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Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.
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Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Alelos , Estudio de Asociación del Genoma Completo/métodos , Humanos , Desequilibrio de Ligamiento , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Five sequence variants in SLC16A11 (rs117767867, rs13342692, rs13342232, rs75418188, and rs75493593), which occur in two non-reference haplotypes, were recently shown to be associated with diabetes in Mexicans from the SIGMA consortium. We aimed to determine whether these previous findings would replicate in the HCHS/SOL Mexican origin group and whether genotypic effects were similar in other HCHS/SOL groups. We analyzed these five variants in 2492 diabetes cases and 5236 controls from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), which includes U.S. participants from six diverse background groups (Mainland groups: Mexican, Central American, and South American; and Caribbean groups: Puerto Rican, Cuban, and Dominican). We estimated the SNP-diabetes association in the six groups and in the combined sample. We found that the risk alleles occur in two non-reference haplotypes in HCHS/SOL, as in the SIGMA Mexicans. The haplotype frequencies were very similar between SIGMA Mexicans and the HCHS/SOL Mainland groups, but different in the Caribbean groups. The SLC16A11 sequence variants were significantly associated with risk for diabetes in the Mexican origin group (P = 0.025), replicating the SIGMA findings. However, these variants were not significantly associated with diabetes in a combined analysis of all groups, although the power to detect such effects was 85% (assuming homogeneity of effects among the groups). Additional analyses performed separately in each of the five non-Mexican origin groups were not significant. We also analyzed (1) exclusion of young controls and, (2) SNP by BMI interactions, but neither was significant in the HCHS/SOL data. The previously reported effects of SLC16A11 variants on diabetes in Mexican samples was replicated in a large Mexican-American sample, but these effects were not significant in five non-Mexican Hispanic/Latino groups sampled from U.S. populations. Lack of replication in the HCHS/SOL non-Mexicans, and in the entire HCHS/SOL sample combined may represent underlying genetic heterogeneity. These results indicate a need for future genetic research to consider heterogeneity of the Hispanic/Latino population in the assessment of disease risk, but add to the evidence suggesting SLC16A11 as a potential therapeutic target for type 2 diabetes.
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Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Hispánicos o Latinos/genética , Transportadores de Ácidos Monocarboxílicos/genética , Estudios de Asociación Genética , Haplotipos/genética , Humanos , Polimorfismo de Nucleótido Simple/genética , Estados UnidosRESUMEN
STUDY QUESTION: Are non-esterified fatty acid (NEFA) kinetics altered in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Women with PCOS, particularly obese subjects, have dysregulated plasma NEFA kinetics in response to changes in plasma insulin and glucose levels, which are associated with insulin resistance (IR) independently of the fasting plasma NEFA levels. WHAT IS KNOWN ALREADY: Elevated plasma NEFA levels are associated with IR in many disorders, although the homeostasis of NEFA kinetics and its relationship to IR in women with PCOS is unknown. STUDY DESIGN, SIZE, DURATION: We prospectively compared insulin sensitivity and NEFA kinetics in 29 PCOS and 29 healthy controls women matched for BMI. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted in a tertiary institution. Plasma NEFA, glucose and insulin levels were assessed during a modified frequently sampled intravenous glucose tolerance test (mFSIVGTT). Minimal models were used to assess insulin sensitivity (Si) and NEFA kinetics (i.e. model-derived initial plasma NEFA level [NEFA0], phi constant [Φ], reflecting glucose-mediated inhibition of lipolysis and measures of maximum rate of lipolysis [SFFA] and NEFA uptake from plasma [KFFA]). MAIN RESULTS AND THE ROLE OF CHANCE: The study provides new evidence that women with PCOS have defective NEFA kinetics characterized by: (i) lower basal plasma NEFA levels, measured directly and modeled (NEFA0), and (ii) a greater glucose-mediated inhibition of lipolysis in the remote or interstitial space (reflected by a lower affinity constant [Φ]). There were no differences, however, in the maximal rates of adipose tissue lipolysis (SFFA) and the rate at which NEFA leaves the plasma pool (KFFA). The differences observed in NEFA kinetics were exacerbated, and almost exclusively observed, in the obese PCOS subjects. LIMITATIONS, REASONS FOR CAUTION: Our study did not study NEFA subtypes. It was also cross-sectional and based on women affected by PCOS as defined by the 1990 National Institutes of Health (NIH) criteria (i.e. Phenotypes A and B) and identified in the clinical setting. Consequently, extrapolation of the present data to other phenotypes of PCOS should be made with caution. Furthermore, our data is exploratory and therefore requires validation with a larger sample size. WIDER IMPLICATIONS OF THE FINDINGS: Dysfunction in NEFA kinetics may be a marker of metabolic dysfunction in nondiabetic obese women with PCOS and may be more important than simply assessing circulating NEFA levels at a single point in time for understanding the mechanism(s) underlying the IR of PCOS. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by NIH grants R01-DK073632 and R01-HD29364 to R.A.; a Career Development Award from MD Medical Group, Moscow, RF, to D.L. and Augusta University funds to Y.-H.C. RA serves as consultant to Ansh Labs, Medtronics, Spruce Biosciences and Latitude Capital. U.E., Z.A., D.L., R.M., Y.-H.C., R.C.B. and Y.D.I.C. have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.
