Novel Human Milk Fat Substitutes Based on Medium- and Long-Chain Triacylglycerol Regulate Thermogenesis, Lipid Metabolism, and Gut Microbiota Diversity in C57BL/6J Mice.

Human milk is naturally rich in medium- and long-chain triacylglycerols (MLCT), accounting for approximately 30% of the total fat. However, infant formula fat is prepared using a physical blend of vegetable oils, which rarely contains MLCT, similar to human milk. The differences in MLCT between human milk and infant formulas may cause different lipid metabolisms and physiological effects on infants, which are unknown. This study aimed to analyze the metabolic characteristics of formula lipid containing novel human milk fat substitutes based on MLCT (FL-MLCT) and compare their effects with those of the physical blend of vegetable oils (FL-PB) on lipid metabolism and gut microbiota in mice. Compared with the FL-PB group, the FL-MLCT group showed increased energy expenditure, decreased serum triacylglycerol level, and significantly lower aspartate aminotransferase level, epididymal and perirenal fat weight, and adipocyte size. Moreover, the abundances of Firmicutes/Bacteroidota, Actinobacteriota, and Desulfovibrionaceae were significantly decreased in the FL-MLCT group. Novel human milk fat substitutes MLCT could inhibit visceral fat accumulation, improve liver function, and modulate the mice gut microbiota composition, which may contribute to controlling obesity.

Comparison of lipid structure and composition in human or cow's milk with different fat globules by homogenization.

Homogenization is used in human milk to add supplements for premature infants and in cow's milk to make it more uniform and stable for commercial purposes. However, it may destroy the milk fat globule (MFG) structure and composition, affecting its functional characteristics. This study aims to compare human and cow's milk with particle size ranges of 4-6 µm (large-sized), 1-2 µm (medium-sized), and 0.3-0.5 µm (small-sized) before and after homogenization at different pressure levels. CLSM and SDS-PAGE were used to perform the structural characterization. The lipid compositions were analyzed using GC and LC-MS. The results showed that homogenization obviously changed the MFG structure and its lipid composition. After homogenization, more caseins and whey proteins were adsorbed on both the human and cow's milk fat globule interface, while the proteins observed in human milk were dispersed. This could be attributed to the different types and contents of proteins initially. The influence of homogenization on milk phospholipids was higher than triacylglycerols and fatty acids, which was highly correlated with their initial distributions in MFGs. These results provide new information about the interfacial composition of human and cow's milk fat globules upon homogenization and establish the scientific basis for homogenization application in human and cow's milk to help explore their potential functions.

Medium- and long-chain triacylglycerols and di-unsaturated fatty acyl-palmitoyl-glycerols in Chinese human milk: Association with region during the lactation.

The triacylglycerols (TAGs) of medium- and long-chain triacylglycerols (MLCT) and di-unsaturated fatty acyl-palmitoyl-glycerols (UPU) in human milk provide better nutritional effects, and should be prioritized as crucial focuses on neonatal nutrition research. However, little has been done on the influences of the lactation stage and regional diversity on MLCT and UPU. In this study, we collected 204 human milk samples during colostrum, 1st and 4th month from the north (Baotou), central (Beijing), east (Jinan), southwest (Kunming), southeast (Shenzhen), and northwest (Xining) regions of China. There were 122 species of TAGs detected with UPLC-Q-TOF-MS, including 60 kinds of MLCT and 15 kinds of UPU. The MLCT and UPU type TAGs in human milk were ~27 and ~38%, respectively. The sum content of MLCT and UPU in human milk was stable. Compared to the regional diversity, lactation stages showed more obvious influences on MLCT and UPU composition. Moreover, a summary of TAG studies indicated that Chinese human milk showed a higher ratio of O-P-L to O-P-O than in western countries.

[Seasonal dynamics of the physicochemical properties of biological crusts exopolysaccharides and the microbial community structure]. / 生物结皮胞外多糖理化特性及菌群结构的季节动态.

