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1.
Am J Hum Genet ; 105(4): 773-787, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564431

RESUMO

Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic traits including type 2 diabetes (T2D), lipid levels, body fat distribution, and adiposity, although most causal genes remain unknown. We used subcutaneous adipose tissue RNA-seq data from 434 Finnish men from the METSIM study to identify 9,687 primary and 2,785 secondary cis-expression quantitative trait loci (eQTL; <1 Mb from TSS, FDR < 1%). Compared to primary eQTL signals, secondary eQTL signals were located further from transcription start sites, had smaller effect sizes, and were less enriched in adipose tissue regulatory elements compared to primary signals. Among 2,843 cardiometabolic GWAS signals, 262 colocalized by LD and conditional analysis with 318 transcripts as primary and conditionally distinct secondary cis-eQTLs, including some across ancestries. Of cardiometabolic traits examined for adipose tissue eQTL colocalizations, waist-hip ratio (WHR) and circulating lipid traits had the highest percentage of colocalized eQTLs (15% and 14%, respectively). Among alleles associated with increased cardiometabolic GWAS risk, approximately half (53%) were associated with decreased gene expression level. Mediation analyses of colocalized genes and cardiometabolic traits within the 434 individuals provided further evidence that gene expression influences variant-trait associations. These results identify hundreds of candidate genes that may act in adipose tissue to influence cardiometabolic traits.

3.
Am J Hum Genet ; 105(1): 15-28, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31178129

RESUMO

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

4.
Bioinformatics ; 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31099385

RESUMO

SUMMARY: Tens of thousands of reproducibly identified GWAS (Genome-Wide Association Studies) variants, with the vast majority falling in non-coding regions resulting in no eventual protein products, call urgently for mechanistic interpretations. Although numerous methods exist, there are few, if any methods, for simultaneously testing the mediation effects of multiple correlated SNPs via some mediator (e.g. the expression of a gene in the neighborhood) on phenotypic outcome. We propose multi-SNP mediation intersection-union test (SMUT) to fill in this methodological gap. Our extensive simulations demonstrate the validity of SMUT as well as substantial, up to 92%, power gains over alternative methods. In addition, SMUT confirmed known mediators in a real dataset of Finns for plasma adiponectin level, which were missed by many alternative methods. We believe SMUT will become a useful tool to generate mechanistic hypotheses underlying GWAS variants, facilitating functional follow-up. AVAILABILITY AND IMPLEMENTATION: The R package SMUT is publicly available from CRAN at https://CRAN.R-project.org/package=SMUT. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

5.
J Perinatol ; 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30518802

RESUMO

OBJECTIVE: Patent ductus arteriosus (PDA) is a commonly observed condition in preterm infants. Prior studies have suggested a role for genetics in determining spontaneous ductal closure. Using samples from a large neonatal cohort we tested the hypothesis that common genetic variations are associated with PDA in extremely preterm infants. STUDY DESIGN: Preterm infants (n = 1013) enrolled at NICHD Neonatal Research Network sites were phenotyped for PDA. DNA was genotyped for 1634 single nucleotide polymorphisms (SNPs) from candidate genes. Analyses were adjusted for ancestral eigenvalues and significant epidemiologic variables. RESULTS: SNPs in several genes were associated with the clinical diagnosis of PDA and with surgical ligation in extremely preterm neonates diagnosed with PDA (p < 0.01). None of the associations were significant after correction for multiple comparisons. CONCLUSION: We identified several common genetic variants associated with PDA. These findings may inform further studies on genetic risk factors for PDA in preterm infants.

6.
Nat Commun ; 9(1): 5052, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30487518

RESUMO

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.

