RESUMEN
Accompanied with nutrition transition, non-HDL-C levels of individuals in Asian countries has increased rapidly, which has caused the global epicenter of nonoptimal cholesterol to shift from Western countries to Asian countries. Thus, it is critical to underline major genetic and dietary determinants. In the current study of 2,330 Chinese individuals, genetic risk scores (GRSs) were calculated for total cholesterol (TC; GRSTC, 57 SNPs), LDL-C (GRSLDL-C, 45 SNPs), and HDL-C (GRSHDL-C, 65 SNPs) based on SNPs from the Global Lipid Genetics Consortium study. Cholesterol intake was estimated by a 74-item food-frequency questionnaire. Associations of dietary cholesterol intake with plasma TC and LDL-C strengthened across quartiles of the GRSTC (effect sizes: -0.29, 0.34, 2.45, and 6.47; Pinteraction = 0.002) and GRSLDL-C (effect sizes: -1.35, 0.17, 5.45, and 6.07; Pinteraction = 0.001), respectively. Similar interactions with non-HDL-C were observed between dietary cholesterol and GRSTC (Pinteraction = 0.001) and GRSLDL-C (Pinteraction = 0.004). The adverse effects of GRSTC on TC (effect sizes across dietary cholesterol quartiles: 0.51, 0.82, 1.21, and 1.31; Pinteraction = 0.023) and GRSLDL-C on LDL-C (effect sizes across dietary cholesterol quartiles: 0.66, 0.52, 1.12, and 1.56; Pinteraction = 0.020) were more profound in those having higher cholesterol intake compared with those with lower intake. Our findings suggest significant interactions between genetic susceptibility and dietary cholesterol intake on plasma cholesterol profiles in a Chinese population.
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Colesterol en la Dieta/administración & dosificación , LDL-Colesterol/genética , Colesterol/genética , Anciano , Pueblo Asiatico , Colesterol/sangre , Colesterol en la Dieta/efectos adversos , LDL-Colesterol/sangre , Femenino , Variación Genética/genética , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND: Animal studies suggest vital roles of sphingolipids, especially ceramides, in the pathogenesis of type 2 diabetes (T2D) via pathways involved in insulin resistance, ß-cell dysfunction, and inflammation, but human studies are limited. We aimed to evaluate the associations of circulating sphingolipids with incident T2D and to explore underlying mechanisms. METHODS AND FINDINGS: The current study included 826 men and 1,148 women who were aged 50-70 years, from Beijing and Shanghai, and without T2D in 2005 and who were resurveyed in 2011. Cardiometabolic traits were measured at baseline and follow-up surveys. A total of 76 sphingolipids were quantified using high-coverage targeted lipidomics. Summary data for 2-sample Mendelian randomization were obtained from genome-wide association studies of circulating sphingolipids and the China Health and Nutrition Survey (n = 5,731). During the 6-year period, 529 participants developed T2D. Eleven novel and 3 reported sphingolipids, namely ceramides (d18:1/18:1, d18:1/20:0, d18:1/20:1, d18:1/22:1), saturated sphingomyelins (C34:0, C36:0, C38:0, C40:0), unsaturated sphingomyelins (C34:1, C36:1, C42:3), hydroxyl-sphingomyelins (C34:1, C38:3), and a hexosylceramide (d18:1/20:1), were positively associated with incident T2D (relative risks [RRs]: 1.14-1.21; all P < 0.001), after multivariate adjustment including lifestyle characteristics and BMI. Network analysis further identified 5 modules, and 2 modules containing saturated sphingomyelins showed the strongest associations with increased T2D risk (RRQ4 versus Q1 = 1.59 and 1.43; both Ptrend < 0.001). Mediation analysis suggested that the detrimental associations of 13 sphingolipids with T2D were largely mediated through ß-cell dysfunction, as indicated by HOMA-B (mediation proportion: 11.19%-42.42%; all P < 0.001). Moreover, Mendelian randomization evidenced a positive association between a genetically instrumented ceramide (d18:1/20:1) and T2D (odds ratio: 1.15 [95% CI 1.05-1.26]; P = 0.002). Main limitations in the current study included potential undiagnosed cases and lack of an independent population for replication. CONCLUSIONS: In this study, we observed that a panel of novel sphingolipids with unique structures were positively associated with incident T2D, largely mediated through ß-cell dysfunction, in Chinese individuals.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Células Secretoras de Insulina/metabolismo , Insulina/sangre , Esfingolípidos/sangre , Anciano , Biomarcadores/sangre , China/epidemiología , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Incidencia , Lipidómica , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Metaanálisis en Red , Encuestas Nutricionales , Estudios Prospectivos , Medición de Riesgo , Factores de RiesgoRESUMEN
