Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 186
Filtrar
1.
Am J Hum Genet ; 105(4): 706-718, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564435

RESUMO

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

2.
J Am Coll Cardiol ; 74(13): 1658-1664, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31558248

RESUMO

BACKGROUND: Cigarette smoking is known to increase the risk of atrial fibrillation (AF), and a recent cross-sectional analysis suggested that parental smoking may be an AF risk factor. OBJECTIVES: The purpose of this study was to assess if parental smoking predicts offspring AF in the Framingham Heart Study. METHODS: This study analyzed Framingham Offspring cohort participants with parents in the Original cohort with known smoking status during the offspring's childhood. Framingham participants were evaluated every 2 to 8 years and were under routine surveillance for incident AF. The authors assessed AF incidence among Offspring participants exposed to parental smoking through age 18 years and performed a mediation analysis to determine the extent to which offspring smoking might explain observed associations. RESULTS: Of 2,816 Offspring cohort participants with at least 1 parent in the Original cohort, 82% were exposed to parental smoking. For every pack/day increase in parental smoking, there was an 18% increase in offspring AF incidence (adjusted hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 1.00 to 1.39; p = 0.04). Additionally, parental smoking was a risk factor for offspring smoking (adjusted odds ratio [OR]: 1.34; 95% CI: 1.17 to 1.54; p < 0.001). Offspring smoking mediated 17% (95% CI: 1.5% to 103.3%) of the relationship between parental smoking and offspring AF. CONCLUSIONS: Childhood secondhand smoke exposure predicted increased risk for adulthood AF after adjustment for AF risk factors. Some of this relationship may be mediated by a greater propensity among offspring of smoking parents to smoke themselves. These findings highlight potential new pathways for AF risk that begin during childhood, offering new evidence to motivate smoking avoidance and cessation.

3.
Diabetes ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506343

RESUMO

Epigenetic changes may contribute substantially to risks of diseases of ageing. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based EPIC-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset to investigate the role of methylation in the aetiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM, and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1 and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs, and found one MVP, cg00574958 at CPT1A, with a possible direct causal role on T2DM. None of the implicated genes was previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

4.
Mol Nutr Food Res ; : e1900226, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31432628

RESUMO

SCOPE: Insulin resistance (IR) and inflammation are hallmarks of type 2 diabetes (T2D). The nod-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a metabolic sensor activated by saturated fatty acids (SFA) initiating IL-1ß inflammation and IR. Interactions between SFA intake and NLRP3-related genetic variants may alter T2D risk factors. METHODS: Meta-analyses of six Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 19 005) tested interactions between SFA and NLRP3-related single-nucleotide polymorphisms (SNPs) and modulation of fasting insulin, fasting glucose, and homeostasis model assessment of insulin resistance. RESULTS: SFA interacted with rs12143966, wherein each 1% increase in SFA intake increased insulin by 0.0063 IU mL-1 (SE ± 0.002, p = 0.001) per each major (G) allele copy. rs4925663, interacted with SFA (ß ± SE = -0.0058 ± 0.002, p = 0.004) to increase insulin by 0.0058 IU mL-1 , per additional copy of the major (C) allele. Both associations are close to the significance threshold (p < 0.0001). rs4925663 causes a missense mutation affecting NLRP3 expression. CONCLUSION: Two NLRP3-related SNPs showed potential interaction with SFA to modulate fasting insulin. Greater dietary SFA intake accentuates T2D risk, which, subject to functional validation, may be further elaborated depending on NLRP3-related genetic variants.

5.
Sci Rep ; 9(1): 9439, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263163

RESUMO

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31339356

RESUMO

Rationale Interstitial lung abnormalities (ILA) are associated with the highest genetic risk locus for IPF; however, the extent to which there is additional overlap with IPF, or unique associations among those with ILA is not known. Objectives To perform a genome-wide association study (GWAS) of ILA. Methods: ILA and the subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES, COPDGene, Framingham Heart, ECLIPSE, MESA, and SPIROMICS studies. We performed a GWAS of ILA in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF. Measurements and Main Results Genome-wide genotyping data were available in 1,699 ILA cases and 10,274 controls. The MUC5B promoter variant rs35705950 was significantly associated with both ILA (p=2.6x10-27) and subpleural ILA (p=1.6x10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, p=3.8x10-8) and FCF1P3 (rs73199442, p=4.8x10-8) with ILA, and HTRE1 (rs7744971, p=4.2x10-8) with subpleural-predominant ILA. These novel associations were not associated with IPF. Of 12 previously reported IPF GWAS loci, 5 (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (p<0.05/12) with ILA. Conclusions In a GWAS of ILA in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common and suggest distinct genetically-driven biologic pathways between ILA and IPF.