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Ácidos Grasos no Esterificados/metabolismo , Resistencia a la Insulina , Obesidad/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Adolescente , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Estudios Transversales , Ácidos Grasos no Esterificados/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Lipólisis , Obesidad/sangre , Obesidad/complicaciones , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/complicaciones , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10-4 from the 16â 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10â 951 statin-treated individuals, providing a total sample size of 27â 720 individuals. The only associations of genome-wide significance (p<5×10-8) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
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Proteínas de Transferencia de Ésteres de Colesterol/genética , HDL-Colesterol/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , HDL-Colesterol/efectos de los fármacos , HDL-Colesterol/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Resultado del Tratamiento , Población Blanca/genéticaRESUMEN
Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (↓ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC.
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Enfermedades Cardiovasculares/etiología , Colesterol/metabolismo , Diabetes Mellitus Tipo 2/etiología , Obesidad/complicaciones , Anciano , Anciano de 80 o más Años , delta-5 Desaturasa de Ácido Graso , Femenino , Dosificación de Gen , Regulación de la Expresión Génica , Humanos , Masculino , Transcriptoma , Pérdida de Peso/fisiologíaRESUMEN
BACKGROUND: Resistant hypertension (RHTN), defined by lack of blood pressure (BP) control despite treatment with at least 3 antihypertensive drugs, increases cardiovascular risk compared with controlled hypertension. Yet, there are few data on genetic variants associated with RHTN. METHODS AND RESULTS: We used a gene-centric array containing ≈50 000 single-nucleotide polymorphisms (SNPs) to identify polymorphisms associated with RHTN in hypertensive participants with coronary artery disease (CAD) from INVEST-GENES (the INnternational VErapamil-SR Trandolapril STudy-GENEtic Substudy). RHTN was defined as BP≥140/90 on 3 drugs, or any BP on 4 or more drugs. Logistic regression analysis was performed in European Americans (n=904) and Hispanics (n=837), using an additive model adjusted for age, gender, randomized treatment assignment, body mass index, principal components for ancestry, and other significant predictors of RHTN. Replication of the top SNP was conducted in 241 European American women from WISE (Women's Ischemia Syndrome Evaluation), where RHTN was defined similarly. To investigate the functional effect of rs12817819, mRNA expression was measured in whole blood. We found ATP2B1 rs12817819 associated with RHTN in both INVEST European Americans (P-value=2.44×10(-3), odds ratio=1.57 [1.17 to 2.01]) and INVEST Hispanics (P=7.69×10(-4), odds ratio=1.76 [1.27 to 2.44]). A consistent trend was observed at rs12817819 in WISE, and the INVEST-WISE meta-analysis result reached chip-wide significance (P=1.60×10(-6), odds ratio=1.65 [1.36 to 1.95]). Expression analyses revealed significant differences in ATP2B1 expression by rs12817819 genotype. CONCLUSIONS: The ATP2B1 rs12817819 A allele is associated with increased risk for RHTN in hypertensive participants with documented CAD or suspected ischemic heart disease. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov; Unique identifiers: NCT00133692 (INVEST), NCT00000554 (WISE).
