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1.
J Hypertens ; 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31356403

RESUMO

OBJECTIVE: We studied associations of circulating collagen type I carboxy-terminal telopeptide (ICTP) and procollagen type III N-terminal propeptide (PIIINP) with long-term renal function decline. METHODS: In the Multi-Ethnic Study of Atherosclerosis, we included 2492 participants initially aged 45-84 years and free of clinical cardiovascular disease (CVD), excluding people with estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m or urine albumin/creatinine (UAC) at least 30 mg/g. The primary outcome in median 9.4-year follow-up was renal function decline (≥30% decline in eGFR between any two exams or incident UAC ≥ 30 mg/g). The associations of baseline plasma ICTP and PIIINP with renal function decline were estimated using Poisson regression, adjusting for baseline variables race/ethnicity, sex, age, and continuous eGFR and UAC, with further adjustment for CVD risk factors and medications. RESULTS: Baseline serum ICTP was 3.27 ±â€Š1.43 µg/l and PIIINP was 5.43 ±â€Š1.85 µg/l. Mean baseline eGFR was 91.5 ±â€Š18.4 ml/min per 1.73 m. Renal function decline occurred in 19.5% during 9.4-year follow-up. The renal function decline outcome was positively associated with serum ICTP and PIIINP: relative incidence density (95% confidence interval) per SD 1.22 (1.11-1.33) and 1.27 (1.16-1.40), respectively. Additional adjustment for other risk factors did not greatly alter findings. CONCLUSION: High collagen biomarker concentrations in serum were associated with future decline in renal function in people initially free of CVD and with normal eGFR, consistent with collagen production signaling renal decline. The continuous association observed for ICTP which, unlike PIIINP, is filtered by the kidney, may owe to its double status as a sensitive marker of glomerular function and collagen degradation.

2.
Nature ; 570(7759): 71-76, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31118516

RESUMO

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.


Assuntos
Diabetes Mellitus Tipo 2/genética , Exoma/genética , Sequenciamento Completo do Exoma , Animais , Estudos de Casos e Controles , Técnicas de Apoio para a Decisão , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos Knockout
3.
Environ Toxicol Pharmacol ; 66: 24-35, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30594847

RESUMO

BACKGROUND: Some evidence in humans suggests that persistent organic pollutants (POPs), including organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), may alter the blood lipid composition. This study analyzed associations between serum POPs concentrations in young adulthood with blood lipid levels up to 23 years later. METHODS: Serum POPs were measured in year 2 of follow-up (n = 180 men and women, ages: 20-32y), and plasma lipids in follow-up years 2, 7, 10, 15, 20 and 25. 32 POPs were detectable in ≥75% of participants (23 PCBs, 8 OCPs and PBB-153). We created summary scores for PCBs and OCPs for both wet-weight, and lipid standardized (LP) concentrations. We used repeated measures regression adjusting for demographic factors, BMI, smoking, diabetes status, among others. RESULTS: We observed positive associations of the 23 LP-PCB score with total cholesterol (ßper SD increase [95%CI]: 5.0 mg/dL [0.7, 9.2]), triglycerides (7.8 mg/dL [-0.9, 16.5]), LDL (4.2 mg/dL [0.2, 8.2]), oxidized LDL 3.4 U/L (-0.05, 6.8), and cholesterol/HDL ratio (0.2 [0.02, 0.3]). The associations for triglycerides (14.7 mg/dL [0.4, 20.1]), cholesterol/HDL (0.33 [0.09, 0.56]) and, to some extent, LDL (4.7 md/dL [-1.6, 10.9]) were only observed among participants in the upper 50th percentile of BMI. Non-dioxin-like PCBs had stronger associations that dioxin-like PCBs. OCPs and PBB-s had positive associations with most outcomes. CONCLUSIONS: PCBs and PBB-153 measured in young adulthood were positively associated with prospective alterations in most blood lipid components, with evidence of effect modification by BMI. Further longitudinal studies with multiple measures of POPs overtime are needed.