7.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
8.
Adipocyte ; 8(1): 144-153, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31033395

RESUMO

Intramuscular fat (IMF) accumulates in muscles of the rotator cuff after tendon tear. The number and cross-sectional area of fat clumps and of adipocytes were quantified on osmium tetroxide stained sections of the proximal, middle and distal quarters of SSP muscles 4, 8 and 12 weeks after SSP tendon division in a rabbit model. Linear mixed-effects models were fitted to the data and statistical significance was evaluated by ANOVA. Both the number (P<0.001) and cross-sectional area (P<0.0005) of fat clumps increased after tendon detachment while time had no significant effect (both at P>0.01). IMF accumulation was more important in the distal quarter of detached SSP muscle near tendon sectioning and characterized by increases of the number (P<0.0005) and cross-sectional area of fat clumps (P<0.0005) compared to the proximal quarter. Adipocyte number increased after tendon detachment (P<0.0005) and over time (P<0.01). The cross-sectional area of adipocytes increased in the detached group compared to controls (P<0.01) while time had no significant effect (P>0.01). Interestingly, the number of adipocytes in the distal quarter increased (P<0.0005) but the cross-sectional area was smaller (P<0.0005) compared to adipocytes in the proximal quarter. Adipocyte hyperplasia localized near tendon sectioning was the main contributor to fat accumulation in the detached SSP muscles.

9.
Diabetes Care ; 42(7): 1202-1208, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30659074

RESUMO

OBJECTIVE: Observational studies show that higher hemoglobin A1c (A1C) predicts coronary artery disease (CAD). It remains unclear whether this association is driven entirely by glycemia. We used Mendelian randomization (MR) to test whether A1C is causally associated with CAD through glycemic and/or nonglycemic factors. RESEARCH DESIGN AND METHODS: To examine the association of A1C with CAD, we selected 50 A1C-associated variants (log10 Bayes factor ≥6) from an A1C genome-wide association study (GWAS; n = 159,940) and performed an inverse-variance weighted average of variant-specific causal estimates from CAD GWAS data (CARDIoGRAMplusC4D; 60,801 CAD case subjects/123,504 control subjects). We then replicated results in UK Biobank (18,915 CAD case subjects/455,971 control subjects) and meta-analyzed all results. Next, we conducted analyses using two subsets of variants, 16 variants associated with glycemic measures (fasting or 2-h glucose) and 20 variants associated with erythrocyte indices (e.g., hemoglobin [Hb]) but not glycemic measures. In additional MR analyses, we tested the association of Hb with A1C and CAD. RESULTS: Genetically increased A1C was associated with higher CAD risk (odds ratio [OR] 1.61 [95% CI 1.40, 1.84] per %-unit, P = 6.9 × 10-12). Higher A1C was associated with increased CAD risk when using only glycemic variants (OR 2.23 [1.73, 2.89], P = 1.0 × 10-9) and when using only erythrocytic variants (OR 1.30 [1.08, 1.57], P = 0.006). Genetically decreased Hb, with concomitantly decreased mean corpuscular volume, was associated with higher A1C (0.30 [0.27, 0.33] %-unit, P = 2.9 × 10-6) per g/dL and higher CAD risk (OR 1.19 [1.04, 1.37], P = 0.02). CONCLUSIONS: Genetic evidence supports a causal link between higher A1C and higher CAD risk. This relationship is driven not only by glycemic but also by erythrocytic, glycemia-independent factors.

10.
Eur J Hum Genet ; 27(5): 811-823, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30683923

RESUMO

Complex diseases are usually associated with multiple correlated phenotypes, and the analysis of composite scores or disease status may not fully capture the complexity (or multidimensionality). Joint analysis of multiple disease-related phenotypes in genetic tests could potentially increase power to detect association of a disease with common SNPs (or genes). Gene-based tests are designed to identify genes containing multiple risk variants that individually are weakly associated with a univariate trait. We combined three multivariate association tests (O'Brien method, TATES, and MultiPhen) with two gene-based association tests (GATES and VEGAS) and compared performance (type I error and power) of six multivariate gene-based methods using simulated data. Data (n = 2000) for genetic sequence and correlated phenotypes were simulated by varying causal variant proportions and phenotype correlations for various scenarios. These simulations showed that two multivariate association tests (TATES and MultiPhen, but not O'Brien) paired with VEGAS have inflated type I error in all scenarios, while the three multivariate association tests paired with GATES have correct type I error. MultiPhen paired with GATES has higher power than competing methods if the correlations among phenotypes are low (r < 0.57). We applied these gene-based association methods to a GWAS dataset from the Alzheimer's Disease Genetics Consortium containing three neuropathological traits related to Alzheimer disease (neuritic plaque, neurofibrillary tangles, and cerebral amyloid angiopathy) measured in 3500 autopsied brains. Gene-level significant evidence (P < 2.7 × 10-6) was identified in a region containing three contiguous genes (TRAPPC12, TRAPPC12-AS1, ADI1) using O'Brien and VEGAS. Gene-wide significant associations were not observed in univariate gene-based tests.