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Presión Sanguínea/genética , Resistencia a Medicamentos/genética , Hipertensión/genética , ATPasas Transportadoras de Calcio de la Membrana Plasmática/genética , Polimorfismo de Nucleótido Simple , Anciano , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Quimioterapia Combinada , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Hispánicos o Latinos/genética , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/etnología , Hipertensión/fisiopatología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Fenotipo , Puerto Rico/epidemiología , Factores de Riesgo , Estados Unidos/epidemiología , Población Blanca/genéticaRESUMEN
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
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LDL-Colesterol/genética , Estudio de Asociación del Genoma Completo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Humanos , Farmacogenética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)
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Diabetes Mellitus Tipo 2/genética , Antígeno HLA-B27/genética , Proteína HMGA2/genética , Canal de Potasio KCNQ1/genética , Proteínas Mutantes Quiméricas/genética , Proteína 2 Similar al Factor de Transcripción 7/genética , Negro o Afroamericano/genética , Diabetes Mellitus Tipo 2/patología , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: To profile the differential gene expression of the KEGG Adipocytokine Signaling pathway in omental compared to subcutaneous tissue in normal pregnancy. STUDY DESIGN: Subjects included 14 nonobese, normal glucose tolerant, healthy pregnant women. Matched omental and subcutaneous tissue were obtained at elective cesarean delivery. Gene expression was evaluated using microarray and validated by RT-PCR. Differential gene expression was defined as ≥1.5 fold increase at p < 0.05. RESULTS: Six genes were significantly downregulated with two upregulated genes in omental tissue. Downregulation of Adiponectin and Insulin Receptor substrate, key genes mediating insulin sensitivity, were observed with borderline upregulation of GLUT-1. There were downregulations of CD36 and acyl-CoA Synthetase Long-chain Family Member 1which are genes involved in fatty acid uptake and activation. There was a novel expression of Carnitine palmitoyltransferase 1C. CONCLUSION: Differential gene expression of Adipocytokine Signaling Pathway in omental relative to subcutaneous adipose tissue in normal pregnancy suggests a pattern of insulin resistance, hyperlipidemia, and inflammation.
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Common genetic variation frequently accounts for only a modest amount of interindividual variation in quantitative traits and complex disease susceptibility. Circulating adiponectin, an adipocytokine implicated in metabolic disease, is a model for assessing the contribution of genetic and clinical factors to quantitative trait variation. The adiponectin locus, ADIPOQ, is the primary source of genetically mediated variation in plasma adiponectin levels. This study sought to define the genetic architecture of ADIPOQ in the comprehensively phenotyped Hispanic (n = 1,151) and African American (n = 574) participants from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Through resequencing and bioinformatic analysis, rare/low frequency (<5% MAF) and common variants (>5% MAF) in ADIPOQ were identified. Genetic variants and clinical variables were assessed for association with adiponectin levels and contribution to adiponectin variance in the Hispanic and African American cohorts. Clinical traits accounted for the greatest proportion of variance (POV) at 31% (P = 1.16 × 10-(47)) and 47% (P = 5.82 × 10-(20)), respectively. Rare/low frequency variants contributed more than common variants to variance in Hispanics: POV = 18% (P = 6.40 × 10-(15)) and POV = 5% (P = 0.19), respectively. In African Americans, rare/low frequency and common variants both contributed approximately equally to variance: POV = 6% (P = 5.44 × 10-(12)) and POV = 9% (P = 1.44 × 10-(10)), respectively. Importantly, single low frequency alleles in each ethnic group were as important as, or more important than, common variants in explaining variation in adiponectin. Cumulatively, these clinical and ethnicity-specific genetic contributors explained half or more of the variance in Hispanic and African Americans and provide new insight into the sources of variation for this important adipocytokine.
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Adiponectina/sangre , Adiponectina/genética , Frecuencia de los Genes , Variación Genética , Diabetes Mellitus Tipo 2/genética , Femenino , Hispánicos o Latinos/genética , Humanos , Resistencia a la Insulina/genética , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: The presence and severity of coronary artery calcified plaque (CAC) differs markedly between individuals of African and European descent, suggesting that admixture mapping may be informative for identifying genetic variants associated with subclinical cardiovascular disease. METHODS AND RESULTS: Admixture mapping of CAC was performed in 1040 unrelated African Americans with type 2 diabetes mellitus from the African American-Diabetes Heart Study, Multi-Ethnic Study of Atherosclerosis and Family Heart Study using the Illumina custom ancestry informative marker panel. All cohorts obtained computed tomography scanning of the coronary arteries using identical protocols. For each ancestry informative marker, the probability of inheriting 0, 1, and 2 copies of a European-derived allele was determined. Linkage analysis was performed by testing for association between each ancestry informative marker using these probabilities and CAC, accounting for global ancestry, age, sex, and study. Markers on 1p32.3 in the GLIS1 gene (rs6663966, logarithm of odds [LOD]=3.7), 1q32.1 near CHIT1 (rs7530895, LOD=3.1), 4q21.2 near PRKG2 (rs1212373, LOD=3.0), and 11q25 in the OPCML gene (rs6590705, LOD=3.4) had statistically significant LOD scores, whereas markers on 8q22.2 (rs6994682, LOD=2.7), 9p21.2 (rs439314, LOD=2.7), and 13p32.1 (rs7492028, LOD=2.8) manifested suggestive evidence of linkage. These regions were uniformly characterized by higher levels of European ancestry associating with higher levels or odds of CAC. Findings were replicated in 1350 African Americans without diabetes mellitus and 2497 diabetic European Americans from Multi-Ethnic Study of Atherosclerosis and the Diabetes Heart Study. CONCLUSIONS: Fine mapping these regions will likely identify novel genetic variants that contribute to CAC and clarify racial differences in susceptibility to subclinical cardiovascular disease.