Assuntos
Hidrocarbonetos Clorados/sangue , Lipídeos/sangue , Praguicidas/sangue , Adulto , Estudos de Casos e Controles , Exposição Ambiental , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
Circ Arrhythm Electrophysiol ; 11(10): e006557, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30354407

RESUMO

BACKGROUND: Atrial fibrosis is a hallmark of structural remodeling in atrial fibrillation (AF). Plasma procollagen type III N-terminal propeptide (PIIINP) reflects collagen synthesis and degradation while collagen type I carboxy-terminal telopeptide (ICTP) reflects collagen degradation. We aimed to study baseline plasma PIIINP and ICTP and their associations with incident AF in participants initially free of overt cardiovascular disease. METHODS: In a stratified sample of the Multi-Ethnic Study of Atherosclerosis, initially aged 45-84 years, 3071 participants had both PIIINP and ICTP measured at baseline. Incident AF in 10-year follow-up was based on a hospital International Classification of Diseases code for AF or atrial flutter, in- or outpatient Medicare claims through 2011 (primarily in those aged 65-84 years), or ECG 10 years after baseline (n=357). The associations of PIIINP and ICTP with incident AF were estimated using Poisson regression with follow-up time offset. RESULTS: Baseline PIIINP (5.50±1.55 µg/L) and ICTP (mean±SD, 3.41±1.37 µg/L) were positively related (both P<0.0001) to incident AF in a model adjusting for age, race/ethnicity, and sex, with an apparent threshold (relative incidence density 2.81 [1.94-4.08] for PIIINP ≥8.5 µg/L [3.5% of the sample] and 3.46 [2.36-5.07] for ICTP ≥7 µg/L [1.7% of the sample]). Findings were attenuated but remained statistically significant after further adjustment for systolic blood pressure, height, body mass index, smoking, and renal function. Additional adjustment for other risk factors and biomarkers of inflammation did not alter conclusions. CONCLUSIONS: Plasma collagen biomarkers, particularly at elevated levels, were associated with excess risk for AF.

5.
J Nutr ; 148(9): 1453-1461, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30184224

RESUMO

Background: Although α- and γ-tocopherol are co-consumed antioxidants, circulating γ-tocopherol concentrations were paradoxically found to be inversely associated with total vitamin E intake and circulating α-tocopherol concentrations. There are limited data on this apparent paradox or on determinants of circulating γ-tocopherol concentrations. Objective: To help clarify possible determinants of circulating γ-tocopherol concentrations, we investigated associations of circulating γ-tocopherol concentrations with various dietary and lifestyle factors and biomarkers of oxidative stress and inflammation. Methods: We pooled cross-sectional data from 2 outpatient, adult, elective colonoscopy populations (pooled n = 419) on whom extensive dietary, lifestyle, and medical information was collected, and the following plasma concentrations were measured: α- and γ-tocopherol (via HPLC), F2-isoprostanes (FiPs; via gas chromatography-mass spectrometry), and high-sensitivity C-reactive protein (hsCRP; via latex-enhanced immunonephelometry). Multivariable general linear models were used to assess mean γ-tocopherol differences across quantiles of plasma antioxidant micronutrients, FiPs, and hsCRP; an oxidative balance score [OBS; a composite of anti- and pro-oxidant dietary and lifestyle exposures (a higher score indicates higher antioxidant relative to pro-oxidant exposures)]; and multiple dietary and lifestyle factors. Results: Adjusted for serum total cholesterol, mean γ-tocopherol concentrations among those in the highest relative to the lowest tertiles of circulating α-tocopherol and ß-carotene, the OBS, and total calcium and dietary fiber intakes were 31.0% (P < 0.0001), 29.0% (P < 0.0001), 27.6% (P = 0.0001), 29.7% (P < 0.0001), and 18.6% (P = 0.008) lower, respectively. For those in the highest relative to the lowest tertiles of circulating FiPs and hsCRP, mean γ-tocopherol concentrations were 50% (P < 0.0001) and 39.0% (P < 0.0001) higher, respectively. Conclusions: These findings support the conclusion that circulating γ-tocopherol concentrations are inversely associated with antioxidant exposures and directly associated with systemic oxidative stress and inflammation in adults. Additional research on possible mechanisms underlying these findings and on whether circulating γ-tocopherol may serve as a biomarker of oxidative stress, inflammation, or both is needed.