The effects of PUFAs on metabolic syndrome (MetS) remain to be characterized, particularly in Asians. We aimed to investigate the prospective associations of PUFAs with MetS and the role of acylcarnitines in these associations in Chinese individuals. Among 1,245 Chinese men and women aged 50-70 years who completed a 6 year follow-up, baseline erythrocyte FAs and plasma acylcarnitines were profiled using gas chromatography coupled with positive chemical ionization and liquid chromatography-tandem mass spectrometry, respectively. Total n-6 PUFAs and three 22-carbon n-6 PUFAs were significantly associated with lower MetS risk comparing extreme quartiles: relative risks (RRs) (95% CIs) were 0.75 (0.57, 0.97) for total n-6 PUFAs, 0.69 (0.56, 0.85) for 22:2n-6, 0.76 (0.59, 0.99) for 22:4n-6, and 0.74 (0.58, 0.94) for 22:5n-6, while 18:3n-3 and 18:3n-6 were positively associated with MetS risk. In a network analysis, a module mostly consisting of long-chain n-6 PUFAs and very-long-chain saturated FAs was inversely associated with incident MetS (RR per SD: 0.84; 95% CI: 0.76, 0.92), and this module was more strongly associated with lower MetS risk when a short- to medium-chain acylcarnitine (C5-C10) module score was lower (Pinteraction = 0.03). Our data suggested inverse associations of total n-6 and certain long-chain n-6 PUFAs with cardiometabolic disorders, and this association might be modified by certain acy-l-carnitines.
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Carnitina/análogos & derivados , Eritrocitos/metabolismo , Ácidos Grasos Insaturados/metabolismo , Síndrome Metabólico/epidemiología , Síndrome Metabólico/metabolismo , Anciano , Carnitina/metabolismo , China/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.
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Colesterol/genética , Triglicéridos/genética , Adulto , Alelos , Pueblo Asiatico/genética , Colesterol/metabolismo , Etnicidad , Femenino , Frecuencia de los Genes/genética , Estudios de Asociación Genética/métodos , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento/genética , Lípidos/genética , Lipoproteínas HDL/genética , Lipoproteínas LDL/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo , Triglicéridos/metabolismo , Población Blanca/genéticaRESUMEN
Epidemiological studies suggest that levels of n-3 and n-6 long-chain polyunsaturated fatty acids are associated with risk of cardio-metabolic outcomes across different ethnic groups. Recent genome-wide association studies in populations of European ancestry have identified several loci associated with plasma and/or erythrocyte polyunsaturated fatty acids. To identify additional novel loci, we carried out a genome-wide association study in two population-based cohorts consisting of 3521 Chinese participants, followed by a trans-ethnic meta-analysis with meta-analysis results from 8962 participants of European ancestry. Four novel loci (MYB, AGPAT4, DGAT2 and PPT2) reached genome-wide significance in the trans-ethnic meta-analysis (log10(Bayes Factor) ≥ 6). Of them, associations of MYB and AGPAT4 with docosatetraenoic acid (log10(Bayes Factor) = 11.5 and 8.69, respectively) also reached genome-wide significance in the Chinese-specific genome-wide association analyses (P = 4.15 × 10(-14) and 4.30 × 10(-12), respectively), while associations of DGAT2 with gamma-linolenic acid (log10(Bayes Factor) = 6.16) and of PPT2 with docosapentaenoic acid (log10(Bayes Factor) = 6.24) were nominally significant in both Chinese- and European-specific genome-wide association analyses (P ≤ 0.003). We also confirmed previously reported loci including FADS1, NTAN1, NRBF2, ELOVL2 and GCKR. Different effect sizes in FADS1 and independent association signals in ELOVL2 were observed. These results provide novel insight into the genetic background of polyunsaturated fatty acids and their differences between Chinese and European populations.