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Enfermedades Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Ligamiento Genético , Adulto , Negro o Afroamericano/genética , Anciano , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/patología , Estudios de Cohortes , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placa Aterosclerótica , Polimorfismo de Nucleótido SimpleRESUMEN
CONTEXT: Adiponectin is an adipocytokine associated with a variety of metabolic traits. These associations in human studies, in conjunction with functional studies in model systems, have implicated adiponectin in multiple metabolic processes. OBJECTIVE: We hypothesize that genetic variants associated with plasma adiponectin would also be associated with glucose homeostasis and adiposity phenotypes. DESIGN AND SETTING: The Insulin Resistance Atherosclerosis Family Study was designed to identify the genetic and environmental basis of insulin resistance and adiposity in the Hispanic- (n=1,424) and African-American (n=604) population. MAIN OUTCOME MEASURES: High quality metabolic phenotypes, e.g. insulin sensitivity (S(I)), acute insulin response (AIR), disposition index (DI), fasting glucose, body mass index (BMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and waist circumference, were explored. RESULTS: Based on association analysis of more than 40 genetic polymorphisms in the adiponectin gene (ADIPOQ), we found no consistent association of ADIPOQ variants with plasma adiponectin levels and adiposity phenotypes. However, there were two promoter variants, rs17300539 and rs822387, associated with plasma adiponectin levels (P=0.0079 and 0.021, respectively) in the Hispanic-American cohort that were also associated with S(I) (P=0.0067 and 0.013, respectively). In contrast, there was only a single promoter SNP, rs17300539, associated with plasma adiponectin levels (P=0.0018) and fasting glucose (P=0.042) in the African-American cohort. Strikingly, high impact coding variants did not show evidence of association. CONCLUSIONS: The lack of consistent patterns of association between variants, adiponectin levels, glucose homeostasis, and adiposity phenotypes suggests a reassessment of the influence of adiponectin in these pathways.
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Adiponectina/sangre , Adiponectina/genética , Adiposidad/genética , Glucosa/metabolismo , Fenotipo , Polimorfismo de Nucleótido Simple , Adulto , Negro o Afroamericano/genética , Alelos , Femenino , Estudios de Asociación Genética , Hispánicos o Latinos/genética , Homeostasis/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We developed a multinomial ordinal probit model with singular value decomposition for testing a large number of single nucleotide polymorphisms SNPs simultaneously for association with multidisease status when sample size is much smaller than the number of SNPs. The validity and performance of the method was evaluated via simulation. We applied the method to our real study sample recruited through the Mexican-American Coronary Artery Disease study. We found 3 genes SORCS1, AMPD1, and PPARα to be associated with the development of both IGT and IFG, while 5 genes AMPD2, PRKAA2, C5, TCF7L2, and ITR with the IGT mechanism only and 6 genes CAPN10, IL4, NOS3, CD14, GCG, and SORT1 with the IFG mechanism only. These data suggest that IGT and IFG may indicate different physiological mechanism to prediabetes, via different genetic determinants.
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Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7 × 10(-08)). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.