6.
J Ren Nutr ; 2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30098859

RESUMO

OBJECTIVE: Nutritional intervention targeting dietary intake modification is a major component of treatment for chronic kidney disease; however, little is known about the relationship between dietary intake and kidney function decline in individuals with preserved kidney function. DESIGN AND METHODS: In this prospective cohort study we examined the association of biomarkers of dietary intake with kidney function decline over a 5-year interval in 2,152 men and women with cystatin-C-based estimated glomerular filtration rate > 60 mL/minute/1.73 m2 from the Coronary Artery Risk Development in Young Adults study. The biomarkers of interest included carotenoids, tocopherols, and ascorbic acid. Multivariable logistic regression was used to explore the relationship between serum concentrations of the sum of 4 carotenoids (α-carotene, ß-carotene, ß-cryptoxanthin, and lutein/zeaxanthin), lycopene, α-tocopherol, γ-tocopherol, and ascorbic acid and rapid kidney function decline, defined as .15% decline in cystatin-C-based estimated glomerular filtration rate over 5 years. RESULTS: During the 5-year follow-up, 290 participants (13.5%) experienced rapid kidney function decline. Relative to individuals in the lowest quartile of serum carotenoids, those in the highest quartile had significantly lower odds of rapid kidney function decline in the fully adjusted model (odds ratio, 0.51; 95% confidence interval [CI], 0.32-0.80; P trend, .02). No association of levels of serum tocopherols, ascorbic acid, or lycopene with kidney function decline was found. There was no evidence that results differed for individuals with hypertension or diabetes. CONCLUSIONS: These results demonstrate that higher serum carotenoid levels, reflective of a fruit- and vegetable-rich dietary pattern, inversely associate with rapid kidney function decline in early middle adulthood and provide insight into how diet might play a role in chronic kidney disease prevention.

7.
PLoS One ; 13(7): e0200486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30044860

RESUMO

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.

8.
Respir Med ; 140: 108-114, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29957270

RESUMO

BACKGROUND: Lung fibrosis is attributed to derangements in extracellular matrix remodeling, a process driven by collagen turnover. We examined the association of two collagen biomarkers, carboxy-terminal telopeptide of collagen type I (ICTP) and amino-terminal propeptide of type III procollagen (PIIINP), with subclinical interstitial lung disease (ILD) in adults. METHODS: We performed a cross-sectional analysis of 3244 participants age 45-84 years in the Multi-Ethnic Study of Atherosclerosis. Serum ICTP and PIIINP levels were measured at baseline by radioimmunoassay. Subclinical ILD was defined as high attenuation areas (HAA) in the lung fields on baseline cardiac CT scans. Interstitial lung abnormalities (ILA) were measured in 1082 full-lung CT scans at 9.5 years median follow-up. We used generalized linear models to examine the associations of collagen biomarkers with HAA and ILA. RESULTS: Median (IQR) for ICTP was 3.2 µg/L (2.6-3.9 µg/L) and for PIIINP was 5.3 µg/L (4.5-6.2 µg/L). In fully adjusted models, each SD increment in ICTP was associated with a 1.3% increment in HAA (95% CI 0.2-2.4%, p = 0.02) and each SD increment in PIIINP was associated with a 0.96% increment in HAA (95% CI 0.06-1.9%, p = 0.04). There was no association between ICTP or PIIINP and ILA. There was no evidence of effect modification by gender, race, smoking status or eGFR. CONCLUSIONS: Higher levels of collagen biomarkers are associated with greater HAA independent of gender, race and smoking status. This suggests that extracellular matrix remodeling may accompany subclinical ILD prior to the onset of clinically evident disease.

