentration by 2·0 times after adjusting for covariates. The PRS interacted with age: older participants with High-PRS had much higher serum CRP concentrations than those with Low-PRS. Intake of carbohydrates, MUFA and vitamin D exhibited an interaction with PRS for inflammation risk (P < 0·05). In participants with high-carbohydrate/low-fat diets and low vitamin D intakes, those with High-PRS had a higher risk of serum CRP concentrations than those with Low-PRS. In conclusion, the participants with inflammation-related PRS potentially worsened inflammation status, especially in diets with high carbohydrates, low fat (especially MUFA) and low vitamin D. These results can be applied to personalised nutrition to reduce inflammation risk.

Portulaca oleracea L. Extract Regulates Hepatic Cholesterol Metabolism via the AMPK/MicroRNA-33/34a Pathway in Rats Fed a High-Cholesterol Diet.

This study examined the effect of extruded Portulaca oleracea L. extract (PE) in rats fed a high-cholesterol diet through the AMP-activated protein kinase (AMPK) and microRNA (miR)-33/34a pathway. Sprague-Dawley rats were randomized into three groups and fed either a standard diet (SD), a high-cholesterol diet containing 1% cholesterol and 0.5% cholic acid (HC), or an HC diet containing 0.8% PE for 4 weeks. PE supplementation improved serum, liver, and fecal lipid profiles. PE upregulated the expression of genes involved in cholesterol efflux and bile acids' synthesis such as liver X receptor alpha (LXRα), ATP-binding cassette subfamily G5/G8 (ABCG5/8), and cholesterol 7 alpha-hydroxylase (CYP7A1), and downregulated farnesoid X receptor (FXR) in the liver. In addition, hepatic gene expression levels of apolipoprotein A-l (apoA-1), paraoxonase 1 (PON1), ATP-binding cassette subfamily A1/G1 (ABCA1/G1), lecithin-cholesterol acyltransferase (LCAT), and scavenger receptor class B type 1 (SR-B1), which are related to serum high-density lipoprotein cholesterol metabolism, were upregulated by PE. Furthermore, hepatic AMPK activity in the PE group was higher than in the HC group, and miR-33/34a expression levels were suppressed. These results suggest that PE improves the cholesterol metabolism by modulating AMPK activation and miR-33/34a expression in the liver.

Protection against Osteoarthritis Symptoms by Aerobic Exercise with a High-Protein Diet by Reducing Inflammation in a Testosterone-Deficient Animal Model.

A testosterone deficiency potentially increases osteoarthritis (OA) symptoms, and dietary protein and exercise affect them. However, their efficacy and their interactions are still unclear. We hypothesized that a high-protein diet (HPD) and regular exercise modulated OA symptoms in testosterone-deficient rats, and it was examined in bilateral orchidectomized (ORX) and monoiodoacetate (MIA)-injected rats. The ORX rats were given a 30 energy percent (En%) protein (HPD) or 17.5 En% protein (CD). Both groups had 39 En% fat in the diet. Non-ORX-CD rats (sham-operation of ORX) were given the CD and no exercise (normal control). After an eight-week intervention, all rats had an injection of MIA into the left knee, and the treatments were continued for an additional four weeks. The non-ORX-CD rats showed a significant increase in body weight compared to the ORX rats, but the ORX rats had elevated fat mass. ORX exacerbated the glucose tolerance by lowering the serum insulin concentrations and increasing insulin resistance. ORX exacerbated the OA symptoms more than the non-ORX-CD. The HPD and exercise improved bone mineral density and glucose metabolism without changing serum testosterone concentrations, while only exercise increased the lean body mass and decreased fat mass, lipid peroxide, and inflammation. Exercise, but not HPD, reduced the OA symptoms, the weight distribution in the left leg, and running velocity and provided better relief than the non-ORX-CD rats. Exercise with HPD improved the histology of the knee joint in the left leg. Exercise reduced lipid peroxide contents and TNF-α and IL-1ß mRNA expression in the articular cartilage, while exercise with HPD decreased MMP-3 and MMP-13 mRNA expression as much as in the non-ORX-CD group. In conclusion, moderate aerobic exercise with HPD alleviated OA symptoms and articular cartilage degradation in a similar way in the non-ORX rats with OA by alleviating inflammation and oxidative stress.