7.
PLoS Genet ; 14(4): e1007275, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29621232

RESUMO

To identify genetic contributions to type 2 diabetes (T2D) and related glycemic traits (fasting glucose, fasting insulin, and HbA1c), we conducted genome-wide association analyses (GWAS) in up to 7,178 Chinese subjects from nine provinces in the China Health and Nutrition Survey (CHNS). We examined patterns of population structure within CHNS and found that allele frequencies differed across provinces, consistent with genetic drift and population substructure. We further validated 32 previously described T2D- and glycemic trait-loci, including G6PC2 and SIX3-SIX2 associated with fasting glucose. At G6PC2, we replicated a known fasting glucose-associated variant (rs34177044) and identified a second signal (rs2232326), a low-frequency (4%), probably damaging missense variant (S324P). A variant within the lead fasting glucose-associated signal at SIX3-SIX2 co-localized with pancreatic islet expression quantitative trait loci (eQTL) for SIX3, SIX2, and three noncoding transcripts. To identify variants functionally responsible for the fasting glucose association at SIX3-SIX2, we tested five candidate variants for allelic differences in regulatory function. The rs12712928-C allele, associated with higher fasting glucose and lower transcript expression level, showed lower transcriptional activity in reporter assays and increased binding to GABP compared to the rs12712928-G, suggesting that rs12712928-C contributes to elevated fasting glucose levels by disrupting an islet enhancer, resulting in reduced gene expression. Taken together, these analyses identified multiple loci associated with glycemic traits across China, and suggest a regulatory mechanism at the SIX3-SIX2 fasting glucose GWAS locus.


Assuntos
Glicemia/genética , Diabetes Mellitus Tipo 2/genética , Inquéritos Epidemiológicos , China , Jejum , Feminino , Estudo de Associação Genômica Ampla , Humanos , Ilhotas Pancreáticas/metabolismo , Masculino , Mutação de Sentido Incorreto , Inquéritos Nutricionais , Locos de Características Quantitativas
9.
Nat Genet ; 49(12): 1722-1730, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29083407

RESUMO

Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.


Assuntos
Doença da Artéria Coronariana/genética , Exoma/genética , Predisposição Genética para Doença/genética , Variação Genética , Metabolismo dos Lipídeos/genética , Grupo com Ancestrais do Continente Asiático/genética , Doença da Artéria Coronariana/etnologia , Europa (Continente) , Grupo com Ancestrais do Continente Europeu/genética , Extremo Oriente , Frequência do Gene , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lipídeos/análise
10.
Hum Mol Genet ; 26(9): 1770-1784, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28334899

RESUMO

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.


Assuntos
Colesterol/genética , Triglicerídeos/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Colesterol/metabolismo , Grupos Étnicos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação/genética , Lipídeos/genética , Lipoproteínas HDL/genética , Lipoproteínas LDL/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas , Triglicerídeos/metabolismo
11.
Hypertens Pregnancy ; 36(1): 30-35, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27657194

RESUMO

OBJECTIVE: To examine the association between genetic predisposition to elevated C-reactive protein (CRP)and risk for preeclampsia using validated genetic loci for C-reactive protein. METHODS: Preeclampsia cases (n = 177) and normotensive controls (n = 116) were selected from live birth certificates to nulliparous Iowa women during the period August 2002-May 2005. Disease status was verified by the medical chart review. Genetic predisposition to CRP was estimated by a genetic risk score on the basis of established loci for CRP levels. Logistic regression analyses were used to evaluate the relationships between the genotype score and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. RESULTS: The genetic risk score (GRS) related to higher levels of CRP demonstrated a significantly decreased risk of preeclampsia (OR 0.89, 95% CI 0.82-0.96). When the GRS was analyzed by quartile, an inverse linear trend was observed (p = 0.0006). The results were similar after adjustments for the body mass index (BMI), smoking, and leisure-time physical activity. In the independent replication population, the association with the CRP GRS was also marginally significant (OR 0.97, 95% CI 0.92, 1.02). Meta-analysis of the two studies was statistically significant (OR 0.95, 95% CI 0.90, 0.99). CONCLUSION: Our data suggest an inverse, counterintuitive association between the genetic predisposition to elevated levels of CRP and a decreased risk of preeclampsia. This suggests that the blood CRP level is a marker of preeclampsia, but it does not appear to be a factor on the causal pathway.