9.
Am J Epidemiol ; 187(9): 1923-1930, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29788105

RESUMO

Concentration of 25-hydroxyvitamin D3 (25(OH)D3), the main circulating form of vitamin D, is inversely associated with incident, sporadic colorectal adenoma risk. We investigated whether this association differs by 2 functional variants in the vitamin D-binding protein (DBP) gene, group-specific component (GC), that encode for common protein isoforms Gc1s, Gc1f, and Gc2 linked to differences in vitamin D metabolism. We pooled data (418 patients with adenoma and 524 polyp-free control subjects) from 3 colonoscopy-based case-control studies (Minnesota, 1991-1994; North Carolina, 1994-1997; South Carolina, 2002). We estimated 25(OH)D3-adenoma associations, stratified by DBP isoforms, using multivariable logistic regression. Higher 25(OH)D3 concentrations were inversely associated with colorectal adenoma risk among those with the Gc2 isoform (per 10-ng/mL increase in 25(OH)D3, odds ratio = 0.71, 95% confidence interval: 0.56, 0.90), but not among those with only Gc1 isoforms (odds ratio = 1.07, 95% confidence interval: 0.87, 1.32; P for interaction = 0.03). Thus, the vitamin D-incident, sporadic colorectal adenoma association may differ by common DBP isoforms, and patients with the Gc2 isoform may particularly benefit from maintaining higher circulating 25(OH)D3 concentrations for adenoma prevention.

10.
J Hypertens ; 36(11): 2245-2250, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29782392

RESUMO

OBJECTIVE: Vascular remodeling associated with increased extracellular matrix (ECM) may precede hypertension. Procollagen type III N-terminal propeptide (PIIINP) and collagen type I carboxy-terminal telopeptide (ICTP) reflect collagen turnover and are important in ECM remodeling. PIIINP and ICTP are increased in cardiovascular diseases (CVD). We hypothesized that PIIINP and ICTP among normotensives predict incident hypertension. METHODS: We included 1252 Multi-Ethnic Study of Atherosclerosis participants with mean age 58.1 ±â€Š12.4 years, 48% men, free of overt CVD, having SBP and DBP less than 130/85 mmHg and not using any antihypertensive medication, and having plasma PIIINP and ICTP measurements, all assessed at baseline. We studied the association of baseline PIIINP and ICTP with the relative incidence density (RID) of incident hypertension, defined as SBP/DBP at least 140/90 mmHg, or antihypertensive therapy use during follow-up (four examinations over median 9.4 years). RESULTS: Baseline mean SBP/DBP was 110.9 ±â€Š14.0/67.9 ±â€Š10.4 mmHg. Mean concentration of PIIINP was 5.39 ±â€Š1.95 µg/l and ICTP was 3.18 ±â€Š1.39 µg/l. During follow-up visits, 35.9% of the participants developed hypertension. After adjustment for age, race, and sex there was a significant RID for new onset of hypertension of 1.16 (1.06, 1.28), P = 0.0017 for PIIINP and 1.20 (1.08,1.33) for ICTP, P = 0.0008. After additional adjustment for renal function, CVD risk factors and inflammatory variables, RID for new onset hypertension was 1.28 (1.15,1.42), P < 0.001 for PIIINP and 1.29 (1.15,1.44) for ICTP, P < 0.0001. CONCLUSION: Biomarkers of ECM remodeling predicted the development of hypertension in normotensive participants free of overt CVD.