Association of Estrogen-Related Polygenetic Risk Scores with Breast Cancer and Interactions with Alcohol Intake, Early Menarche, and Nulligravida.

BACKGROUNDS: Early menstruation, late menopause, no pregnancy, and genetic factors are known risk factors of the disease, but their effects may differ in Asian and Caucasian women. The purpose of this study was to identify genetic variants of genes related to estrogen signaling in a large city hospital-based cohort and to determine their interactions with lifestyles. METHODS: This is a case-control study. Three hundred ninety participants diagnosed with breast cancer were compared with 36,290 controls(no cancer)to explore the genetic variants to influence breast cancer risk. Based on GWAS results, the selected genetic variants were subjected to their interactions by generalized multifactor dimensionality reduction (GMDR) analysis. RESULTS: Early menstruation(OR=1.55), early menopause (OR=1.70), and no experience of pregnancy(OR=2.86) had a positive association with breast cancer risk(P<0.05). The selected polygenetic risk score(PRS) models included four SNPs and seven SNPs: The four-SNP PRS model included CDH13_rs12600325, SMYD3_rs3753686, FGF12_rs2134635, and ESRRB_rs10873289, and in the seven-SNP PRS model, ESR1_ rs2046210, estrogen-related receptor gamma(ESRRG)_rs17043393, and EGFR_ rs6958497 were added into the four-SNP PRS model. Early menstruation, early menopause, and no pregnancy experience interacted with four-SNP PRS. For the participants who had early menstruation and early menopause, high-PRS had an association with a much higher breast cancer risk than the low-PRS in the four-SNP model. However, metabolic parameters, nutrient intakes, and different dietary patterns did not interact with PRS for breast cancer risk. However, alcohol intake interacted with PRS for breast cancer risk (OR=2.33 and 8.07 for mild and moderate alcohol consumption, respectively; P=0.0004). CONCLUSION: Consideration of age at menarche and menopause, pregnancy experience, and alcohol intake may be required to reduce breast cancer risk in women with a high-PRS of genes related to the estrogen signaling pathway.

Association of Age-Related Cataract Risk with High Polygenetic Risk Scores Involved in Galactose-Related Metabolism and Dietary Interactions.

INTRODUCTION: Cataracts are associated with the accumulation of galactose and galactitol in the lens. We determined the polygenetic risk scores for the best model (PRSBM) associated with age-related cataract (ARC) risk and their interaction with diets and lifestyles in 40,262 Korean adults aged over 50 years belonging to a hospital-based city cohort. METHODS: The genetic variants for ARC risk were selected in lactose and galactose metabolism-related genes with multivariate logistic regression using PLINK 1.9 version. PRSBM from the selected genetic variants were estimated by generalized multifactor dimensionality reduction (GMDR) after adjusting for covariates. The interactions between the PRSBM and each lifestyle factor were determined to modulate ARC risk. RESULTS: The genetic variants for ARC risk related to lactose and galactose metabolism were SLC2A1_rs3729548, ST3GAL3_rs3791047, LCT_rs2304371, GALNT5_rs6728956, ST6GAL1_rs2268536, GALNT17_rs17058752, CSGALNACT1_rs1994788, GALNTL4_rs10831608, B4GALT6_rs1667288, and A4GALT_ rs9623659. In GMDR, the best model included all ten genetic variants. The highest odds ratio for a single SNP in the PRSBM was 1.26. However, subjects with a high-PRSBM had a higher ARC risk by 2.1-fold than a low-PRSBM after adjusting for covariates. Carbohydrate, dairy products, kimchi, and alcohol intake interacted with PRSBM for ARC risk, where participants with high-PRSBM had a much higher ARC risk than those with low-PRSBM when consuming diets with high carbohydrate and low dairy product and kimchi intake. However, only with low alcohol intake, the participants with high-PRSBM had a higher ARC risk than those with low-PRSBM. CONCLUSION: Adults aged >50 years having high-PRSBM may modulate dietary habits to reduce ARC risk.