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Ácidos Grasos Insaturados/genética , Población Blanca/genética , Pueblo Asiatico/genética , Teorema de Bayes , delta-5 Desaturasa de Ácido Graso , Ácidos Grasos Insaturados/sangre , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Previously identified common variants explain only a small fraction of the trait heritability and at most loci the identities of the underlying causal genes and their functional variants still remain unknown. To identify the low-frequency and rare coding variants that influence lipid levels, we conducted a meta-analysis of exome-wide association studies in 14,473 Chinese subjects, followed by a joint analysis with 1000 genomes imputed data from 6,534 samples. We replicated 24 previously reported lipid loci with exome-wide significance (P < 3.3 × 10 - 7), including fourteen coding variants at ten confirmed lipid loci (P range from 1.44 × 10 - 7 to 1.64 × 10 - 45). Of these, six coding variants showed population-specific associations and were independent of previously identified associations in European populations, including four low-frequency (PCSK9 p.Arg93Cys, HMGCR p.Tyr311Ser, APOA5 p.Gly185Cys and CETP p.Asp399Gly) and two common (APOB p.Arg532Trp and APOA4 p.Ser147Asn) variants. Furthermore, we detected three new lead non-coding variants at LPA, LIPC and LDLR in Chinese. The independent variants at PCSK9, HMGCR, LPA, APOA5 and LDLR were also associated with increased risk of coronary artery disease in the expected direction. In gene-based tests, the burden of rare or low frequency variants in PCSK9, HMGCR and CEPT exhibited strong associations with blood lipid levels (P < 2.8 × 10 - 6). Our findings identify additional population-specific possible causal variants. Our data demonstrate that the inter-ethnic differences in allele frequencies of coding variants may lead to different association signals across ethnic groups, highlighting the importance of including diverse populations to uncover genetic variation associated with lipid levels.
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Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad , Lípidos/sangre , Triglicéridos/sangre , Anciano , Pueblo Asiatico , LDL-Colesterol/sangre , LDL-Colesterol/genética , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/patología , Exoma/genética , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Humanos , Hidroximetilglutaril-CoA Reductasas/genética , Metabolismo de los Lípidos/genética , Lípidos/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proproteína Convertasa 9/genética , Triglicéridos/genética , Población BlancaRESUMEN
BACKGROUND: Bone turnover markers (BTMs) are proposed as alternative indicators for bone mineral density in diagnosis and management of osteoporosis. However, little is known about the effects of vitamin D supplementation on BTMs in nonwhite populations. OBJECTIVE: We aimed to investigate the responses in BTMs after vitamin D supplementation in Asians. METHODS: In this secondary data analysis of a randomized, double-blind, placebo-controlled trial, 448 Chinese adults [mean ± SD age: 31.9 ± 8.0 y; mean ± SD body mass index (kg/m2): 22.1 ± 2.6; 69% were women] with vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] <50 nmol/L) received 2000 IU/d cholecalciferol or placebo for 20 wk. Serum concentrations of 25(OH)D, parathyroid hormone (PTH), calcium, and markers of bone formation and resorption were measured at weeks 0 and 20. Intention-to-treat analysis was applied, and between-group differences were compared by general linear models with adjustments. RESULTS: Cholecalciferol supplementation increased the serum bone alkaline phosphatase (BALP) concentration (+1.7 ± 1.9 µg/L) significantly more than placebo (+1.1 ± 1.7 µg/L; P = 0.004), but not circulating concentrations of procollagen type I N-terminal propeptide (PINP), ß-isomerized C-terminal telopeptide of type I collagen (ß-CTX), or tartrate-resistant acid phosphatase 5b (TRAP5b) (P ≥ 0.53). Notably, a pooled analysis indicated that changes in serum 25(OH)D were positively associated with changes in serum BALP, PINP, and TRAP5b (r = 0.07-0.16, P ≤ 0.02), but inversely with changes in PTH (r = -0.15, P < 0.001). Among cholecalciferol-treated participants, individuals who achieved serum 25(OH)D ≥75 nmol/L had greater increases in serum ß-CTX (224% compared with 146%; P = 0.02) and TRAP5b (22.2% compared with 9.1%; P = 0.007), but smaller decreases in serum calcium (-1.3% compared with -1.9%; P = 0.005) and calcium-phosphorus product (-2.6% compared with -3.3%; P = 0.02) compared with those with serum 25(OH)D <75 nmol/L. CONCLUSIONS: Daily supplementation with 2000 IU cholecalciferol for 20 wk may promote bone formation in Chinese adults with vitamin D deficiency. More studies are needed to elucidate the potential clinical implications of BTMs.This trial was registered at clinicaltrials.gov as NCT01998763.