Assuntos
Proteína C-Reativa/metabolismo , Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/sangue , Biomarcadores/sangue , Pressão Sanguínea/genética , Feminino , Estudos de Associação Genética , Loci Gênicos , Humanos , Pré-Eclâmpsia/genética , Gravidez , Fatores de Risco
12.
J Gerontol A Biol Sci Med Sci ; 72(4): 543-547, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27440911

RESUMO

Background: There is strong evidence that low and high birth weight due to in-utero programming results in elevated risk for adult diseases, though less research has been performed examining the influence of birth weight and physical disability later in life. Methods: Baseline data from 76,055 postmenopausal women in the Women's Health Initiative, a large multi-ethnic cohort, were used to examine the association between self-reported birth weight category (<6 lbs, 6-7 lbs 15 oz, 8-9 lbs 15 oz, and ≥10 lbs) and the self-reported physical functioning score on the RAND 36-item Health Survey. Linear regression models were adjusted for age, education, race/ethnicity, body mass index, and a comorbidity score. Results: Unadjusted models indicate that women born in the lowest and highest birth weight categories have significantly lower physical functioning scores as compared to women born in the normal weight category (ß = -2.22, p < .0001 and ß = -3.56, p < .0001, respectively). After adjustments, the relationship between the lowest birth weight category and physical functioning score remained significant (ß = -1.52, p < .0001); however, the association with the highest birth weight category dissipated. Conclusions: Preconception and prenatal interventions aimed at reducing the incidence of low birth weight infants may subsequently reduce the burden of later-life physical disability.


Assuntos
Deficiências do Desenvolvimento/epidemiologia , Idoso , Estudos Transversais , Feminino , Humanos , Recém-Nascido de Baixo Peso , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
13.
Matern Child Health J ; 20(6): 1193-202, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26910608

RESUMO

OBJECTIVE: Physical activity (PA) is hypothesized to reduce the risk of preeclampsia, but few epidemiologic studies have simultaneously evaluated leisure time PA (LTPA), sedentary activity, occupational activity, and non-occupational, non-leisure time PA. Thus, we assessed the independent and combined effects of these different types of PA during pregnancy on preeclampsia and gestational hypertension risk. METHODS: Preeclamptic (n = 258), gestational hypertensive (n = 233), and normotensive (n = 182) women identified from Iowa live birth records (2002-2005) were participants in Study of Pregnancy Hypertension in Iowa. Disease status was verified by medical chart review. All PA exposures were self-reported. Multinomial logistic regression was used to test for associations between various PA types and risk for preeclampsia or gestational hypertension. RESULTS: After adjusting for prepregnancy BMI, increasing levels of LTPA were associated with a reduced risk of preeclampsia (trend, p = 0.02). Additionally, increasing amount of time spent active each day was associated with decreasing risks for preeclampsia (adjusted, trend; p = 0.03). Increasing amount of time spent sitting per day was associated with an increasing risk of preeclampsia (adjusted, trend; p = 0.10). Women whose activity averaged >8.25 h per day were at a significantly reduced risk of preeclampsia relative to women active <4.2 h per day (adjusted OR 0.58, 95 % CI 0.36, 0.95). Most analyses evaluating the risk of gestational hypertension yielded null results or results that trended in the direction opposite of the preeclampsia results. CONCLUSION: Consistent with previous studies, these data suggest increasing PA during pregnancy may reduce preeclampsia risk while increasing levels of sedentary activity may increase disease risk.


Assuntos
Emprego , Exercício , Hipertensão Induzida pela Gravidez/etiologia , Atividades de Lazer , Pré-Eclâmpsia/etiologia , Adolescente , Adulto , Estudos de Casos e Controles , Estudos Epidemiológicos , Feminino , Humanos , Hipertensão Induzida pela Gravidez/epidemiologia , Iowa/epidemiologia , Modelos Logísticos , Pré-Eclâmpsia/epidemiologia , Gravidez , Fatores de Risco , Adulto Jovem
14.
Am J Hypertens ; 29(1): 17-24, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26002928