Association between Polygenetic Risk Scores of Low Immunity and Interactions between These Scores and Moderate Fat Intake in a Large Cohort.

White blood cell (WBC) counts represent overall immunity. However, a few studies have been conducted to explore the genetic impacts of immunity and their interaction with lifestyles. We aimed to identify genetic variants associated with a low-WBC risk and document interactions between polygenetic risk scores (PRS), lifestyle factors, and nutrient intakes that influence low-WBC risk in a large hospital-based cohort. Single nucleotide polymorphisms (SNPs) were selected by genome-wide association study of participants with a low-WBC count (<4 × 109/L, n = 4176; low-WBC group) or with a normal WBC count (≥4 × 109/L, n = 36,551; control group). The best model for gene-gene interactions was selected by generalized multifactor dimensionality reduction. PRS was generated by summing selected SNP risk alleles of the best genetic model. Adjusted odds ratio (ORs) of the low-WBC group were 1.467 (1.219-1.765) for cancer incidence risk and 0.458 (0.385-0.545) for metabolic syndrome risk. Vitamin D intake, plant-based diet, and regular exercise were positively related to the low-WBC group, but smoking and alcohol intake showed an inverse association. The 7 SNPs included in the best genetic model were PSMD3_rs9898547, LCT_rs80157389, HLA-DRB1_rs532162239 and rs3097649, HLA-C rs2308575, CDKN1A_rs3176337 and THRA_rs7502539. PRS with 7 SNP model were positively associated with the low-WBC risk by 2.123-fold (1.741 to 2.589). PRS interacted with fat intake and regular exercise but not with other nutrient intakes or lifestyles. The proportion with the low WBC in the participants with high-PRS was lower among those with moderate-fat intake and regular exercise than those with low-fat intake and no exercise. In conclusion, adults with high-PRS had a higher risk of a low WBC count, and they needed to be advised to have moderate fat intake (20-25 energy percent) and regular exercise.

Menopause, Ultraviolet Exposure, and Low Water Intake Potentially Interact with the Genetic Variants Related to Collagen Metabolism Involved in Skin Wrinkle Risk in Middle-Aged Women.

Genetic and environmental factors influence wrinkle development. We evaluated the polygenetic risk score (PRS) by pooling the selected single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) for wrinkles and the interaction of PRS with lifestyle factors in middle-aged women. Under the supervision of a dermatologist, the skin status of 128 women aged over 40 years old was evaluated with Mark-Vu, a skin diagnosis system. PRS was generated from the selected SNPs for wrinkle risk from the genome-wide association study. Lifestyle interactions with PRS were also evaluated for wrinkle risk. Participants in the wrinkled group were more likely to be post-menopausal, eat less fruit, take fewer vitamin supplements, exercise less, and be more tired after awakening in the morning than those in the less-wrinkled group. The PRS included EGFR_rs1861003, MMP16_rs6469206, and COL17A1_rs805698. Subjects with high PRS had a wrinkle risk 15.39-fold higher than those with low PRS after adjusting for covariates, and they had a 10.64-fold higher risk of a large skin pore size. Menopause, UV exposure, and water intake interacted with PRS for wrinkle risk: the participants with high PRS had a much higher incidence of wrinkle risk than those with low PRS, only among post-menopausal women and those with UV exposure. Only with low water intake did the participants with medium PRS have increased wrinkle risk. In conclusion, women aged >40 years with high PRS-related collagen metabolism may possibly avoid wrinkle risk by avoiding UV exposure by applying sunscreen, maintaining sufficient water intake, and managing estrogen deficiency.

A Korean-Style Balanced Diet Has a Potential Connection with Ruminococcaceae Enterotype and Reduction of Metabolic Syndrome Incidence in Korean Adults.