11.
J Am Heart Assoc ; 7(5)2018 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-29475876

RESUMO

BACKGROUND: Collagen biomarkers may correlate with incident heart failure (HF) and its subtypes. We hypothesized that circulating procollagen type III N-terminal propeptide (PIIINP) and collagen type I carboxy-terminal telopeptide (ICTP) predict incident HF. METHODS AND RESULTS: We used a stratified sampling design in a multiethnic sample of 3187 subjects, initially aged 45 to 84 years and free of cardiovascular disease. We assayed baseline serum PIIINP and ICTP concentrations using radioimmunoassay. Incident HF was adjudicated, distinguishing reduced ejection fraction (HFrEF; EF <45%) from preserved EF (HFpEF; EF ≥45%). The incidence density for HFpEF and HFrEF was computed using Poisson regression per SD for each of PIIINP and ICTP, adjusting in model 1 for age, race, sex, and renal function or in model 2 for these variables plus blood pressure and medication. Mean (SD) ICTP was 3.38±1.77 µg/L, and mean (SD) PIIINP was 5.48±2.04 µg/L. Among the HF cases, 96 were HFrEF and 107 were HFpEF. Neither ICTP nor PIIINP significantly predicted incident HFrEF. The incidence density for HFpEF per 100 people observed for 13 years was 1.65 for low PIIINP (lower 6 octiles) versus 3.00 for higher PIIINP (P=0.002) in model 1 and correspondingly 1.45 versus 2.59 (P=0.003) in model 2. For low ICTP (lower 7 octiles) versus higher ICTP (octile 8), incidence densities were 1.79 versus 3.64 (P=0.002) in model 1 and 1.58 versus 3.12 (P=0.002) in model 2. CONCLUSIONS: High levels of circulating ICTP and PIIINP as collagen biomarkers appear to be associated with incident HFpEF, but not HFrEF.

12.
Mol Carcinog ; 57(5): 598-605, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29323753

RESUMO

Somatic mutations in mitochondrial DNA have been reported in colorectal adenomatous polyps (adenomas), the precursors to most colorectal cancers. However, there are no reports of associations of germline variation in mitochondrial DNA with adenoma risk. We investigated associations of germline polymorphisms in the displacement loop (D-loop) and non-D-loop region of the mitochondrial genome with incident, sporadic colorectal adenoma in three pooled colonoscopy-based case-control studies (n = 327 adenoma cases, 420 controls) that used identical methods for case and risk factor ascertainment. We sequenced a 1124 bp fragment to identify all genetic variation in the mitochondrial D-loop region, and used the Sequenom platform to genotype 64 tagSNPs in the non-D-loop region. We used multivariable unconditional logistic regression to estimate associations of the polymorphisms with adenoma. The odds ratios (OR) for associations of four polymorphisms in the HV1 region (mt16294, mt16296, mt16278, mt16069) with adenoma were 2.30, 2.63, 3.34, and 0.56, respectively; all 95% confidence intervals (CI) excluded 1.0, however, after correction for multiple comparisons, none of the findings remained statistically significant. Similar results were found for six polymorphisms in the non-D-loop region. In the HV1 region poly C tract, relative to those with 5 repeats, the ORs for those with fewer or more repeats were, respectively, 2.29 (95%CI 1.07-4.89) and 0.63 (95%CI 0.36-1.08), but repeat numbers in the HV2 region were not associated with adenoma. These findings suggest that mitochondrial D-loop HV1 region polymorphisms may be associated with colorectal adenoma risk and support further investigation.