RESUMO

BACKGROUND: Preeclampsia is a hypertensive complication of pregnancy characterized by novel onset of hypertension after 20 weeks gestation, accompanied by proteinuria. Epidemiological evidence suggests that genetic susceptibility exists for preeclampsia; however, whether preeclampsia is the result of underlying genetic risk for essential hypertension has yet to be investigated. Based on the hypertensive state that is characteristic of preeclampsia, we aimed to determine if established genetic risk scores (GRSs) for hypertension and blood pressure are associated with preeclampsia. METHODS: Subjects consisted of 162 preeclamptic cases and 108 normotensive pregnant controls, all of Iowa residence. Subjects' DNA was extracted from buccal swab samples and genotyped on the Affymetrix Genome-wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA). Missing genotypes were imputed using MaCH and Minimac software. GRSs were calculated for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) using established genetic risk loci for each outcome. Regression analyses were performed to determine the association between GRS and risk of preeclampsia. These analyses were replicated in an independent US population of 516 cases and 1,097 controls of European ancestry. RESULTS: GRSs for hypertension, SBP, DBP, and MAP were not significantly associated with risk for preeclampsia (P > 0.189). The results of the replication analysis also yielded nonsignificant associations. CONCLUSIONS: GRSs for hypertension and blood pressure are not associated with preeclampsia, suggesting that an underlying predisposition to essential hypertension is not on the causal pathway of preeclampsia.


Assuntos
Pressão Sanguínea/fisiologia , Predisposição Genética para Doença , Hipertensão/complicações , Pré-Eclâmpsia/etiologia , Medição de Risco , Determinação da Pressão Arterial , Hipertensão Essencial , Feminino , Seguimentos , Genótipo , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Incidência , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/genética , Gravidez , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologia
15.
Vaccine ; 33(20): 2316-21, 2015 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-25835577

RESUMO

OBJECTIVES: Infants are at high risk of developing chronic, life-threatening disease as a result of hepatitis B virus infection. Universal vaccination of infants against hepatitis B virus, before discharge from the hospital after delivery is recommended as a measure to eradicate infection and associated mortality and morbidity. The purpose of this study was to determine rates of perinatal hepatitis B vaccine (Hep B) administration at a tertiary care center in Iowa and to assess the impact of maternal factors on Hep B uptake. METHODS: Data concerning mother-infant pairs that received care at one institution from 1/2009 to 4/1/2013 were extracted from the system's electronic medical record. Characteristics of study participants were compared using chi-square tests. Multivariate logistic regression was used to assess the association between each factor and vaccination status, controlling for other characteristics. RESULTS: Of 5663 mother-infant pairs, 5175 (91.4%) infants received Hep B within 7 days after delivery. The majority of those not vaccinated had a medical indication to delay vaccination. Single women were significantly more likely to have an infant not vaccinated, after adjustment for all other factors. Women of minority groups were significantly less likely to have an infant who lacked Hep B at hospital discharge than Caucasian women. CONCLUSIONS: Significant improvements have occurred in Hep B rates in the state and region. Infants of single mothers may be at the greatest risk for lacking vaccination at hospital discharge.


Assuntos
Vacinas contra Hepatite B/administração & dosagem , Hepatite B/prevenção & controle , Vacinação em Massa/estatística & dados numéricos , Adolescente , Adulto , Grupos de Populações Continentais , Grupos Étnicos , Feminino , Humanos , Lactente , Recém-Nascido , Iowa , Estado Civil , Pessoa de Meia-Idade , Grupos Minoritários , Mães , Alta do Paciente , Gravidez , Estudos Retrospectivos , Centros de Atenção Terciária/estatística & dados numéricos , Fatores de Tempo , Adulto Jovem
16.
J Reprod Immunol ; 109: 74-83, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25721621