Metabolic syndrome is associated with usual dietary patterns that may be involved in enterotypes. We aimed to understand the potential relationship of enterotypes and dietary patterns to influence metabolic syndrome in the Koreans. Using the Korea National Health and Nutrition Examination Survey (KNHANES)-VI in 2014, metabolic parameters were also analyzed among the dietary patterns classified by principal component analysis in Korean adults. The fecal microbiota data of 1199 Korean adults collected in 2014 were obtained from the Korea Centers for Disease Control and Prevention. Enterotypes were classified based on Dirichlet multinomial mixtures (DMM) by Mothur v.1.36. The functional abundance of fecal bacteria was analyzed using the PICRUSt2 pipeline. Korean adults were clustered into three dietary patterns including Korean-style balanced diets (KBD, 20.4%), rice-based diets (RBD, 17.2%), and Western-style diets (WSD, 62.4%) in KNHANES. The incidence of metabolic syndrome was lowered in the order of RBD, WSD, and KBD. The participants having a KBD had lower serum C-reactive protein and triglyceride concentrations than those with RBD and WSD (p < 0.05). Three types of fecal bacteria were classified as Ruminococcaceae type (ET-R, 28.7%), Prevotella type (ET-P, 52.2%), and Bacteroides type (ET-B, 42.1%; p < 0.05). ET-P had a higher abundance of Prevotella copri, while ET-R contained a higher abundance of Alistipes, Akkermansia muciniphila, Bifidobacterium adolescentis, and Faecalibacterium prausnitzii. ET-B had a higher abundance of the order Bilophila (p < 0.05). Metabolism of propanoate, starch, and sucrose in fecal microbiome was higher in ET-P and ET-R, whereas fatty acid metabolism was enhanced in ET-B. Fecal microbiota in ET-P and ET-B had higher lipopolysaccharide biosynthesis activity than that in ET-R. The metabolic results of KBD and RBD were consistent with ET-R and ET-P's gut microbiota metabolism, respectively. In conclusion, Korean enterotypes of ET-P, ET-B, and ET-R were associated with RBD, WSD, and KBD, respectively. This study suggests a potential link between dietary patterns, metabolic syndrome, and enterotypes among Korean adults.

Improving noise policies in South Korea: non-market valuation based on an impact pathway approach.

The contingent valuation method (CVM) is used to measure non-market value. However, the CVM evaluates values using the subjective survey responses of consumers. Therefore, to analyze non-market value, we improve an integrated analysis module, which is divided into the following three parts: (1) a dose-response function that describes the relationship between noise exposure and annoyance, (2) the calculation of willingness to pay to reduce the noise level from the spike model in the CVM analysis, and (3) the calculation of the non-market value-related benefits by linking steps 1 and 2 above. We use the proposed integrated analysis module to analyze the value of noise reduction in South Korea. From this integrated analysis module, we find that a 1 dB reduction in living noise generated from a construction site has a value from 4578 KRW (USD$3.94) to 5794 KRW (USD$4.99) and that this value varies depending on the noise exposure level. The integrated analysis module can thus be used to improve noise policies in South Korea.

Protection against Alzheimer's disease by luteolin: Role of brain glucose regulation, anti-inflammatory activity, and the gut microbiota-liver-brain axis.