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Remodelación Ósea/efectos de los fármacos , Colecalciferol/administración & dosificación , Deficiencia de Vitamina D/dietoterapia , Adulto , Fosfatasa Alcalina/sangre , Pueblo Asiatico , Biomarcadores/sangre , Densidad Ósea/efectos de los fármacos , Densidad Ósea/fisiología , Remodelación Ósea/fisiología , China , Suplementos Dietéticos , Método Doble Ciego , Femenino , Humanos , Masculino , Hormona Paratiroidea/sangre , Fragmentos de Péptidos/sangre , Procolágeno/sangre , Fosfatasa Ácida Tartratorresistente/sangre , Vitamina D/análogos & derivados , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Adulto JovenRESUMEN
MUFAs are unsaturated FAs with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels are associated with cardiometabolic disorders, including CVD, T2D, and metabolic syndrome (MS). Previous genome-wide association studies (GWASs) have identified seven loci for plasma and erythrocyte palmitoleic and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential functional variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in more than 15,000 participants of Chinese and European ancestry. We identified novel genome-wide significant associations for vaccenic acid at FADS1/2 and PKD2L1 [log10(Bayes factor) ≥ 8.07] and for gondoic acid at FADS1/2 and GCKR [log10(Bayes factor) ≥ 6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR, where the number of variants in the 99% credible set was reduced from 16 (covering 94.8 kb) to 5 (covering 19.6 kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1, FADS1/2, GCKR, and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and the trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were in unsaturated FA metabolism and signaling pathways. Our findings provide novel insight into the genetic basis relevant to MUFA metabolism and biology.
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Pueblo Asiatico/genética , Mapeo Cromosómico/métodos , Ácidos Grasos Monoinsaturados/metabolismo , Sitios Genéticos/genética , Población Blanca/genética , delta-5 Desaturasa de Ácido Graso , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians.
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Pueblo Asiatico/genética , Estatura/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Asia Oriental , Femenino , Frecuencia de los Genes , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Redes y Vías Metabólicas/genética , Persona de Mediana Edad , Proteínas Tirosina Fosfatasas/genética , Población Blanca/genética , Adulto JovenRESUMEN
Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature deaths worldwide. Genome-wide association studies (GWASs) in the European population have identified multiple chromosomal regions associated with blood pressure, and the identified loci altogether explain only a small fraction of the variance for blood pressure. The differences in environmental exposures and genetic background between Chinese and European populations might suggest potential different pathways of blood pressure regulation. To identify novel genetic variants affecting blood pressure variation, we conducted a meta-analysis of GWASs of blood pressure and hypertension in 11 816 subjects followed by replication studies including 69 146 additional individuals. We identified genome-wide significant (P < 5.0 × 10(-8)) associations with blood pressure, which included variants at three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. We also replicated 14 previously reported loci, 8 (CASZ1, MOV10, FGF5, CYP17A1, SOX6, ATP2B1, ALDH2, and JAG1) at genome-wide significance, and 6 (FIGN, ULK4, GUCY1A3, HFE, TBX3-TBX5, and TBX3) at a suggestive level of P = 1.81 × 10(-3) to 5.16 × 10(-8). These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments.