13.
JAMA Intern Med ; 178(3): 328-337, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29340577

RESUMO

Importance: Lactation duration has shown weak protective associations with incident diabetes (3%-15% lower incidence per year of lactation) in older women based solely on self-report of diabetes, studies initiated beyond the reproductive period are vulnerable to unmeasured confounding or reverse causation from antecedent biochemical risk status, perinatal outcomes, and behaviors across the childbearing years. Objective: To evaluate the association between lactation and progression to diabetes using biochemical testing both before and after pregnancy and accounting for prepregnancy cardiometabolic measures, gestational diabetes (GD), and lifestyle behaviors. Design, Setting, and Participants: For this US multicenter, community-based 30-year prospective cohort study, there were 1238 women from the Coronary Artery Risk Development in Young Adults (CARDIA) study of young black and white women ages 18 to 30 years without diabetes at baseline (1985-1986) who had 1 or more live births after baseline, reported lactation duration, and were screened for diabetes up to 7 times during 30 years after baseline (1986-2016). Exposures: Time-dependent lactation duration categories (none, >0 to 6 months, >6 to <12 months, and ≥12 months) across all births since baseline through 30 years. Main Outcomes and Measures: Diabetes incidence rates per 1000 person-years and adjusted relative hazards (RH) with corresponding 95% CIs, as well as proportional hazards regression models adjusted for biochemical, sociodemographic, and reproductive risk factors, as well as family history of diabetes, lifestyle, and weight change during follow-up. Results: Overall 1238 women were included in this analysis (mean [SD] age, 24.2 [3.7] years; 615 black women). There were 182 incident diabetes cases during 27 598 person-years for an overall incidence rate of 6.6 cases per 1000 person-years (95% CI, 5.6-7.6); and rates for women with GD and without GD were 18.0 (95% CI, 13.3-22.8) and 5.1 (95% CI, 4.2-6.0), respectively (P for difference < .001). Lactation duration showed a strong, graded inverse association with diabetes incidence: adjusted RH for more than 0 to 6 months, 0.75 (95% CI, 0.51-1.09); more than 6 months to less than 12 months, 0.52 (95% CI, 0.31-0.87), and 12 months or more 0.53 (0.29-0.98) vs none (0 days) (P for trend = .01). There was no evidence of effect modification by race, GD, or parity. Conclusions and Relevance: This study provides longitudinal biochemical evidence that lactation duration is independently associated with lower incidence of diabetes. Further investigation is required to elucidate mechanisms that may explain this relationship.

14.
J Hum Genet ; 63(3): 327-337, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29321517

RESUMO

Homocysteine (Hcy) is a heritable biomarker for CVD, peripheral artery disease, stroke, and dementia. Little is known about genetic associations with Hcy in individuals of African ancestry. We performed a genome-wide association study for Hcy in 4927 AAs from the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Coronary Artery Risk in Young Adults (CARDIA) study. Analyses were stratified by sex and results were meta-analyzed within and across sex. In the sex-combined meta-analysis, we observed genome-wide significant evidence (p < 5.0 × 10-8) for the NOX4 locus (lead variant rs2289125, ß = -0.15, p = 5.3 × 1011). While the NOX4 locus was previously reported as associated with Hcy in European-American populations, rs2289125 remained genome-wide significant when conditioned on the previously reported lead variants. Previously reported genome-wide significant associations at NOX4, MTR, CBS, and MMACHC were also nominally (p < 0.050) replicated in AAs. Associations at the CPS1 locus, previously reported in females only, also was replicated specifically in females in this analysis, supporting sex-specific effects for this locus. These results suggest that there may be a combination of cross-population and population-specific genetic effects, as well as differences in genetic effects between males and females, in the regulation of Hcy levels.


Assuntos
Afro-Americanos/genética , Aterosclerose/sangue , Aterosclerose/genética , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Homocisteína/sangue , Adulto , Alelos , Aterosclerose/epidemiologia , Doença da Artéria Coronariana/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mississippi/epidemiologia , Polimorfismo de Nucleotídeo Único , Vigilância da População , Locos de Características Quantitativas , Característica Quantitativa Herdável , Adulto Jovem
15.
Cancer Prev Res (Phila) ; 11(1): 52-58, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29074536