Luteolin is a widely distributed flavone herbs and vegetables. It has anti-oxidant and anti-inflammatory activities and improves glucose metabolism by potentiating insulin sensitivity and improving ß-cell function and mass. Alzheimer's disease (AD) is induced by the deposition of amyloid-beta (Aß) in the hippocampus and the formation of neurotoxic Aß plaques. The Aß deposition is associated with increased formation of Aß from amyloid precursor protein by up-regulation of ß-secretase and ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1). Furthermore, Aß accumulation is increased by brain insulin resistance. The impairment of insulin/IGF-1 signaling mainly in the hippocampus and brain insulin resistance is connected to signals originating in the liver and gut microbiota, known as the gut microbiota-liver-brain axis. This indicates that the changes in the production of short-chain fatty acids by the gut microbiota and pro-inflammatory cytokines can alter insulin resistance in the liver and brain. Luteolin is detected in the brain tissues after passing through the blood-brain barrier, where it can directly influence neuroinflammation and brain insulin resistance and modulate Aß deposition. Luteolin (10-70 mg/kg bw for rodents) can modulate the systemic and brain insulin resistance, and it suppresses AD development directly, and it influences Aß deposition by activation of the gut microbiota-liver-brain axis. In this review, we evaluate the potential of luteolin to mitigate two potential causes of AD, neuroinflammatory processes, and disruption of glucose metabolism in the brain. This review suggests that luteolin intake can enhance brain insulin resistance and neuroinflammation, directly and indirectly, to protect against the development of Alzheimer's-like disease, and the gut microbiota-liver-brain axis is mainly involved in the indirect pathway. However, most studies have been conducted in animal studies, and human clinical trials are needed.

A Western-style diet interacts with genetic variants of the LDL receptor to hyper-LDL cholesterolemia in Korean adults.

OBJECTIVE: To evaluate the association of genetic risk scores (GRS) of LDLR, APOB and proprotein convertase subtilisin-kexin type 9 (PCSK9) SNP and plasma LDL concentrations and to identify lifestyle interactions with the GRS in Korean middle-aged adults. DESIGN: Korean genome and epidemiology study (KoGES) was conducted to determine genetic variants and lifestyle factors, including nutrient intakes, in a retrospective hospital-based city cohort conducted by the Korean Center for Disease and Control during 2004-2013. SETTINGS: Hospitals in Korea. PARTICIPANTS: Adults aged 40-77 years (n 28 445) without serious diseases. RESULTS: Subjects with the major alleles (risk allele) of LDLR rs1433099 and rs11557092, APOB rs13306194 and PCSK9 rs11583723 had higher plasma LDL concentration by 1·20-folds than those with the minor alleles. Subjects with High-GRS (major alleles) of the four SNP had higher adjusted OR for plasma total and LDL-cholesterol and TAG concentrations by 1·24-, 1·203- and 1·167-folds, respectively, but not HDL-cholesterol, than those with Low-GRS. Western-style flour-rich dietary patterns, but not balanced Korean-style and rice-based dietary patterns, had interactions with GRS to increase plasma LDL concentrations. Daily energy intake also interacted with GRS. In the high intake of Western-style flour-rich dietary patterns, carriers with High-GRS had much higher plasma LDL concentrations than the Low-GRS. With high energy intake, carriers with High-GRS had much higher plasma LDL concentrations than those with Low-GRS. CONCLUSIONS: Adults with major alleles of four SNP are recommended to have low-energy intakes with a balanced Korean diet need to avoid high-energy intakes especially with Western-style flour-rich diet patterns.

Polygenetic-Risk Scores Related to Crystallin Metabolism Are Associated with Age-Related Cataract Formation and Interact with Hyperglycemia, Hypertension, Western-Style Diet, and Na Intake.