11.
Ann Am Thorac Soc ; 16(4): 447-454, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30543456

RESUMO

RATIONALE: There is increasing evidence that aberrant processes occurring in the airways may precede the development of idiopathic pulmonary fibrosis (IPF); however, there has been no prior confirmatory data derived from imaging studies. OBJECTIVES: To assess quantitative measures of airway wall thickness (AWT) in populations characterized for interstitial lung abnormalities (ILA) and for IPF. METHODS: Computed tomographic imaging of the chest and measures of AWT were available for 6,073, 615, 1,167, and 38 participants from COPDGene (Genetic Epidemiology of COPD study), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study), and the Framingham Heart Study (FHS) and in patients with IPF from the Brigham and Women's Hospital Herlihy Registry, respectively. To evaluate these associations, we used multivariable linear regression to compare a standardized measure of AWT (the square root of AWT for airways with an internal perimeter of 10 mm [Pi10]) and characterizations of ILA and IPF by computed tomographic imaging of the chest. RESULTS: In COPDGene, ECLIPSE, and FHS, research participants with ILA had increased measures of Pi10 compared with those without ILA. Patients with IPF had mean measures of Pi10 that were even greater than those noted in research participants with ILA. After adjustment for important covariates (e.g., age, sex, race, body mass index, smoking behavior, and chronic obstructive pulmonary disease severity when appropriate), research participants with ILA had increased measures of Pi10 compared with those without ILA (0.03 mm in COPDGene, 95% confidence interval [CI], 0.02-0.03; P < 0.001; 0.02 mm in ECLIPSE, 95% CI, 0.005-0.04; P = 0.01; 0.07 mm in FHS, 95% CI, 0.01-0.1; P = 0.01). Compared with COPDGene participants without ILA older than 60 years of age, patients with IPF were also noted to have increased measures of Pi10 (2.0 mm, 95% CI, 2.0-2.1; P < 0.001). Among research participants with ILA, increases in Pi10 were correlated with reductions in lung volumes in some but not all populations. CONCLUSIONS: These results demonstrate that measurable increases in AWT are consistently noted in research participants with ILA and in patients with IPF. These findings suggest that abnormalities of the airways may play a role in, or be correlated with, early pathogenesis of pulmonary fibrosis.

12.
PLoS Genet ; 14(10): e1007591, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30325923

RESUMO

A primary goal of the recent investment in sequencing is to detect novel genetic associations in health and disease improving the development of treatments and playing a critical role in precision medicine. While this investment has resulted in an enormous total number of sequenced genomes, individual studies of complex traits and diseases are often smaller and underpowered to detect rare variant genetic associations. Existing genetic resources such as the Exome Aggregation Consortium (>60,000 exomes) and the Genome Aggregation Database (~140,000 sequenced samples) have the potential to be used as controls in these studies. Fully utilizing these and other existing sequencing resources may increase power and could be especially useful in studies where resources to sequence additional samples are limited. However, to date, these large, publicly available genetic resources remain underutilized, or even misused, in large part due to the lack of statistical methods that can appropriately use this summary level data. Here, we present a new method to incorporate external controls in case-control analysis called ProxECAT (Proxy External Controls Association Test). ProxECAT estimates enrichment of rare variants within a gene region using internally sequenced cases and external controls. We evaluated ProxECAT in simulations and empirical analyses of obesity cases using both low-depth of coverage (7x) whole-genome sequenced controls and ExAC as controls. We find that ProxECAT maintains the expected type I error rate with increased power as the number of external controls increases. With an accompanying R package, ProxECAT enables the use of publicly available allele frequencies as external controls in case-control analysis.