RESUMO

In vitro evidence implicates oxidative stress in many adverse health conditions, including colorectal neoplasia. In human studies, however, oxidative stress is measured by imperfect biomarkers, which are inconsistently associated with health outcomes. Structural equation modeling (SEM) offers one possible solution by modeling a latent (unobserved) construct from multiple biomarkers. Our goal was to investigate the association of a latent oxidative stress variable with colorectal adenoma. Using SEM, we analyzed pooled data from two cross-sectional studies of colorectal adenoma (n = 526) that measured five plasma biomarkers of oxidative stress and inflammation that comprised the latent oxidative stress variable: F2-isoprostanes (FIP), fluorescent oxidation products (FOP), mitochondrial DNA (MtDNA) copy number, γ-tocopherol (Gtoc), and C-reactive protein (CRP). Higher levels of oxidative stress were associated with colorectal adenoma [OR = 3.23 per SD increase in oxidative stress; 95% confidence interval (CI), 1.28-8.18]. The latent variable estimate was considerably stronger than the associations of adenoma with the individual biomarkers, which were modest and mostly nonsignificant. Risk factors were associated with adenoma via the oxidative stress pathway, particularly overweight and obesity with an OR = 1.50; 95% CI, 1.10-2.81; and OR = 2.95; 95% CI, 1.28-12.45, respectively. Oxidative stress may be positively associated with colorectal adenoma, and important risk factors may act through this mechanism, but the cross-sectional design of the current study precludes observing the directionality of associations. The presence of an adenoma could affect levels of the circulating biomarkers; thus, we should be cautious of strong conclusions until the findings are replicated in a follow-up study. Cancer Prev Res; 11(1); 52-58. ©2017 AACR.

17.
Diabetologia ; 60(12): 2384-2398, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28905132

RESUMO

AIMS/HYPOTHESIS: Elevated levels of fasting glucose and fasting insulin in non-diabetic individuals are markers of dysregulation of glucose metabolism and are strong risk factors for type 2 diabetes. Genome-wide association studies have discovered over 50 SNPs associated with these traits. Most of these loci were discovered in European populations and have not been tested in a well-powered multi-ethnic study. We hypothesised that a large, ancestrally diverse, fine-mapping genetic study of glycaemic traits would identify novel and population-specific associations that were previously undetectable by European-centric studies. METHODS: A multiethnic study of up to 26,760 unrelated individuals without diabetes, of predominantly Hispanic/Latino and African ancestries, were genotyped using the Metabochip. Transethnic meta-analysis of racial/ethnic-specific linear regression analyses were performed for fasting glucose and fasting insulin. We attempted to replicate 39 fasting glucose and 17 fasting insulin loci. Genetic fine-mapping was performed through sequential conditional analyses in 15 regions that included both the initially reported SNP association(s) and denser coverage of SNP markers. In addition, Metabochip-wide analyses were performed to discover novel fasting glucose and fasting insulin loci. The most significant SNP associations were further examined using bioinformatic functional annotation. RESULTS: Previously reported SNP associations were significantly replicated (p ≤ 0.05) in 31/39 fasting glucose loci and 14/17 fasting insulin loci. Eleven glycaemic trait loci were refined to a smaller list of potentially causal variants through transethnic meta-analysis. Stepwise conditional analysis identified two loci with independent secondary signals (G6PC2-rs477224 and GCK-rs2908290), which had not previously been reported. Population-specific conditional analyses identified an independent signal in G6PC2 tagged by the rare variant rs77719485 in African ancestry. Further Metabochip-wide analysis uncovered one novel fasting insulin locus at SLC17A2-rs75862513. CONCLUSIONS/INTERPRETATION: These findings suggest that while glycaemic trait loci often have generalisable effects across the studied populations, transethnic genetic studies help to prioritise likely functional SNPs, identify novel associations that may be population-specific and in turn have the potential to influence screening efforts or therapeutic discoveries. DATA AVAILABILITY: The summary statistics from each of the ancestry-specific and transethnic (combined ancestry) results can be found under the PAGE study on dbGaP here: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000356.v1.p1.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu , Jejum/sangue , Feminino , Estudo de Associação Genômica Ampla , Humanos , Insulina/sangue , Masculino , Polimorfismo de Nucleotídeo Único/genética
19.
J Nutr ; 147(9): 1693-1699, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28747487