RESUMO

Over the past decade, there has been heightened interest in determining if there is an increased risk of adverse reproductive outcomes among women who had a loop electrosurgical excision procedure (LEEP) to remove cervical intraepithelial neoplasia (CIN). The objective of this exploratory study was to determine if the treatment of CIN with a LEEP is associated with changes in cervical soluble immune markers. Cervical cytokine concentrations were measured in women treated with LEEP and a control group of women who had colposcopy only and did not undergo LEEP. Cytokines were examined in cervical secretions collected in Merocel(®) sponges at study entry and at 6-month follow-up. Cytokines were measured using a Luminex 18-plex cytokine bead assay. The mean cytokine levels were not significantly changed from baseline to follow-up in either group, with the exception of TNF-α, which decreased among women who underwent a LEEP. When the mean levels of cytokines of the treated and untreated groups at baseline or follow-up were compared, cytokine levels tended to be lower in the treated group (particularly IFN-γ, IL-6, IL-8, and MCP-1). Findings from adjusted repeated measures analyses revealed no differences between the two groups with regard to changes in cytokine levels over time. Overall, women undergoing a LEEP showed few changes in the cervical microenvironment relative to untreated women. Future studies with additional cervical environment markers and larger sample sizes are needed to determine if a LEEP is associated with dysregulation of the cervical microenvironment.


Assuntos
Neoplasia Intraepitelial Cervical/metabolismo , Neoplasia Intraepitelial Cervical/cirurgia , Colo do Útero/metabolismo , Colo do Útero/cirurgia , Citocinas/metabolismo , Eletrocirurgia , Adolescente , Adulto , Feminino , Humanos
17.
Pediatr Res ; 77(3): 472-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25521918

RESUMO

BACKGROUND: In recent years, increasing numbers of preterm infants have been exposed to inhaled nitric oxide (iNO). This population has decreased methemoglobin (MetHb) reductase activity in their erythrocytes, which may increase the risk of MetHb toxicity. We sought to determine if genetic factors are associated with the observed variance in MetHb levels. METHODS: A population of 127 preterm infants was genotyped for five single-nucleotide polymorphisms (SNPs) in the CYB5A and CYB5R3 genes. iNO dose and levels of MetHb were obtained by chart abstraction. ANOVA was performed to identify genetic associations with MetHb levels. RESULTS: An association was found between the heterozygous genotype (GA) of rs916321 in the CYB5R3 gene and the mean of the first recorded MetHb levels in Caucasian infants (P = 0.01). This result remained significant after adjustment for the iNO dose (P = 0.009), gender (P = 0.03), multiple gestation (P = 0.03), birth weight (P = 0.02), and gestational age (P = 0.02). No significant associations were found with the other SNPs. CONCLUSION: We demonstrate a novel genetic association with neonatal MetHb levels. Identification of genetic risk factors may be useful in determining which preterm infants are most at risk of developing MetHb toxicity with the use of iNO.


Assuntos
Citocromo-B(5) Redutase/genética , Metemoglobina/metabolismo , Óxido Nítrico/farmacologia , Análise de Variância , Citocromo-B(5) Redutase/metabolismo , Citocromos b5/genética , Eritrócitos/efeitos dos fármacos , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Óxido Nítrico/administração & dosagem , Polimorfismo de Nucleotídeo Único/genética
18.
Am J Hypertens ; 28(7): 915-23, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25523295

RESUMO

BACKGROUND: Large epidemiologic studies support the role of dyslipidemia in preeclampsia; however, the etiology of preeclampsia or whether dyslipidemia plays a causal role remains unclear. We examined the association between the genetic predisposition to dyslipidemia and risk of preeclampsia using validated genetic markers of dyslipidemia. METHODS: Preeclampsia cases (n = 164) and normotensive controls (n = 110) were selected from live birth certificates to nulliparous Iowa women during the period August 2002 to May 2005. Disease status was verified by medical chart review. Genetic predisposition to dyslipidemia was estimated by 4 genetic risk scores (GRS) (total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglycerides) on the basis of established loci for blood lipids. Logistic regression analyses were used to evaluate the relationships between each of the 4 genotype scores and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. RESULTS: The GRS related to higher levels of TC, LDL-C, and triglycerides demonstrated no association with the risk of preeclampsia in either the Iowa or replication population. The GRS related to lower HDL-C was marginally associated with an increased risk for preeclampsia (odds ratio (OR) = 1.03, 95% confidence interval (CI) = 0.99-1.07; P = 0.10). In the independent replication population, the association with the HDL-C GRS was also marginally significant (OR = 1.03, 95% CI: 1.00-1.06; P = 0.04). CONCLUSIONS: Our data suggest a potential effect between the genetic predisposition to dyslipidemic levels of HDL-C and an increased risk of preeclampsia, and, as such, suggest that dyslipidemia may be a component along the causal pathway to preeclampsia.