Age-related cataract (ARC) development is associated with loss of crystalline lens transparency related to interactions between genetic and environmental factors. We hypothesized that polygenetic risk scores (PRS) of the selected genetic variants among the ARC-related genes might reveal significant genetic impacts on ARC risk, and the PRS might have gene-gene and gene-lifestyle interactions. We examined the hypothesis in 1972 and 39,095 subjects aged ≥50 years with and without ARC, respectively, in a large-scale hospital-based cohort study conducted from 2004 to 2013. Single nucleotide polymorphisms (SNPs) of the genes related to ARC risk were identified, and polygenetic risk scores (PRS) were generated based on the results of a generalized multifactor dimensionality reduction analysis. Lifestyle interactions with PRS were evaluated. The PRS derived from the best model included the following six SNPs related to crystallin metabolism: ULK4_rs1417380362, CRYAB_rs2070894, ACCN1_rs55785344, SSTR2_rs879419608, PTN_rs322348, and ICA1_rs200053781. The risk of ARC in the high-PRS group was 2.47-fold higher than in the low-PRS group after adjusting for confounders. Age, blood pressure, and glycemia interacted with PRS to influence the risk of ARC: the incidence of ARC was much higher in the elderly (≥65 years) and individuals with hypertension or hyperglycemia. The impact of PRS on ARC risk was greatest in middle-aged individuals with hypertension or hyperglycemia. Na, coffee, and a Western-style diet intake also interacted with PRS to influence ARC risk. ARC risk was higher in the high-PRS group than in the low-PRS group, and high Na intake, Western-style diet, and low coffee intake elevated its risk. In conclusion, ARC risk had a positive association with PRS related to crystallin metabolism. The genetic impact was greatest among those with high Na intake or hypertension. These results can be applied to precision nutrition interventions to prevent ARC.

Polygenetic-Risk Scores for A Glaucoma Risk Interact with Blood Pressure, Glucose Control, and Carbohydrate Intake.

Glaucoma, a leading cause of blindness, has multifactorial causes, including environmental and genetic factors. We evaluated genetic risk factors of glaucoma with gene-gene interaction and explored modifications of genetic risk with gene-lifestyles interaction in adults >40 years. The present study included 377 subjects with glaucoma and 47,820 subjects without glaucoma in a large-scale hospital-based cohort study from 2004 to 2013. The presence of glaucoma was evaluated by a diagnostic questionnaire evaluated by a doctor. The genome-wide association study was performed to identify genetic variants associated with glaucoma risk. Food intake was assessed using a semiquantitative food frequency questionnaire. We performed generalized multifactor dimensionality reduction analysis to construct polygenetic-risk score (PRS) and explored gene × nutrient interaction. PRS of the best model included LIM-domain binding protein-2 (LDB2) rs3763969, cyclin-dependent kinase inhibitor 2B (CDKN2B) rs523096, ABO rs2073823, phosphodiesterase-3A (PDE3A) rs12314390, and cadherin 13 (CDH13) rs12449180. Glaucoma risk in the high-PRS group was 3.02 times that in the low-PRS group after adjusting for confounding variables. For those with low serum glucose levels (<126 mg/dL), but not for those with high serum glucose levels, glaucoma risk in the high-PRS group was 3.16 times that in the low-PRS group. In those with high carbohydrate intakes (≥70%), but not in those with low carbohydrate intakes, glaucoma risk was 3.74 times higher in the high-PRS group than in the low-PRS group. The glaucoma risk was 3.87 times higher in the high-PRS group than in the low-PRS group only in a low balanced diet intake. In conclusion, glaucoma risk increased by three-fold in adults with a high PRS, and it can be reduced by good control of serum glucose concentrations and blood pressure (BP) with a balanced diet intake. These results can be applied to precision nutrition to reduce glaucoma risk.

High carbohydrate and noodle/meat-rich dietary patterns interact with the minor haplotype in the 22q13 loci to increase its association with non-alcoholic fatty liver disease risk in Koreans.

Non-alcoholic fatty liver(NAFLD) is prevalent in Asians despite the low obesity rate. We hypothesized that the haplotype of genetic variants in the 22q13 loci has a strong association with non-alcoholic fatty liver disease (NAFLD) that can be identified by genome-wide association study and that lifestyles may interact with the haplotype. We tested the hypothesis in middle-aged and elderly adults in a large city hospital-based cohort from the KoGES study. Men and women diagnosed with fatty liver, but who respectively consumed over 40 and 30 g ethanol per day were excluded. The haplotype of the selected SNPs from the 22q13 loci that influences NAFLD risk was generated. Among the 27374 participants, 1486 (5.4%) were diagnosed with NAFLD. LARGE_rs240072, RBFOX2_rs11089778, TRIOBP_rs12628603, PNPLA3_rs738409, and PARVB_rs2073080 in the 22q13 loci were included in the haplotype. Participants with the minor haplotype had 1.8, 2.3, and 1.8 times higher in the risk for NAFLD and serum AST and ALT activities, respectively, than those with the major haplotype. BMI, waist circumferences, serum glucose concentrations, and blood pressure interacted with the haplotype for NAFLD risk. We also found that a high carbohydrate intake and a dietary pattern characterized by high noodle and meat consumption significantly interacted with the minor haplotype to increase the risk of NAFLD. We hypothesized that the high incidence of NAFLD among Koreans, despite a relatively low incidence of obesity, might be due to genetic factors and perhaps their interactions with dietary patterns. The hypothesis was accepted since this study confirmed that participants with the minor allele of the haplotype in the 22q13 loci had a higher NAFLD risk that was exacerbated by high intakes of carbohydrates and a dietary pattern characterized by high noodle and meat consumption.

