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1.
Nature ; 610(7933): 704-712, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36224396

RESUMO

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.


Assuntos
Estatura , Mapeamento Cromossômico , Polimorfismo de Nucleotídeo Único , Humanos , Estatura/genética , Frequência do Gene/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Haplótipos/genética , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Europa (Continente)/etnologia , Tamanho da Amostra , Fenótipo
2.
Nature ; 582(7811): 240-245, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499647

RESUMO

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.


Assuntos
Povo Asiático/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Aldeído-Desidrogenase Mitocondrial/genética , Alelos , Anquirinas/genética , Índice de Massa Corporal , Estudos de Casos e Controles , Europa (Continente)/etnologia , Proteínas do Olho/genética , Ásia Oriental/etnologia , Feminino , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/análise , Fatores de Transcrição/genética , Transcrição Gênica , Proteína Homeobox SIX3
3.
BMC Womens Health ; 24(1): 546, 2024 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-39363289

RESUMO

BACKGROUND: Women who reach menarche and menopause at earlier ages have been shown to be at increased risk for numerous conditions including cardiovascular disease, cancer, depression, and obesity; however, risk factors for earlier ages of menarche and menopause are not fully understood. Therefore, we aimed to perform a retrospective investigation of the associations between a personal birthweight and/or being born preterm and the age of and menarche and menopause and related events in the Women's Health Initiative, a large, racially and ethnically diverse cohort of postmenopausal women. METHODS: At study entry, women reported their birthweight by category (< 6 lbs., 6-7 lbs. 15 oz, 8-9 lbs. 15 oz, or ≥ 10 lbs.) and preterm birth status (4 or more weeks premature). Ages at events related to menarche and menopause were also self-reported. Linear regression and logistic regression models were used to estimate unadjusted and adjusted effect estimates (ß) and odds ratios (OR), respectively (n ≤ 86,857). Individuals born preterm were excluded from all birthweight analyses. RESULTS: After adjustments, individuals born weighing < 6lbs. were more likely to reach natural menopause at an earlier age (adjusted ß=-0.361, SE = 0.09, P = < 0.001) and have a shorter reproductive window (adjusted ß = -0.287, SE = 0.10, p < 0.004) compared to individuals weighing 6-7 lbs. 15 oz. Individuals born preterm were also more likely to reach natural menopause at an earlier age (adjusted ß=-0.506, SE = 0.16, P = 0.001) and have a shorter reproductive window (adjusted ß = -0.418, SE = 0.17, p < 0.006). CONCLUSIONS: These findings raise concerns that, as more preterm and low birthweight individuals survive to adulthood, the prevalence of earlier-onset menarche and menopause may increase. Clinical counseling and interventions aimed at reducing the incidence of preterm and low birthweight births, as well as intensification of lifestyle modifications to reduce CVD risk among women with these early-life risk factors, should be prioritized.


Assuntos
Peso ao Nascer , Menarca , Menopausa , Nascimento Prematuro , Humanos , Feminino , Menarca/fisiologia , Nascimento Prematuro/epidemiologia , Peso ao Nascer/fisiologia , Menopausa/fisiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Etários , Fatores de Risco , Idoso , Recém-Nascido , Gravidez
4.
Am J Hum Genet ; 106(1): 112-120, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31883642

RESUMO

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.


Assuntos
Povo Asiático/genética , População Negra/genética , Proteína C-Reativa/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , População Branca/genética , Sequenciamento Completo do Genoma/métodos , Estudos de Coortes , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação
5.
PLoS Genet ; 16(9): e1009019, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32915782

RESUMO

Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin: ADIPOQ, CDH13, IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r2<0.01). Two loci exhibited allelic heterogeneity, ADIPOQ and CDH13. Of seven association signals at the ADIPOQ locus, two signals colocalized with adipose tissue expression quantitative trait loci (eQTLs) for three transcripts: trait-increasing alleles at one signal were associated with increased ADIPOQ and LINC02043, while trait-increasing alleles at the other signal were associated with decreased ADIPOQ-AS1. In reporter assays, adiponectin-increasing alleles at two signals showed corresponding directions of effect on transcriptional activity. Putative mechanisms for the seven ADIPOQ signals include a missense variant (ADIPOQ G90S), a splice variant, a promoter variant, and four enhancer variants. Of two association signals at the CDH13 locus, the first signal consisted of promoter variants, including the lead adipose tissue eQTL variant for CDH13, while a second signal included a distal intron 1 enhancer variant that showed ~2-fold allelic differences in transcriptional reporter activity. Fine-mapping and experimental validation demonstrated that multiple, distinct association signals at these loci can influence multiple transcripts through multiple molecular mechanisms.


Assuntos
Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Alelos , Caderinas/genética , Caderinas/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Frequência do Gene/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Síndrome Metabólica/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
6.
Am J Hum Genet ; 105(4): 773-787, 2019 10 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.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/genética , Expressão Gênica , Obesidade/genética , Alelos , Índice de Massa Corporal , Finlândia , Estudo de Associação Genômica Ampla , Humanos , Masculino , Locos de Características Quantitativas , Relação Cintura-Quadril
7.
Am J Hum Genet ; 105(1): 15-28, 2019 07 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.