RESUMO

Background: Dietary factors, such as antioxidant nutrients, contribute significantly to the maintenance of an appropriate balance between antioxidant defense and free radical production in the body.Objective: The objective of this study was to examine the relation between oxidative stress as assessed by plasma F2-isoprostane (IsoP) concentration, glycemic load (GL), glycemic index (GI), intake of antioxidant nutrients, dietary fiber, and polyunsaturated fatty acids (PUFAs).Methods: This study was a cross-sectional secondary analysis of baseline data collected from a random sample of 269 postmenopausal women participating in the Minnesota Green Tea Trial. GL, GI, and dietary variables were calculated from the diet history questionnaire. Subjects filled out surveys about the use of anti-inflammatory drugs and physical activity. Plasma IsoP concentration was assessed by GC-mass spectrometry. IsoP concentrations were compared across quartiles of GL, GI, insoluble fiber, PUFAs, and antioxidant nutrients with the use of linear regression.Results: Antioxidant supplement intake, including zinc, copper, vitamin C and vitamin E, was reported by >60% of the participants. Mean intake of PUFAs was 12.5 g. Mean plasma IsoP concentrations increased from 34 to 36.7 pg/mL in the lowest quartiles of GL and GI, respectively, to 45.2 and 41.6 pg/mL, respectively, in the highest quartiles (P-trend = 0.0014 for GL and P-trend = 0.0379 for GI), whereas mean IsoP concentrations decreased from 41.8 pg/mL in the lowest quartile of PUFAs to 34.9 pg/mL in the highest quartile (P-trend = 0.0416). Similarly, mean IsoP concentrations decreased from 44.4 pg/mL in the lowest quartile of insoluble fiber to 36 pg/mL in the highest quartile (P-trend = 0.0243) after adjustment for potential confounders.Conclusions: We concluded that dietary PUFAs and insoluble fiber are inversely associated with oxidative stress whereas GL and GI are positively associated with oxidative stress in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00917735.


Assuntos
Dieta , Fibras na Dieta/farmacologia , F2-Isoprostanos/sangue , Ácidos Graxos Insaturados/farmacologia , Índice Glicêmico , Carga Glicêmica , Estresse Oxidativo , Antioxidantes/administração & dosagem , Estudos Transversais , Gorduras Insaturadas na Dieta/farmacologia , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Inquéritos e Questionários
20.
Front Cardiovasc Med ; 4: 37, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28596958

RESUMO

OBJECTIVE: Higher circulating concentrations of cellular adhesion molecules (CAMs) can be used as markers of endothelial dysfunction. Given that the brain is highly vascularized, we assessed whether endothelial function is associated with cognitive performance. METHOD: Within the Coronary Artery Risk Development in Young Adults (CARDIA) Study, excluding N = 54 with stroke before year 25, we studied CAMs among N = 2,690 black and white men and women in CARDIA year 7 (1992-1993, ages 25-37) and N = 2,848 in CARDIA year 15 (2000-2001, ages 33-45). We included subjects with levels of circulating soluble CAMs measured in year 7 or 15 and cognitive function testing in year 25 (2010-2011, ages 43-55). Using multiple regression analysis, we evaluated the association between CAMs and year 25 cognitive test scores: Rey Auditory Verbal Learning Test (RAVLT, memory), Digit Symbol Substitution Test (DSST, speed of processing), and the Stroop Test (executive function). RESULT: All CAM concentrations were greater in year 15 vs. year 7. Adjusting for age, race, sex, education, smoking, alcohol, diet, physical activity, participants in the fourth vs. the first quartile of CARDIA year 7 of circulating intercellular adhesion molecule-1 (ICAM-1) scored worse on RAVLT, DSST, and Stroop Test (p ≤ 0.05) in CARDIA year 25. Other CAMs showed little association with cognitive test scores. Findings were similar for ICAM-1 assessed at year 15. Adjustment for possibly mediating physical factors attenuated the findings. CONCLUSION: Higher circulating ICAM-1 at average ages 32 and 40 was associated with lower cognitive skills at average age 50. The study is consistent with the hypothesis that endothelial dysfunction is associated with worse short-term memory, speed of processing, and executive function.

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