A minor allele of the haplotype located in the 19q13 loci is associated with a decreased risk of hyper-LDL-cholesterolemia, and a balanced diet and high protein intake can reduce the risk.

BACKGROUND: Although the human chromosome 19q13 loci are reported to be associated with hyper-LDL-cholesterolemia, the haplotype of single nucleotide polymorphism (SNP) has not been studied. Therefore, the association of the haplotype in 19q13 loci with hyper-LDL-cholesterolemia was determined and their interactions with lifestyles and nutrient intakes were evaluated in 28,445 Koreans aged > 40 years. METHODS: SNPs were selected from 19q13 loci that had an association with hyper-LDL-cholesterolemia with the adjustment of confounders (age, gender, area of residence, and body mass index). Haplotype was constructed from the selected SNPs. An adjusted odds ratio of the haplotype for hyper-LDL-cholesterolemia and the interaction between haplotype and lifestyles was analyzed after adjusting for covariates. RESULTS: Hyper-LDL-cholesterolemia had an association with apolipoprotein E (APOE)_ rs7259620, translocase of outer mitochondrial membrane 40(TOMM40)_rs157581, poliovirus receptor-related 2(PVRL2)_rs403155, exocyst complex component 3-like 2(EXOC3L2)_ rs10406604 and CD3e molecule-associated protein (CD3EAP)_rs3212986 in 19q13. The haplotype of these SNPs had a negative association with hyper-total-cholesterolemia and hyper-LDL-cholesterolemia by 0.669 and 0.684 times, respectively, after adjusting for covariates. The incidence of cardiovascular diseases, especially myocardial infarction, had a negative association with the minor alleles. The balanced diet pattern (BD) and protein intake had a significant interaction with the haplotype: the major-allele of the haplotype exhibited a positive association with hyper-LDL-cholesterolemia, compared to the minor allele, only when combined with a high intake of BD. The participants with the minor allele exhibited a lower hyper-LDL-cholesterolemia risk compared to those with the major allele only with high protein intake. CONCLUSION: The minor allele of haplotype located in 19q13 loci protected against hyper-LDL-cholesterolemia, especially with BD and high protein intake. The minor allele also had a negative association with myocardial infarction events.

Alcohol, Carbohydrate, and Calcium Intakes and Smoking Interactions with APOA5 rs662799 and rs2266788 were Associated with Elevated Plasma Triglyceride Concentrations in a Cross-Sectional Study of Korean Adults.