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Pueblo Asiatico/genética , Presión Sanguínea/genética , Canales de Calcio Tipo L/genética , Hipertensión/genética , Complejo Mediador/genética , Simportadores de Sodio-Bicarbonato/genética , Esteroide 21-Hidroxilasa/genética , Adulto , Anciano , China , Femenino , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
PURPOSE: We aimed to characterize common genetic variants that influence saturated fatty acid concentrations in East Asians. METHODS: Meta-analysis of genome-wide association studies for circulating SFAs was conducted in two population-based cohorts comprising 3521 participants of Chinese ancestry. RESULTS: We identified two novel 14:0-associated loci at LMX1A (LIM homeobox transcription factor 1) and AMPD3 (AMP deaminase 3) (P = 5.08 × 10-9 and P = 4.33 × 10-8, respectively), and a novel 20:0-associated locus at CERS4 (ceramide synthase 4) (P = 1.76 × 10-10). We also confirmed the previously reported association of FADS1/2-rs102275 with 18:0 (P = 1.12 × 10-5). In addition, the A alleles of rs11042834 in AMPD3 and rs17159388 in CERS4 also exhibited evidence of associations with high-density lipoprotein cholesterol (P = 0.0162 and P = 0.0161, respectively). CONCLUSIONS: To our knowledge, this is the first GWAS analysis to examine SFA concentrations in East Asian populations. Our findings provide novel evidence that genetic variations of several genes from multiple pathways are associated with SFA concentrations in human body.
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Pueblo Asiatico/genética , Ácidos Grasos/sangre , Sitios Genéticos , Estudio de Asociación del Genoma Completo , AMP Desaminasa/genética , Anciano , Alelos , China , Colesterol/sangre , delta-5 Desaturasa de Ácido Graso , Ácido Graso Desaturasas/genética , Femenino , Variación Genética , Técnicas de Genotipaje , Humanos , Proteínas con Homeodominio LIM/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Esfingosina N-Aciltransferasa/genética , Factores de Transcripción/genética , Triglicéridos/sangre , Estados UnidosRESUMEN
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.
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Adiponectina/sangre , Enfermedades Cardiovasculares/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Pueblo Asiatico , Enfermedades Cardiovasculares/sangre , Estudios de Cohortes , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and â¼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.
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5'-Nucleotidasa/genética , Aldehído Deshidrogenasa/genética , Pueblo Asiatico/genética , Proteínas Sanguíneas/genética , Miosinas Cardíacas/genética , Glicoproteínas/genética , Canal de Potasio KCNQ1/genética , Cadenas Ligeras de Miosina/genética , Obesidad/genética , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Aldehído Deshidrogenasa Mitocondrial , Índice de Masa Corporal , Asia Oriental , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
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.
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Pueblo Asiatico , Colecalciferol/administración & dosificación , Suplementos Dietéticos , Adulto , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , Índice de Masa Corporal , Calcio de la Dieta/administración & dosificación , Calcio de la Dieta/sangre , Colecalciferol/sangre , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Factores Socioeconómicos , Deficiencia de Vitamina D/sangre , Circunferencia de la Cintura , Adulto Joven , gamma-Glutamiltransferasa/sangreRESUMEN
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.