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Tejido Adiposo , Estudio de Asociación del Genoma Completo , Péptidos y Proteínas de Señalización Intracelular/genética , Obesidad/genética , Pericardio , Tejido Adiposo/metabolismo , Adulto , Animales , Pueblo Asiatico/genética , Aterosclerosis/genética , Población Negra/genética , Distribución de la Grasa Corporal , Índice de Masa Corporal , Proteínas Quinasas Dependientes de Calcio-Calmodulina , Enfermedad Coronaria/genética , Femenino , Regulación de la Expresión Génica , Hispánicos o Latinos/genética , Humanos , Grasa Intraabdominal/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Pericardio/metabolismo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Tomografía Computarizada por Rayos X , Población Blanca/genéticaRESUMEN
Family-based linkage analysis has been a powerful tool for identification of genes contributing to traits with monogenic patterns of inheritance. These approaches have been of limited utility in identification of genes underlying complex traits. In contrast, searches for common genetic variants associated with complex traits have been highly successful. It is now widely recognized that common variations frequently explain only part of the inter-individual variation in populations. 'Rare' genetic variants have been hypothesized to contribute significantly to phenotypic variation in the population. We have developed a combination of family-based linkage, whole-exome sequencing, direct sequencing and association methods to efficiently identify rare variants of large effect. Key to the successful application of the method was the recognition that only a few families in a sample contribute significantly to a linkage signal. Thus, a search for mutations can be targeted to a small number of families in a chromosome interval restricted to the linkage peak. This approach has been used to identify a rare (1.1%) G45R mutation in the gene encoding adiponectin, ADIPOQ. This variant explains a strong linkage signal (LOD > 8.0) and accounts for â¼17% of the variance in plasma adiponectin levels in a sample of 1240 Hispanic Americans and 63% of the variance in families carrying the mutation. Individuals carrying the G45R mutation have mean adiponectin levels that are 19% of non-carriers. We propose that rare variants may be a common explanation for linkage peaks observed in complex trait genetics. This approach is applicable to a wide range of family studies and has potential to be a discovery tool for identification of novel genes influencing complex traits.
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Negro o Afroamericano/genética , Ligamiento Genético , Hispánicos o Latinos/genética , Adiponectina/sangre , Adiponectina/genética , Adiposidad , Aterosclerosis , Secuencia de Bases , Cromosomas Humanos Par 3 , Estudios de Cohortes , Colorado , Análisis Mutacional de ADN , Familia , Salud de la Familia , Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Resistencia a la Insulina , Polimorfismo de Nucleótido Simple , TexasRESUMEN
We developed a multinomial probit model with singular value decomposition for testing a large number of single nucleotide polymorphisms (SNPs) simultaneously, using maximum likelihood estimation and permutation. The method was validated by simulation. We simulated 1000 SNPs, including 9 associated with disease states, and 8 of the 9 were successfully identified. Applying the method to study 32 genes in our Mexican-American samples for association with prediabetes through either impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), we found 3 genes (SORCS1, AMPD1, PPAR) associated with both IGT and IFG, while 5 genes (AMPD2, PRKAA2, C5, TCF7L2, ITR) with the IGT mechanism only and 6 genes (CAPN10, IL4,NOS3, CD14, GCG, SORT1) with the IFG mechanism only. These data suggest that IGT and IFG may indicate different physiological mechanism to prediabetes, via different genetic determinants.
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Adiponectin (APM1) is an adipocyte-derived peptide that contributes to glucose, lipid, and energy homeostasis. We assessed the genetic basis of plasma adiponectin in Hispanic-American and African-American families enrolled through the Insulin Resistance Atherosclerosis Study Family Study. A 10-cM genome scan was performed in two batches: an original set (set 1) consisting of 66 families (45 Hispanic American and 21 African American) and a replication set (set 2) consisting of 66 families (45 Hispanic American and 21 African American). Adiponectin levels were measured by radioimmunoassay in 1,727 individuals from 131 of 132 families. Linkage analysis was carried out in Hispanic Americans and African Americans separately in set 1, set 2, and the pooled set (set 1 plus set 2), with and without diabetic subjects. A major gene was mapped to 3q27 with a logarithm of odds (LOD) score of 8.21 in the Hispanic-American sample. Ninety-six unrelated individuals were screened for polymorphisms in the APM1 gene, and 18 single nucleotide polymorphisms (SNPs) were genotyped in the Hispanic-American sample. Plasma adiponectin level was modestly associated with two SNPs and their accompaning haplotypes. Incorporating each or both SNPs in the linkage analysis, however, did not significantly reduce the LOD score. Therefore, a quantitative trait locus at 3q27, likely distinct from the APM1 gene, contributes to the variation of plasma adiponectin levels in the Hispanic-American population.