BACKGROUND: Plasma triglyceride (TG) concentrations are markedly higher among Asians, which may be associated with the interaction of genetics and lifestyle factors. OBJECTIVE: The purpose of this study was to investigate the genetic variants that have a strong association with plasma TG concentrations from genome-wide association study and to identify lifestyle interactions with the genetic variants that are associated with dyslipidemia in a cohort of Korean adults. DESIGN: Korean genome and epidemiology study utilized a cross-sectional design of Koreans to determine genetic variants and lifestyle factors, including nutrient intakes, in a retrospective hospital-based city cohort conducted by the Korean Center for Disease and Control during 2004-2013. PARTICIPANTS: Korean adults aged 40 to 77 years were participants (n=28,445). MAIN OUTCOME MEASURES: The genetic variants that influence plasma TG concentrations were selected by genome-wide association study using an allele genetic model after adjusting for age, sex, area of residence, and body mass index. Lipid profiles and nutrient intakes from food frequency questionnaires were measured. The interactions between the single nucleotide polymorphisms and lifestyle factors were determined to influence plasma TG levels. RESULTS: Carrying the minor alleles of APOA5 rs662799 and rs2266788 had an association with higher plasma TG concentrations by 1.86- and 1.51-fold, respectively, compared with those with the major allele (P=8.89E-150 and P=4.75E-68, respectively). Sex had an interaction with these single nucleotide polymorphisms, with males having higher plasma TG concentrations. The single nucleotide polymorphisms had significant interactions with carbohydrate, fat, and calcium intakes; alcohol consumption; and smoking status that were associated with plasma TG concentrations. Carriers with the minor allele of each single nucleotide polymorphisms had higher plasma TG concentrations when consuming-low fat (<15%) and high carbohydrate (≥72%) diets than those with major alleles. Carriers of the minor alleles with low calcium intakes (<500 mg/day) experienced elevated plasma TG concentrations compared with carriers of the major alleles. Smokers and alcohol drinkers with either of the minor alleles of APOA5, rs662799 or rs2266788, had higher plasma TG concentrations than those with its major allele. CONCLUSIONS: These results indicated that carrying the minor alleles of APOA5 rs662799 and rs2266788, especially for men, was associated with elevated TG concentrations and suggested that Korean carriers of the minor alleles could be at increased risk of hypertriglyceridemia. Further research is needed to investigate the efficacy of modulating lifestyle factors to prevent dyslipidemia in people carrying the minor alleles of APOA5 rs662799 and rs2266788.

Severe calcium deficiency increased visceral fat accumulation, down-regulating genes associated with fat oxidation, and increased insulin resistance while elevating serum parathyroid hormone in estrogen-deficient rats.

Menopause impairs calcium(Ca) metabolism and reduces bone mineral density (BMD), but the interaction of menopause with Ca deficiency in energy, glucose, lipid, and bone metabolism has not been studied. Herein we hypothesized that Ca deficiency at levels for post-menopausal women would impair energy, glucose, lipid, and bone metabolism in estrogen-deficient rats. This hypothesis was examined in ovariectomized (OVX) rats fed high-fat diets with different Ca levels for 12 weeks. OVX rats were allocated into either very low Ca (0.02%, VLCA), low Ca (0.7%, LCA), adequate Ca (1.18%, ACA, control), or excessive Ca (2.1%, EXCA). Sham-operated rats had the same diet as ACA (Normal-control). Ca intake was 37, 107, 190, and 311 mg/kg bw/d in the VLCA, LCA, ACA, and EXCA groups. The ACA group had higher serum parathyroid hormone concentrations than the Normal-control but were highest in VLCA. VLCA decreased BMD and lean body mass compared to ACA. Fasting serum glucose concentrations, even with higher serum insulin concentrations, were higher in the VLCA than ACA, indicating increased insulin resistance in VLCA. VLCA deteriorated glucose tolerance after oral glucose administration and impaired lipid profiles. LCA and EXCA had similar effects on metabolism as ACA, but LCA did not improve insulin sensitivity and lipid profiles as much as ACA. Expressions of hepatic genes related to fatty acid and cholesterol synthesis (FAS and SREBP-1c and HMGCR) were much higher in the VLCA than ACA and expressions of genes related fatty acid degradation(CPT1 and CYP7A1) were much lower in VLCA than ACA. In conclusion, we accepted the hypothesis. Very low Ca intake (350-400 mg/d as a human equivalent) exacerbated estrogen-deficiency-induced impairments of energy, glucose, and lipid metabolism by elevating serum parathyroid hormone levels and inducing visceral fat accumulation and insulin resistance in estrogen-deficient rats, but there was no added benefit of excessive Ca.