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Composición Corporal , Absorciometría de Fotón , Tejido Adiposo/metabolismo , Adulto , Anciano , Presión Sanguínea , Índice de Masa Corporal , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , China , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Cardiopatías/fisiopatología , Humanos , Modelos Lineales , Masculino , Matemática , Persona de Mediana Edad , Obesidad/fisiopatología , Estudios Prospectivos , Factores de Riesgo , Factores Sexuales , Triglicéridos/sangre , Circunferencia de la CinturaRESUMEN
OBJECTIVE: To investigate whether the variations of genes encoding pro-inflammatory cytokines is associated with longevity in Uyghurs in Xinjiang. METHODS: A total of 240 individuals aged ≥90 years from Xinjiang Uyghur Autonomous Region were enrolled between 1999 and 2012 as the longevity group, 92 unrelated individuals from the same area who died naturally at the age of 59-73 in the same period were selected as the control group. Seven single nucleotide polymorphisms (SNPs) of 4 genes (tumor necrosis factor (TNF)-α(rs1800629), IL-6(rs1800796, rs10499563), C-reactive protein (CRP) (rs2808630, rs1205) and IL-1ß(rs1143623, rs16944)) were genotyped. Logistic regression was applied to assess the association between each individual SNP and longevity in case-control analyses. RESULTS: The distribution of C allele of rs1800796 in the longevity group (0.298) was lower than that in the control group (0.435) with statistical significance (P=0.001). The distributions of the other 6 genetic variations between the longevity group and the control group showed no statistically significant differences (all P>0.05). CT genotype of rs1800796 was positively associated with longevity (Padd=0.002, OR=1.983, 95%CI: 1.296-3.023), while no significant association was noted between other genotypes and longevity. CONCLUSIONS: SNP of rs1800796 of IL-6 gene may be significantly associated with longevity in Uyghurs in Xinjiang. CT genotype of rs1800796 is significantly associated with longevity. C allele of rs1800796 may be a negative factor for longevity.
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Longevidad , Polimorfismo de Nucleótido Simple , Anciano , Alelos , Proteína C-Reactiva , Genotipo , Humanos , Interleucina-1beta , Interleucina-6 , Modelos Logísticos , Persona de Mediana Edad , Factor de Necrosis Tumoral alfaRESUMEN
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.
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Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Pueblo Asiatico/genética , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/epidemiología , HumanosRESUMEN
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.
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Proteínas Portadoras/sangre , Glicoproteínas de Membrana/sangre , Síndrome Metabólico/sangre , Síndrome Metabólico/epidemiología , Obesidad/sangre , Obesidad/epidemiología , Proteínas de Fase Aguda , Factores de Edad , Anciano , Pueblo Asiatico , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
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.
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Pueblo Asiatico/estadística & datos numéricos , Diabetes Mellitus Tipo 2/etnología , Diabetes Mellitus Tipo 2/metabolismo , Conducta Alimentaria , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Adipoquinas/sangre , Anciano , Estudios de Cohortes , Femenino , Humanos , Hipertensión/etnología , Hipertensión/metabolismo , Incidencia , Inflamación/etnología , Inflamación/metabolismo , Resistencia a la Insulina/fisiología , Masculino , Persona de Mediana Edad , Obesidad/etnología , Obesidad/metabolismo , Factores de RiesgoRESUMEN
Little is known about the associations of FADS1 genetic variants with circulating levels of PUFA and lipids in Asian populations who have a different dietary pattern and dyslipidemia prevalence compared with Western populations. In a population-based sample of 3,210 unrelated Han Chinese living in Beijing and Shanghai, we examined a FADS1 genetic variant, rs174550, in relation to blood PUFA and lipid levels. C-allele of rs174550 was significantly associated with levels of erythrocyte PUFAs in upstream and downstream pathways of delta-5 desaturase (D5D) (P ≤ 0.003). Moreover, rs174550 C-allele was associated with a lower HDL cholesterol level (P = 0.02) in total population and a higher triglyceride level (P = 0.0002) in Beijing residents. Interestingly, erythrocyte levels of 18:2n-6 and 18:3n-3 modified the effect of rs174550 on HDL cholesterol level: stronger associations between rs174550 C-allele and lower HDL cholesterol levels were exhibited when erythrocyte 18:2n-6 or 18:3n-3 level was low (P for interaction = 0.02 and 0.03, respectively). These data suggested that FADS1 genetic variant was associated with circulating PUFA and lipid levels and that its effect on HDL cholesterol might depend on PUFA status in the Han Chinese population.