Assuntos
Adiponectina/genética , Tecido Adiposo/patologia , Exoma/genética , Predisposição Genética para Doença , Lipídeos/análise , Obesidade/etiologia , Polimorfismo de Nucleotídeo Único , Tecido Adiposo/metabolismo , Adolescente , Adulto , Negro ou Afro-Americano/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Hispânico ou Latino/genética , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/patologia , Fenótipo , Locos de Características Quantitativas , População Branca/genética , Adulto Jovem
8.
BMC Pregnancy Childbirth ; 22(1): 232, 2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35317778

RESUMO

BACKGROUND: Epidemiological research of events related to labor and delivery frequently uses maternal interview or birth certificates as a primary method of data collection; however, the validity of these data are rarely confirmed. This study aimed to examine the validity of birth certificate data and maternal interview of maternal demographics and events related to labor and delivery with data abstracted from medical records in a US setting. METHODS: Birth certificate and maternal recall data from the Iowa Health in Pregnancy Study (IHIPS), a population-based case-control study of risk factors for preterm and small-for-gestational age births, were linked to medical record data to assess the validity of events that occurred during labor and delivery along with reported maternal demographics. Sensitivity, specificity, positive and negative predictive values, and kappa scores were calculated. RESULTS: Postpartum maternal recall and birth certificate data were excellent for infant characteristics (birth weight, gestational age, infant sex) and variables related to labor and delivery (mode of delivery) when compared with medical records. Birth certificate data for labor induction had low sensitivity (46.3%) and positive predictive value (18.3%) compared to medical records. Compared to maternal interview, birth certificate data also had poor agreement for smoking and alcohol use during pregnancy. Agreement between all three methods of data collection was very low for pregnancy weight gain (kappa = 0.07-0.08). CONCLUSIONS: Maternal interview and birth certificate data can be a valid source for collecting data on infant characteristics and events that occurred during labor and delivery. However, caution should be used if solely using birth certificate data to gather data on maternal demographic and/or lifestyle factors.


Assuntos
Declaração de Nascimento , Parto Obstétrico , Trabalho de Parto , Prontuários Médicos , Rememoração Mental , Mães/psicologia , Consumo de Bebidas Alcoólicas , Estudos de Casos e Controles , Feminino , Humanos , Entrevistas como Assunto , Iowa , Trabalho de Parto Induzido , Gravidez , Reprodutibilidade dos Testes , Fumar
9.
Curr Diab Rep ; 21(6): 17, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33846905

RESUMO

PURPOSE OF REVIEW: Prevalence of type 2 diabetes (T2D) and progression of complications differ between worldwide populations. While obesity is a major contributing risk factor, variations in physiological manifestations, e.g., developing T2D at lower body mass index in some populations, suggest other contributing factors. Early T2D genetic associations were mostly discovered in European ancestry populations. This review describes the progression of genetic discoveries associated with T2D in individuals of East Asian ancestry in the last 10 years and highlights the shared genetic susceptibility between the population groups and additional insights into genetic contributions to T2D. RECENT FINDINGS: Through increased sample size and power, new genetic associations with T2D were discovered in East Asian ancestry populations, often with higher allele frequencies than European ancestry populations. As we continue to generate maps of T2D-associated variants across diverse populations, there will be a critical need to expand and diversify other omics resources to enable integration for clinical translation.


Assuntos
Diabetes Mellitus Tipo 2 , Povo Asiático/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética
10.
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
11.
Bioinformatics ; 35(22): 4724-4729, 2019 11 01.
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.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Software
12.
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 , Povo Asiático/genética , Colesterol/metabolismo , Etnicidade , 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 , População Branca/genética
14.
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 Físico , 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
16.
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
17.
Am J Epidemiol ; 180(4): 346-58, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24989239

RESUMO

Published reports examining lipid levels during pregnancy and preeclampsia have been inconsistent. The objective of this meta-analysis was to test the association between preeclampsia and maternal total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and triglyceride levels measured during pregnancy. We conducted a systematic search for studies published between the index date until July 2013 reporting maternal lipid levels in women with preeclampsia and normotensive pregnant women. Seventy-four studies met all eligibility criteria and were included in the meta-analysis. Weighted mean differences in lipid levels were calculated using a random-effects model. Statistical heterogeneity was investigated using the I(2) statistic. Meta-regression was used to identify sources of heterogeneity. Preeclampsia was associated with elevated total cholesterol, non-HDL-C, and triglyceride levels, regardless of gestational age at the time of blood sampling, and with lower levels of HDL-C in the third trimester. A marginal association was found with LDL-C levels. Statistical heterogeneity was detected in all analyses. Meta-regression analyses suggested that differences in body mass index (weight (kg)/height (m)(2)) across studies may be partially responsible for the heterogeneity in the triglyceride and LDL-C analyses. This systematic review and meta-analysis demonstrates that women who develop preeclampsia have elevated levels of total cholesterol, non-HDL-C, and triglycerides during all trimesters of pregnancy, as well as lower levels of HDL-C during the third trimester.