Assuntos
HDL-Colesterol/sangue , Dislipidemias/complicações , Dislipidemias/genética , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/etiologia , Adulto , Biomarcadores/sangue , Pressão Sanguínea , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , LDL-Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/diagnóstico , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Iowa , Modelos Logísticos , Análise Multivariada , Razão de Chances , Fenótipo , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/fisiopatologia , Gravidez , Fatores de Risco , Triglicerídeos/sangue , Adulto Jovem
19.
J Matern Fetal Neonatal Med ; 28(6): 679-84, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24893615

RESUMO

OBJECTIVE: A counterintuitive interaction between smoking during pregnancy and preeclampsia on birth weight for gestational age (BWGA) outcomes was recently reported. In this report, we examine the relationship between these factors in a well-documented study population with exposure data on trimester of maternal smoking. METHODS: Preeclamptic (n = 238), gestational hypertensive (n = 219), and normotensive women (n = 342) were selected from live-births to nulliparous Iowa women. Disease status was verified by medical chart review, and smoking exposure was assessed by self-report. Fetal growth was assessed as z-score of BWGA. Multiple linear regression was used to test for the association of maternal smoking and preeclampsia with BWGA z-score. RESULTS: There was no interaction between smoking with preeclampsia or gestational hypertension on fetal growth. BWGA z-scores were significantly lower among women with preeclampsia and those who smoked any time during pregnancy (ß = -0.33, p = <0.0001 and ß = -0.25, p = 0.05) compared to normotensive and non-smoking women, respectively. Infants of women with gestational hypertension were comparable in size to infants born to normotensive women. CONCLUSIONS: Women who developed preeclampsia and those who smoked during pregnancy delivered infants that were significantly smaller than infants of women who did not develop preeclampsia and non-smoking women, respectively.


Assuntos
Peso ao Nascer , Desenvolvimento Fetal/fisiologia , Idade Gestacional , Pré-Eclâmpsia/epidemiologia , Fumar/epidemiologia , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Retardo do Crescimento Fetal/epidemiologia , Humanos , Hipertensão Induzida pela Gravidez/epidemiologia , Recém-Nascido , Iowa/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Fumar/efeitos adversos , Adulto Jovem
20.
Cancer Epidemiol ; 38(5): 538-43, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25096278

RESUMO

BACKGROUND: We aimed to determine the association between self-reported birth weight and incident cancer in the Women's Health Initiative Observational Study cohort, a large multiethnic cohort of postmenopausal women. METHODS: 65,850 women reported their birth weight by category (<6 lbs, 6-7 lbs 15 oz, 8-9 lbs 15 oz, and ≥10 lbs). All self-reported, incident cancers were adjudicated by study staff. We used Cox proportional hazards regression to estimate crude and adjusted hazard ratios (aHR) for associations between birth weight and: (1) all cancer sites combined, (2) gynecologic cancers, and (3) several site-specific cancer sites. RESULTS: After adjustments, birth weight was positively associated with the risk of lung cancer (p=0.01), and colon cancer (p=0.04). An inverse trend was observed between birth weight and risk for leukemia (p=0.04). A significant trend was not observed with breast cancer risk (p=0.67); however, women born weighing ≥10 lbs were less likely to develop breast cancer compared to women born between 6 lbs-7 lbs 15 oz (aHR 0.77, 95% CI 0.63, 0.94). CONCLUSION: Birth weight category appears to be significantly associated with the risk of any postmenopausal incident cancer, though the direction of the association varies by cancer type.


Assuntos
Peso ao Nascer/fisiologia , Neoplasias/epidemiologia , Pós-Menopausa , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias/patologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Risco
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