13.
BMC Proc ; 12(Suppl 9): 56, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30275899

RESUMO

Statistical power, which is the probability of correctly rejecting a false null hypothesis, is a limitation of genome-wide association studies (GWAS). Sample size is a major component of statistical power that can be easily affected by missingness in phenotypic data and restrain the ability to detect associated single-nucleotide polymorphisms (SNPs) with small effect sizes. Although some phenotypes are hard to collect because of cost and loss to follow-up, correlated phenotypes that are easily collected can be leveraged for association analysis. In this paper, we evaluate a phenotype imputation method that incorporates family structure and correlation between multiple phenotypes using GAW20 simulated data. The distribution of missing values is derived using information contained in the missing sample's relatives and additional correlated phenotypes. We show that this imputation method can improve power in the association analysis compared with excluding observations with missing data, while achieving the correct Type I error rate. We also examine factors that may affect the imputation accuracy.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30199657

RESUMO

RATIONALE: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility. METHODS: Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV1], forced vital capacity [FVC], and [FEV1/FVC]) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs. RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P<0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P2df=9.4×10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency~80%) was associated with lower FVC (PSNP=2.1×10-9; ßSNP= -161.0mL), and the association was attenuated by higher DHA levels (PSNP×DHA interaction=2.1×10-7; ßSNP×DHA interaction=36.2mL). CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.

15.
Br J Nutr ; 120(10): 1159-1170, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30205856

RESUMO

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

16.
BMC Genet ; 19(Suppl 1): 83, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30255771

RESUMO

BACKGROUND: Genome-wide association studies performed on triglycerides (TGs) have not accounted for epigenetic mechanisms that may partially explain trait heritability. RESULTS: Parent-of-origin (POO) effect association analyses using an agnostic approach or a candidate approach were performed for pretreatment TG levels, posttreatment TG levels, and pre- and posttreatment TG-level differences in the real GAW20 family data set. We detected 22 genetic variants with suggestive POO effects with at least 1 phenotype (P ≤ 10- 5). We evaluated the association of these 22 significant genetic variants showing POO effects with close DNA methylation probes associated with TGs. A total of 18 DNA methylation probes located in the vicinity of the 22 SNPs were associated with at least 1 phenotype and 6 SNP-probe pairs were associated with DNA methylation probes at the nominal level of P < 0.05, among which 1 pair presented evidence of POO effect. Our analyses identified a paternal effect of SNP rs301621 on the difference between pre- and posttreatment TG levels (P = 1.2 × 10- 5). This same SNP showed evidence for a maternal effect on methylation levels of a nearby probe (cg10206250; P = 0.01). Using a causal inference test we established that the observed POO effect of rs301621 was not mediated by DNA methylation at cg10206250. CONCLUSIONS: We performed POO effect association analyses of SNPs with TGs, as well as association analyses of SNPs with DNA methylation probes. These analyses, which were followed by a causal inference test, established that the paternal effect at the SNP rs301621 is induced by treatment and is not mediated by methylation level at cg10206250.

17.
BMC Genet ; 19(Suppl 1): 84, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30255775

RESUMO

BACKGROUND: Single-probe analyses in epigenome-wide association studies (EWAS) have identified associations between DNA methylation and many phenotypes, but do not take into account information from neighboring probes. Methods to detect differentially methylated regions (DMRs) (clusters of neighboring probes associated with a phenotype) may provide more power to detect associations between DNA methylation and diseases or phenotypes of interest. RESULTS: We proposed a novel approach, GlobalP, and perform comparisons with 3 methods-DMRcate, Bumphunter, and comb-p-to identify DMRs associated with log triglycerides (TGs) in real GAW20 data before and after fenofibrate treatment. We applied these methods to the summary statistics from an EWAS performed on the methylation data. Comb-p, DMRcate, and GlobalP detected very similar DMRs near the gene CPT1A on chromosome 11 in both the pre- and posttreatment data. In addition, GlobalP detected 2 DMRs before fenofibrate treatment in the genes ETV6 and ABCG1. Bumphunter identified several DMRs on chromosomes 1 and 20, which did not overlap with DMRs detected by other methods. CONCLUSIONS: Our novel method detected the same DMR identified by two existing methods and detected two additional DMRs not identified by any of the existing methods we compared.