Assuntos
Hiperlipidemias/complicações , Pré-Eclâmpsia/etiologia , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Hiperlipidemias/sangue , Pré-Eclâmpsia/sangue , Gravidez , Fatores de Risco , Triglicerídeos/sangue
18.
HGG Adv ; 5(1): 100252, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-37859345

RESUMO

Previous genome-wide association studies (GWASs) for adiponectin, a complex trait linked to type 2 diabetes and obesity, identified >20 associated loci. However, most loci were identified in populations of European ancestry, and many of the target genes underlying the associations remain unknown. We conducted a cross-ancestry adiponectin GWAS meta-analysis in ≤46,434 individuals from the Metabolic Syndrome in Men (METSIM) cohort and the ADIPOGen and AGEN consortiums. We combined study-specific association summary statistics using a fixed-effects, inverse variance-weighted approach. We identified 22 loci associated with adiponectin (p < 5×10-8), including 15 known and seven previously unreported loci. Among individuals of European ancestry, Genome-wide Complex Traits Analysis joint conditional analysis (GCTA-COJO) identified 14 additional distinct signals at the ADIPOQ, CDH13, HCAR1, and ZNF664 loci. Leveraging the cross-ancestry data, FINEMAP + SuSiE identified 45 causal variants (PP > 0.9), which also exhibited potential pleiotropy for cardiometabolic traits. To prioritize target genes at associated loci, we propose a combinatorial likelihood scoring formalism (Gene Priority Score [GPScore]) based on measures derived from 11 gene prioritization strategies and the physical distance to the transcription start site. With GPScore, we prioritize the 30 most probable target genes underlying the adiponectin-associated variants in the cross-ancestry analysis, including well-known causal genes (e.g., ADIPOQ, CDH13) and additional genes (e.g., CSF1, RGS17). Functional association networks revealed complex interactions of prioritized genes, their functionally connected genes, and their underlying pathways centered around insulin and adiponectin signaling, indicating an essential role in regulating energy balance in the body, inflammation, coagulation, fibrinolysis, insulin resistance, and diabetes. Overall, our analyses identify and characterize adiponectin association signals and inform experimental interrogation of target genes for adiponectin.


Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , Masculino , Humanos , Adiponectina/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença/genética , Síndrome Metabólica/genética
19.
Cell Metab ; 2024 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-39383866

RESUMO

Endoplasmic reticulum (ER) and inflammatory stress responses contribute to islet dysfunction in type 2 diabetes (T2D). Comprehensive genomic understanding of these human islet stress responses and whether T2D-associated genetic variants modulate them is lacking. Here, comparative transcriptome and epigenome analyses of human islets exposed ex vivo to these stressors revealed 30% of expressed genes and 14% of islet cis-regulatory elements (CREs) as stress responsive, modulated largely in an ER- or cytokine-specific fashion. T2D variants overlapped 86 stress-responsive CREs, including 21 induced by ER stress. We linked the rs6917676-T T2D risk allele to increased islet ER-stress-responsive CRE accessibility and allele-specific ß cell nuclear factor binding. MAP3K5, the ER-stress-responsive putative rs6917676 T2D effector gene, promoted stress-induced ß cell apoptosis. Supporting its pro-diabetogenic role, MAP3K5 expression correlated inversely with human islet ß cell abundance and was elevated in T2D ß cells. This study provides genome-wide insights into human islet stress responses and context-specific T2D variant effects.

20.
medRxiv ; 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39072045

RESUMO

Discerning the mechanisms driving type 2 diabetes (T2D) pathophysiology from genome-wide association studies (GWAS) remains a challenge. To this end, we integrated omics information from 16 multi-tissue and multi-ancestry expression, protein, and metabolite quantitative trait loci (QTL) studies and 46 multi-ancestry GWAS for T2D-related traits with the largest, most ancestrally diverse T2D GWAS to date. Of the 1,289 T2D GWAS index variants, 716 (56%) demonstrated strong evidence of colocalization with a molecular or T2D-related trait, implicating 657 cis-effector genes, 1,691 distal-effector genes, 731 metabolites, and 43 T2D-related traits. We identified 773 of these cis- and distal-effector genes using either expression QTL data from understudied ancestry groups or inclusion of T2D index variants enriched in underrepresented populations, emphasizing the value of increasing population diversity in functional mapping. Linking these variants, genes, metabolites, and traits into a network, we elucidated mechanisms through which T2D-associated variation may impact disease risk. Finally, we showed that drugs targeting effector proteins were enriched in those approved to treat T2D, highlighting the potential of these results to prioritize drug targets for T2D. These results represent a leap in the molecular characterization of T2D-associated genetic variation and will aid in translating genetic findings into novel therapeutic strategies.

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