Exopolysaccharides (EPS), an important substance of cyanobacteria in resisting stresses, are the main form of carbon storage in biocrusts and play an important role in material cycling and stability of biocrusts. In this study, the biocrusts in different seasons (January, April, July, October) were collected from Gurbantunggut Desert, and the dynamics of EPS content, composition, morphological characteristics and microbial community structures were analyzed. The results showed that: 1) The excretion of EPS showed obvious seasonal dynamics. The EPS contents in January, April, July and October were 81.72, 52.46, 76.77, 70.54 µg·cm-2, and the chlorophyll a contents were 2.7, 4.94, 4.2 and 5.98 µg·cm-2, respectively. Cyanobacteria allocated more fixed organic carbon to EPS in winter and summer, and more to their own biomass accumulation in spring and autumn. 2) EPS in biocrusts of each season was composed of seven kinds of monosaccharides. The sum of relative mole percentages of glucose and galactose was 46%-56%, much higher than the other five monosaccharides. The monosaccharide compositions of EPS were significantly affected by temperature and precipitation. There was no significant difference in the Fourier infrared spectra of EPS in biocrusts across different seasons. 3) The observation results of atomic force microscope showed that more filamentous and thick rope-like structures occurred in EPS in July and October, while the EPS showed block-like morphology in January and April. 4) The results of 16S rDNA high-throughput sequencing showed that Cyanobacteria and Microcoleus were the dominant bacterial phyla and genus in biocrusts in all the four seasons, with significantly higher relative abundance than other bacterial phyla and genera. The relative abundance of Proteobacteria was significantly positively correlated with the relative mole percentages of fucose and galactose, indicating that the composition of monosaccharides affected heterotrophic bacteria in crusts. In deserts, environmental factors such as temperature and moisture changed significantly across seasons. The physicochemical properties of biocrust exopolysaccharides and the seasonal dynamics of bacterial communities were controlled by multiple factors, such as temperature, moisture, and light.

Nitrogen concentration acting as an environmental signal regulates cyanobacterial EPS excretion.

As an important carbon (C) storage in biological soil crusts (BSCs), exopolysaccharides (EPSs) are not only a part of the desert C cycle, but also the key materials for cyanobacteria to resist desert stress. In this study, the influence of initial N concentrations (10, 25 and 50 mg L-1 designated as N10, N25 and N50 respectively) on Microcoleus vaginatusis growth and the excretion of EPSs including RPS (released exopolysaccharides) and CPS (capsule exopolysaccharides) were evaluated at different growth periods. In logarithmic period, higher ratio of biomass to EPSs indicated by (DW-CPS)/EPSs was observed in the N50 group with the highest N concentration (about 40 mg L-1) in the medium, while no difference was observed among the three groups in stationary period when the N concentrations of medium were lower than 25 mg L-1. The CPS/RPS showed similar results with (DW-CPS)/EPSs, and stayed higher than 1 in each group. Notably, obvious difference displayed in the monosaccharidic composition and morphologies between CPS and RPS, but not the N levels. The changes of C/N in cells at different growth period indicate that the excretion of EPSs, a mechanism that maintains the balance of cell C/N ratio, only works when the N in the environment is sufficient. Our results showed that, as the raw material and environmental signal, environmental N concentration regulates the elements (C and N) percentage of cyanobacterial cells and its EPSs excretion pattern, but not the monosaccharidic composition or the morphologies. These results also implied that, as the essential self-protecting materials, more EPSs with higher proportion of CPS would be excreted to response the low N environment.

Correction to: Age at menarche and age at natural menopause in East Asian women: a genome-wide association study.

The original version of this article unfortunately contained a mistake.

Combined effects of vitamin E and omega-3 fatty acids on protecting ambient PM2.5-induced cardiovascular injury in rats.

OBJECTIVE: This study aims to observe whether the combined treatment with vitamin E (vit E) and omega-3 polyunsaturated fatty acids (Ω-3 FA) could prevent the fine particulate matter (PM2.5)-induced cardiovascular injury through alleviating inflammation and oxidative stress. At the same time, the appropriate combination dosage of vit E and Ω-3 FA was explored to find an optimized protective dose to protect the injury induced by PM2.5. METHODS: The SD rats were pretreated with different concentration of vit E and Ω-3 FA separately or jointly. Then the rats were exposed to ambient PM2.5 by intratracheal instillation for three times. The expression of tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) in serum and supernatant of cardiac tissue were detected by ELISA kits. The levels of malondialdehyde (MDA), superoxide Dismutase (SOD) and glutathione-peroxidase (GSH-Px) in myocardium and the level of MDA in serum were measured. Meanwhile, the cardiac injury was evaluated by histopathological examination. RESULTS: Compared with the severe injury of rats in PM2.5 exposure group, the rats in vit E or Ω-3 FA-pretreated groups had a slighter injury in heart. Meanwhile, pretreatment with vit E or Ω-3 FA induced a significantly alleviation of the inflammatory cytokines (TNF-α, IL-1ß, IL-6) and the elevation of the anti-oxidative activity especially in the rats pretreated with combined vit E and Ω-3 FA. In addition, the combined protecting effects of vit E and Ω-3 FA showed a dose-dependent manner. CONCLUSION: Supplementation with vit E and Ω-3 FA could protect the PM2.5-induced injury, and the combination of vit E and Ω-3 FA might produce more effective effects than the separate nutrient did.

Age at menarche and age at natural menopause in East Asian women: a genome-wide association study.

Age at menarche (AM) and age at natural menopause (ANM) are complex traits with a high heritability. Abnormal timing of menarche or menopause is associated with a reduced span of fertility and risk for several age-related diseases including breast, endometrial and ovarian cancer, cardiovascular disease, and osteoporosis. To identify novel genetic loci for AM or ANM in East Asian women and to replicate previously identified loci primarily in women of European ancestry by genome-wide association studies (GWASs), we conducted a two-stage GWAS. Stage I aimed to discover promising novel AM and ANM loci using GWAS data of 8073 women from Shanghai, China. The Stage II replication study used the data from another Chinese GWAS (n = 1230 for AM and n = 1458 for ANM), a Korean GWAS (n = 4215 for AM and n = 1739 for ANM), and de novo genotyping of 2877 additional Chinese women. Previous GWAS-identified loci for AM and ANM were also evaluated. We identified two suggestive menarcheal age loci tagged by rs79195475 at 10q21.3 (beta = -0.118 years, P = 3.4 × 10-6) and rs1023935 at 4p15.1 (beta = -0.145 years, P = 4.9 × 10-6) and one menopausal age locus tagged by rs3818134 at 22q12.2 (beta = -0.276 years, P = 8.8 × 10-6). These suggestive loci warrant a further validation in independent populations. Although limited by low statistical power, we replicated 19 of the 98 menarche loci and 5 of the 20 menopause loci previously identified in women of European ancestry in East Asian women, suggesting a shared genetic architecture for these two traits across populations.

A dose-response study of vitamin D3 supplementation in healthy Chinese: a 5-arm randomized, placebo-controlled trial.

PURPOSE: To determine the dose-response of vitamin D3 supplementation on serum 25-hydroxyvitamin D [25(OH)D] among Chinese adults. METHODS: In this 5-arm, randomized, double-blinded controlled trial, 76 healthy participants were assigned to orally administrate 0, 400, 800, 1200 or 2000 IU/d of vitamin D3 for 16 weeks. Serum 25(OH)D, parathyroid hormone, calcium, biomarkers of liver and renal function were measured at multiple time points. RESULTS: The mean (SD) serum 25(OH)D at baseline was 31.6 (8.7) nmol/L, and the dose-response relationship was curvilinear with a plateau around 6 weeks for all doses. At week 16, 25(OH)D was increased by 6.0 (6.5), 21.7 (15.8), 26.3 (12.6), 32.0 (12.8) and 36.3 (26.0) nmol/L for 0, 400, 800, 1200 and 2000 IU/d (all P ≤ 0.002), corresponding to approximately 19, 53, 67, 77 and 80 % of reversion of vitamin D deficiency, respectively. Daily intake of 800 IU vitamin D3 reached a targeted 25(OH)D ≥ 30 nmol/L in at least 97.5 % of Chinese, but not a targeted 25(OH)D ≥ 50 nmol/L even with 2000 IU/d. Change of 25(OH)D was inversely associated with change of PTH concentration (r = -0.39, P < 0.001) after controlling for age and sex. No between-group differences were observed in terms of the change in serum calcium, alanine transaminase, aspartate aminotransferase, gamma-glutamyltransferase and creatinine (P ≥ 0.22). CONCLUSIONS: Supplementation with 400, 800, 1200 or 2000 IU/d vitamin D could improve the vitamin D deficiency with various degrees. Whether 2000 IU/d vitamin D3 would generate a better result without side effect requires more studies with larger samples in future.

Elevated plasma tumor necrosis factor-α receptor 2 and resistin are associated with increased incidence of kidney function decline in Chinese adults.

Adipokines and inflammatory markers have been linked to kidney disease in animal models; however, evidence from prospective human studies is sparse. Recruited from Beijing and Shanghai in 2005, a total number of 2220 non-institutionalized Chinese individuals aged 50-70 years with baseline estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m(2) were prospectively followed for 6 years. Plasma levels of resistin, retinol-binding protein 4 (RBP4), interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α receptor 2 (TNF-R2) were determined at baseline. Kidney function decrease was assessed by measurements of eGFR over 6 years. Incident-reduced eGFR was defined as the onset of eGFR <60 mL/min/1.73 m(2), according to the Modification of Diet in Renal Disease Study Equation for Chinese. During the 6 years of follow-up, 333 (15.0 %) participants had incident-reduced eGFR. Each 1 standard deviation elevated concentration of resistin [relative risk (RR) 1.10; 95 % CI 1.00-1.24] and TNFR-2 (RR 1.30; 95 % CI 1.13-1.49) at baseline were significantly associated with a higher risk of incident-reduced eGFR. Comparing the highest with the lowest quartiles, the RR of incident-reduced eGFR was 1.43 (95 % CI 1.01-2.03) for resistin and 2.03 (95 % CI 1.41-2.93) for TNF-R2 (both P trend < 0.05) after adjustment for baseline demographic characteristics, lifestyle behaviors, BMI, plasma lipid profile, hypertension, and diabetes. These associations remained significant when further controlling for levels of RBP4, IL-6, and CRP, none of which was significantly associated with the risk of incident-reduced eGFR. In this prospective cohort study, elevated levels of resistin and TNF-R2, but not other adipokines and inflammatory markers, were independently associated with a greater risk of kidney function decline in middle-aged and elderly Chinese.

The development and validation of new equations for estimating body fat percentage among Chinese men and women.

Equations based on simple anthropometric measurements to predict body fat percentage (BF%) are lacking in Chinese population with increasing prevalence of obesity and related abnormalities. We aimed to develop and validate BF% equations in two independent population-based samples of Chinese men and women. The equations were developed among 960 Chinese Hans living in Shanghai (age 46.2 (SD 5.3) years; 36.7% male) using a stepwise linear regression and were subsequently validated in 1150 Shanghai residents (58.7 (SD 6.0) years; 41.7% male; 99% Chinese Hans, 1% Chinese minorities). The associations of equation-derived BF% with changes of 6-year cardiometabolic outcomes and incident type 2 diabetes (T2D) were evaluated in a sub-cohort of 780 Chinese, compared with BF% measured by dual-energy X-ray absorptiometry (DXA; BF%-DXA). Sex-specific equations were established with age, BMI and waist circumference as independent variables. The BF% calculated using new sex-specific equations (BF%-CSS) were in reasonable agreement with BF%-DXA (mean difference: 0.08 (2 SD 6.64) %, P= 0.606 in men; 0.45 (2 SD 6.88) %, P< 0.001 in women). In multivariate-adjusted models, the BF%-CSS and BF%-DXA showed comparable associations with 6-year changes in TAG, HDL-cholesterol, diastolic blood pressure, C-reactive protein and uric acid (P for comparisons ≥ 0.05). Meanwhile, the BF%-CSS and BF%-DXA had comparable areas under the receiver operating characteristic curves for associations with incident T2D (men P= 0.327; women P= 0.159). The BF% equations might be used as surrogates for DXA to estimate BF% among adult Chinese. More studies are needed to evaluate the application of our equations in different populations.

Nickel exposure is associated with the prevalence of type 2 diabetes in Chinese adults.

BACKGROUND: Nickel exposure can induce hyperglycaemia in rodents, but little is known about its association with abnormal glucose metabolism in humans. We aimed to investigate the association of nickel exposure with the prevalence of type 2 diabetes in Chinese adults. METHODS: A total of 2115 non-institutionalized men and women aged 55 to 76 years from Beijing and Shanghai were included, and urinary nickel concentration was assessed by inductively coupled plasma mass spectroscopy. The prevalence of type 2 diabetes was compared across urinary nickel quartiles. Fasting plasma glucose, insulin, lipids, C-reactive protein and glycated haemoglobin A1c, as well as urinary albumin and creatinine were measured. RESULTS: The median concentration of urinary nickel was 3.63 mg/l (interquartile range: 2.29­5.89 mg/l), and the prevalence of diabetes was 35.3% (747 cases/2115 persons). Elevated levels of urinary nickel were associated with higher fasting glucose, glycated haemoglobin A1c, insulin and homeostatic model assessment of insulin resistance (all P<0.01). The odds ratios (95% confidence interval) for diabetes across the increasing urinary nickel quartiles were 1.27 (0.97­1.67), 1.78 (1.36­2.32) and 1.68 (1.29­2.20), respectively (referencing to 1.00), after multivariate adjustment including lifestyle factors, body mass index and family history of diabetes (P for trend <0.001). The association remained unchanged after further controlling for urinary creatinine and C-reactive protein (P for trend <0.001). CONCLUSIONS: Increased urinary nickel concentration is associated with elevated prevalence of type 2 diabetes in humans.

Poor vitamin D status is prospectively associated with greater muscle mass loss in middle-aged and elderly Chinese individuals.

BACKGROUND: Poor vitamin D status can increase age-related muscle mass loss. However, existing prospective evidence is limited and controversial. OBJECTIVE: This study aimed to investigate the association of plasma 25-hydroxyvitamin D [25(OH)D] with muscle mass loss in middle-aged and elderly Chinese individuals over 6 years. DESIGN: We conducted a prospective cohort study. PARTICIPANTS/SETTING: This community-based study included 568 men and women aged 50 to 70 years at baseline. MAIN OUTCOMES MEASURES: Baseline plasma concentrations of 25(OH)D and biomarkers of liver and kidney functions and inflammation were measured. Body composition was assessed at baseline and 6-year follow-up by dual-energy x-ray absorptiometry. Appendicular skeletal muscle mass (ASMM) and trunk lean mass were calculated and total body lean mass was defined as an overall measure of total nonfat and nonbone tissues. STATISTICAL ANALYSES PERFORMED: Descriptive statistics and multiple linear regression were applied. RESULTS: The 6-year loss of ASMM was 1.14 kg (5.3%) in men and 0.47 kg (3.1%) in women (all P values <0.001). Compared with the highest 25(OH)D tertile, participants in the lowest tertile had significantly more absolute loss of ASMM (-1.21 vs -1.00 kg; P for trend=0.024) after multivariate adjustments for conventional confounders, as well as protein intake. The association persisted after additional adjustment of bone mineral density and inflammatory markers (P for trend=0.017). No significant associations were detected between 25(OH)D and absolute loss of trunk lean mass or total body lean mass. CONCLUSIONS: Lower 25(OH)D concentrations were prospectively associated with greater ASMM loss in middle-aged and elderly Chinese individuals independent of bone mineral density, inflammation, diet, and other risk factors.

Lipopolysaccharide binding protein, obesity status and incidence of metabolic syndrome: a prospective study among middle-aged and older Chinese.

AIMS/HYPOTHESIS: Although microbiota-derived endotoxaemia has previously been shown to induce metabolic disorders, data from population-based longitudinal studies are scarce. This study therefore investigated the associations between lipopolysaccharide binding protein (LBP) levels and 6 year incident metabolic syndrome (MetS), as well as the potentially modifying effects of obesity status in middle-aged and older Chinese men and women. METHODS: A total of 2,529 men and women aged 50-70 years from Beijing and Shanghai, China, were followed for 6 years. Those free of MetS at baseline (1,312) were included in the analyses for the risk of developing MetS. Baseline plasma LBP was measured using an ELISA kit. RESULTS: During the 6 year follow-up, 449 (34.2%) participants developed MetS. Baseline LBP was significantly associated with BMI, waist circumference, blood lipid profile and C-reactive protein (CRP) both at baseline and during follow-up (all p < 0.05). The RR for incident MetS comparing extreme quartiles of LBP was 1.28 (95% CI 1.04, 1.58), after multivariate adjustment including BMI and CRP. In stratified analysis, LBP was positively associated with incident MetS only in normal-weight participants (RR, comparing extreme tertiles, 1.59; 95% CI 1.18, 2.15; p(trend)= 0.002), but not in their overweight/obese counterparts (RR, comparing extreme tertiles, 0.99; 95% CI 0.80, 1.22; p(trend) = 0.880). A significant interaction was observed between LBP and obesity status (p(interaction) = 0.013). CONCLUSIONS/INTERPRETATION: Our study suggested that elevated plasma LBP was associated with an increased risk of developing MetS among middle-aged and older Chinese, especially in normal-weight individuals.

Association of genetic predisposition to obesity with type 2 diabetes risk in Han Chinese individuals.

AIMS/HYPOTHESIS: Obesity is a major risk factor for type 2 diabetes, but little is known about the contribution of BMI-associated loci to type 2 diabetes risk in East Asian populations. METHODS: In this study, 30 known BMI-associated variants and a genetic risk score (GRS) calculated by summing the BMI-increasing alleles of these variants were tested for associations with type 2 diabetes and related glycaemic traits in 1,873 cases of type 2 diabetes and 1,839 controls in Han Chinese individuals. Logistic and linear regression analyses were performed to determine the association with type 2 diabetes risk or related glycaemic traits, respectively, under an additive model with or without adjustment for BMI. RESULTS: The GRS was significantly associated with increased BMI (ß [SE] 0.070 [0.016]; p = 1.33 × 0(-5)) in the overall population. Each additional BMI-increasing allele in the GRS increased type 2 diabetes risk by 1.029-fold (95% CI 1.008, 1.050; p = 0.0056) without adjustment for BMI, and the association was slightly attenuated after adjustment for BMI (OR 1.022; 95% CI 1.002, 1.043; p = 0.035). In non-diabetic controls, the GRS was also associated with HOMA of beta cell function (HOMA-B) with adjustment for BMI (ß [SE] -0.876 [0.345]; p = 0.011). Notably, the association of GRS with type 2 diabetes was abolished after adjusting for HOMA-B (OR 1.012; 95% CI 0.986, 1.039; p = 0.380). CONCLUSIONS/INTERPRETATION: Our results suggested that genetic predisposition to obesity leads to increased risk of type 2 diabetes, independent of BMI and partly through impaired beta cell function.

Development of a new risk score for incident type 2 diabetes using updated diagnostic criteria in middle-aged and older chinese.

Type 2 diabetes mellitus (T2DM) reaches an epidemic proportion among adults in China. However, no simple score has been created for the prediction of T2DM incidence diagnosed by updated criteria with hemoglobin A1c (HbA1c) ≥ 6.5% included in Chinese. In a 6-year follow-up cohort in Beijing and Shanghai, China, we recruited a total of 2529 adults aged 50-70 years in 2005 and followed them up in 2011. Fasting plasma glucose (FPG), HbA1c, and C-reactive protein (CRP) were measured and incident diabetes was identified by the recently updated criteria. Of the 1912 participants without T2DM at baseline, 924 were identified as having T2DM at follow-up, and most of them (72.4%) were diagnosed using the HbA1c criterion. Baseline body mass index, FPG, HbA1c, CRP, hypertension, and female gender were all significantly associated with incident T2DM. Based upon these risk factors, a simple score was developed with an estimated area under the receiver operating characteristic curve of 0.714 (95% confidence interval: 0.691, 0.737), which performed better than most of existing risk score models developed for eastern Asian populations. This simple, newly constructed score of six parameters may be useful in predicting T2DM in middle-aged and older Chinese.

Elevated plasma retinol-binding protein 4 is associated with increased risk of type 2 diabetes in middle-aged and elderly Chinese adults.

The association between circulating retinol-binding protein 4 (RBP4) and risk of type 2 diabetes has been inconsistent in cross-sectional studies, but prospective evidence is limited. We aimed to investigate whether plasma RBP4 is associated with future development of type 2 diabetes and whether the association could be explained by iron or other risk factors. A total of 2091 Chinese adults aged 50-70 y were followed up for 6 y. Baseline dietary intakes and fasting plasma RBP4, ferritin, adiponectin, C-reactive protein (CRP), γ-glutamyltransferase, creatinine, and erythrocyte fatty acids were determined. Self-reported doctor-diagnosed diabetes, or usage of antidiabetic agents, or fasting plasma glucose concentration at the follow-up visit ≥7.0 mmol/L was defined as an incident diabetes case. Plasma RBP4 concentration was significantly associated with dietary heme iron intake, plasma ferritin concentration, and other established risk factors. After multivariate adjustment for demographic and lifestyle variables, relative risk (RR) for type 2 diabetes when the extreme quartiles of RBP4 were compared was 1.75 (95% CI: 1.30, 2.37; P-trend < 0.001). This association remained significant when the extreme quartiles were compared (RR = 1.48; 95% CI: 1.06, 2.05; P-trend = 0.036) after further controlling for ferritin and dietary factors, as well as other risk factors, including body mass index, adiponectin, CRP, lipids, liver and kidney function, insulin resistance, and hypertension. A threshold effect of RBP4 concentrations on incident diabetes was suggested by restricted quadratic spline analysis (P = 0.026 for nonlinearity). Our study indicates that plasma RBP4 is independently associated with the 6-y risk of developing type 2 diabetes.

Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians.

Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10(-23)], HBS1L/MYB [8.5 × 10(-15)], MYO9B [9.0 × 10(-12)], and CYBA [1.1 × 10(-8)] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.

Associations of genetic risk score with obesity and related traits and the modifying effect of physical activity in a Chinese Han population.

BACKGROUND/OBJECTIVES: Recent large-scale genome-wide association studies have identified multiple loci robustly associated with BMI, predominantly in European ancestry (EA) populations. However, associations of these loci with obesity and related traits have not been well described in Chinese Hans. This study aimed to investigate whether BMI-associated loci are, individually and collectively, associated with adiposity-related traits and obesity in Chinese Hans and whether these associations are modified by physical activity (PA). SUBJECTS/METHODS: We genotyped 28 BMI-associated single nucleotide polymorphisms (SNPs) in a population-based cohort including 2,894 unrelated Han Chinese. Genetic risk score (GRS), EA and East Asian ancestry (EAA) GRSs were calculated by adding BMI-increasing alleles based on all, EA and EAA identified SNPs, respectively. Interactions of GRS and PA were examined by including the interaction-term in the regression model. RESULTS: Individually, 26 of 28 SNPs showed directionally consistent effects on BMI, and associations of four loci (TMEM18, PCSK1, BDNF and MAP2K5) reached nominal significance (P<0.05). The GRS was associated with increased BMI, trunk fat and body fat percentages; and increased risk of obesity and overweight (all P<0.05). Effect sizes (0.11 vs. 0.17 kg/m2) and explained variance (0.90% vs. 1.45%) of GRS for BMI tended to be lower in Chinese Hans than in Europeans. The EA GRS and EAA GRS were associated with 0.11 and 0.13 kg/m2 higher BMI, respectively. In addition, we found that PA attenuated the effect of the GRS on BMI (Pinteraction = 0.022). CONCLUSIONS: Our observations suggest that the combined effect of obesity-susceptibility loci on BMI tended to be lower in Han Chinese than in EA. The overall, EA and EAA GRSs exert similar effects on adiposity traits. Genetic predisposition to increased BMI is attenuated by PA in this population of Han Chinese.

A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2.

Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10(-14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10(-7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10(-165)), ADIPOQ (P = 1.8 × 10(-22)), PEPD (P = 3.6 × 10(-12)), CMIP (P = 2.1 × 10(-10)), ZNF664 (P = 2.3 × 10(-7)) and GPR109A (P = 7.4 × 10(-6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10(-7)). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10(-4)), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10(-4)) and body mass index (BMI)-adjusted waist-hip ratio (P = 9.8 × 10(-3)). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.