18.
Eur Respir J ; 52(3)2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30049742

RESUMO

Although several genome-wide association studies (GWAS) have investigated the genetics of pulmonary ventilatory function, little is known about the genetic factors that influence gas exchange. The aim of the study was to investigate the heritability of, and genetic variants associated with the diffusing capacity of the lung.GWAS was performed on diffusing capacity of the lung measured by carbon monoxide uptake (DLCO) and per alveolar volume (VA) using the single-breath technique, in 8372 individuals from two population-based cohort studies, the Rotterdam Study and the Framingham Heart Study. Heritability was estimated in related (n=6246) and unrelated (n=3286) individuals.Heritability of DLCO and DLCO/VA ranged between 23% and 28% in unrelated individuals and between 45% and 49% in related individuals. Meta-analysis identified a genetic variant in ADGRG6 that is significantly associated with DLCO/VA Gene expression analysis of ADGRG6 in human lung tissue revealed a decreased expression in patients with chronic obstructive pulmonary disease (COPD) and subjects with decreased DLCO/VADLCO and DLCO/VA are heritable traits, with a considerable proportion of variance explained by genetics. A functional variant in ADGRG6 gene region was significantly associated with DLCO/VA Pulmonary ADGRG6 expression was decreased in patients with COPD.

19.
Genomics ; 2018 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-29857119

RESUMO

The Alzheimer's Disease Sequencing Project (ADSP) performed whole genome sequencing (WGS) of 584 subjects from 111 multiplex families at three sequencing centers. Genotype calling of single nucleotide variants (SNVs) and insertion-deletion variants (indels) was performed centrally using GATK-HaplotypeCaller and Atlas V2. The ADSP Quality Control (QC) Working Group applied QC protocols to project-level variant call format files (VCFs) from each pipeline, and developed and implemented a novel protocol, termed "consensus calling," to combine genotype calls from both pipelines into a single high-quality set. QC was applied to autosomal bi-allelic SNVs and indels, and included pipeline-recommended QC filters, variant-level QC, and sample-level QC. Low-quality variants or genotypes were excluded, and sample outliers were noted. Quality was assessed by examining Mendelian inconsistencies (MIs) among 67 parent-offspring pairs, and MIs were used to establish additional genotype-specific filters for GATK calls. After QC, 578 subjects remained. Pipeline-specific QC excluded ~12.0% of GATK and 14.5% of Atlas SNVs. Between pipelines, ~91% of SNV genotypes across all QCed variants were concordant; 4.23% and 4.56% of genotypes were exclusive to Atlas or GATK, respectively; the remaining ~0.01% of discordant genotypes were excluded. For indels, variant-level QC excluded ~36.8% of GATK and 35.3% of Atlas indels. Between pipelines, ~55.6% of indel genotypes were concordant; while 10.3% and 28.3% were exclusive to Atlas or GATK, respectively; and ~0.29% of discordant genotypes were. The final WGS consensus dataset contains 27,896,774 SNVs and 3,133,926 indels and is publicly available.

20.
Front Pharmacol ; 9: 207, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29740313

RESUMO

Background: Transmembrane tumor necrosis factor (TNF) receptors are involved in inflammatory, apoptotic, and proliferative processes. In the bloodstream, soluble TNF receptor II (sTNFR2) can modify the inflammatory response of immune cells and is predictive of cardiovascular disease risk. We hypothesize that sTNFR2 is associated with epigenetic modifications of circulating leukocytes, which may relate to the pathophysiology underlying atherogenic risk. Methods: We conducted an epigenome-wide association study of sTNFR2 levels in the Framingham Heart Study Offspring cohort (examination 8; 2005-2008). sTNFR2 was quantitated by enzyme immunoassay and DNA methylation by microarray. The concentration of sTNFR2 was loge-transformed and outliers were excluded. We conducted linear mixed effects models to test the association between sTNFR2 level and methylation at over 400,000 CpGs, adjusting for age, sex, BMI, smoking, imputed cell count, technical covariates, and accounting for familial relatedness. Results: The study sample included 2468 participants (mean age: 67 ± 9 years, 52% women, mean sTNFR2 level 2661 ± 1078 pg/ml). After accounting for multiple testing, we identified 168 CpGs (P < 1.2 × 10-7) that were differentially methylated in relation to sTNFR2. A substantial proportion (27 CpGs; 16%) are in the major histocompatibility complex region and in loci overrepresented for antigen binding molecular functions (P = 1.7 × 10-4) and antigen processing and presentation biological processes (P = 1.3 × 10-8). Identified CpGs are enriched in active regulatory regions and associated with expression of 48 cis-genes (±500 kb) in whole blood (P < 1.1 × 10-5) that coincide with genes identified in GWAS of diseases of immune dysregulation (inflammatory bowel disease, type 1 diabetes, IgA nephropathy). Conclusion: Differentially methylated loci in leukocytes associated with sTNF2 levels reside in active regulatory regions, are overrepresented in antigen processes, and are linked to inflammatory diseases.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA