RESUMO
BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus marked by eosinophilic infiltration. Cumulative evidence indicates that the risk of EoE involves the complex interplay of both genetic and environmental factors. Because only a few genetic loci have been identified in EoE, the genetic underpinning of EoE remains largely elusive. OBJECTIVE: We sought to identify genetic loci associated with EoE. METHODS: Four EoE cohorts were genotyped using the Illumina single nucleotide polymorphism array platform, totaling 1,930 cases and 13,634 controls of European ancestry. Genotype imputation was performed with the Michigan Imputation Server using the Trans-Omics for Precision Medicine reference panel including whole-genome sequencing data from more than 100,000 individuals. Meta-analysis was conducted to identify potential novel genetic loci associated with EoE. RESULTS: Our study identified 11 new genome-wide significant loci, of which 6 are common variant loci, including 5q31.1 (rs2106984, P = 4.16 × 10-8; odds ratio [OR], 1.26, RAD50), 15q22.2 (rs2279293, P = 1.23 × 10-10; OR, 0.69, RORA), and 15q23 (rs56062135, P = 2.91 × 10-11; OR, 1.29, SMAD3), which have been previously associated with allergic conditions. Interestingly, a low-frequency synonymous mutation within the MATN2 gene was identified as the most significant single nucleotide polymorphism at the 8q22.1 locus. We also identified 5 sex-specific loci in the EoE cases, including an inflammatory bowel disease-associated locus at 9p24.1 (rs62541556, P = 4.4 × 10-8; OR, 1.11, JAK2). CONCLUSIONS: Our findings demonstrate shared genetic underpinnings between EoE and other immune-mediated diseases and provide novel candidate genes for therapeutic target identification and prioritization.
Assuntos
Esofagite Eosinofílica , Esofagite Eosinofílica/genética , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND AND AIMS: Elevated alanine aminotransferase (ALT >40 IU/mL) is a marker of liver injury but provides little insight into etiology. We aimed to identify and stratify risk factors associated with elevated ALT in a randomly selected population with a high prevalence of elevated ALT (39%), obesity (49%) and diabetes (30%). METHODS: Two machine learning methods, the support vector machine (SVM) and Bayesian logistic regression (BLR), were used to capture risk factors in a community cohort of 1532 adults from the Cameron County Hispanic Cohort (CCHC). A total of 28 predictor variables were used in the prediction models. The recently identified genetic marker rs738409 on the PNPLA3 gene was genotyped using the Sequenom iPLEX assay. RESULTS: The four major risk factors for elevated ALT were fasting plasma insulin level and insulin resistance, increased BMI and total body weight, plasma triglycerides and non-HDL cholesterol, and diastolic hypertension. In spite of the highly significant association of rs738409 in females, the role of rs738409 in the prediction model is minimal, compared to other epidemiological risk factors. Age and drug and alcohol consumption were not independent determinants of elevated ALT in this analysis. CONCLUSIONS: The risk factors most strongly associated with elevated ALT in this population are components of the metabolic syndrome and point to nonalcoholic fatty liver disease (NAFLD). This population-based model identifies the likely cause of liver disease without the requirement of individual pathological diagnosis of liver diseases. Use of such a model can greatly contribute to a population-based approach to prevention of liver disease.
Assuntos
Alanina Transaminase/sangue , Feminino , Humanos , Masculino , Americanos Mexicanos , Fatores de Risco , Máquina de Vetores de Suporte , TexasRESUMO
PURPOSE: This study examined genetic associations of patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and liver aminotransferases in an extensively documented, randomly recruited Mexican American population at high risk of liver disease. METHODS: Two single nucleotide polymorphisms (SNP) in the PNPLA3 gene (i.e., rs738409 and rs2281135) were genotyped in 1532 individuals. Population stratification was corrected by the genotyping of 103 ancestry informative markers (AIMs) for Mexican Americans. RESULTS: Both PNPLA3 SNPs showed highly significant association with alanine aminotransferase (ALT) levels, but was also, in males, associated with aspartate aminotransferase (AST) levels. Haplotypic association test of the two SNPs suggested stronger genetic association with rs738409 than rs2281135. Obvious sex effects were observed: rs738409-sex interaction in ALT levels P = 8.37 x 10(-4); rs738409-sex interaction in AST levels P = 5.03 x 10(-3). CONCLUSIONS: This population study highlights a sex-specific association of PNPLA3 polymorphisms and elevated liver enzymes in a population-based study, independent of common pathological factors of the metabolic syndrome. The strong genetic association found in women ≤ 50 years old, but not in women > 50 years old, suggests that sex hormones may mediate the sex effect.
Assuntos
Alanina Transaminase/genética , Aspartato Aminotransferases/metabolismo , Lipase/genética , Hepatopatias/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Caracteres Sexuais , Adulto , Fatores Etários , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/genética , Feminino , Genótipo , Humanos , Lipase/metabolismo , Fígado/metabolismo , Hepatopatias/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Americanos Mexicanos , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: An elevated insulin resistance index (homeostasis model assessment of insulin resistance [HOMA-IR]) is more commonly seen in the Mexican American population than in European populations. We report quantitative ancestral effects within a Mexican American population, and we correlate ancestral components with HOMA-IR. RESEARCH DESIGN AND METHODS: We performed ancestral analysis in 1,551 participants of the Cameron County Hispanic Cohort by genotyping 103 ancestry-informative markers (AIMs). These AIMs allow determination of the percentage (0-100%) ancestry from three major continental populations, i.e., European, African, and Amerindian. RESULTS: We observed that predominantly Amerindian ancestral components were associated with increased HOMA-IR (ß = 0.124, P = 1.64 × 10(-7)). The correlation was more significant in males (Amerindian ß = 0.165, P = 5.08 × 10(-7)) than in females (Amerindian ß = 0.079, P = 0.019). CONCLUSIONS: This unique study design demonstrates how genomic markers for quantitative ancestral information can be used in admixed populations to predict phenotypic traits such as insulin resistance.
Assuntos
Resistência à Insulina/fisiologia , Feminino , Genótipo , Humanos , Resistência à Insulina/genética , Masculino , Americanos Mexicanos/genética , Americanos Mexicanos/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente PrincipalAssuntos
Indígena Americano ou Nativo do Alasca/genética , Doenças Metabólicas/genética , Americanos Mexicanos/genética , Pesquisa Translacional Biomédica , Doenças Genéticas Inatas/etnologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Variação Genética , Genoma Humano , Humanos , Doenças Metabólicas/patologiaRESUMO
BACKGROUND AND AIMS: Obesity is increasingly a health problem and a risk factor for diabetes in young Mexican-American populations. Genetic association studies in older, mostly non-Hispanic populations have reported that polymorphisms in the candidate genes HSD11B1, CRP, ADIPOQ, PPARG, ANKK1, ABCC8 and SERPINF1 are associated with obesity or diabetes. We analyzed the polymorphisms rs846910, rs1205, rs1501299, rs1801282, rs1800497, rs757110 and rs1136287 in these candidate genes, for association with obesity and metabolic traits in a young Mexican-American population from south Texas. METHODS: Genotyping of the seven common SNPs were performed by allelic discrimination assays in 448 unrelated Mexican Americans (median age = 16 years) from south Texas. χ(2) tests and regression analyses using additive models were used for genetic association analyses adjusting for covariates; p values were corrected for multiple testing by permutation analyses. RESULTS: rs1800497 (ANKK1) shows association with waist circumference (p = 0.009) and retains the association (p = 0.03) after permutation testing. Analysis of metabolic quantitative traits shows that rs846910 (HSD11B1) was associated with HOMA-IR (p = 0.04) and triglycerides (p = 0.03), and rs1205 (CRP) with HOMA-IR (p = 0.03) and fasting glucose levels (p = 0.007). However, the quantitative traits associations are not maintained after permutation analysis. None of the other SNPs in this study showed associations with obesity or metabolic traits in this young Mexican-American population. CONCLUSIONS: We report a potential association between rs1800497 (linked to changes in brain dopamine receptor levels) and central obesity in a young Mexican-American population.
Assuntos
Predisposição Genética para Doença , Americanos Mexicanos/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adolescente , DNA/genética , DNA/isolamento & purificação , Humanos , TexasRESUMO
OBJECTIVE: Adiponectin and leptin play critical roles in the development of Metabolic Syndrome (MetS). This study was designed to assess the feasibility of using circulating levels of adiponectin and leptin for the early diagnosis of MetS. METHODS: A cross-sectional study was performed using data from 367 participants randomly selected from a well-characterized cohort of Mexican-Americans living at the US-Mexico border. RESULTS: Significant differences in circulating levels of adiponectin and leptin were observed between males and females. Adiponectin/leptin correlated significantly with MetS in this population. A receiver-operator characteristic (ROC) analysis demonstrated that adiponectin/leptin showed a high sensitivity (70.9% for males, 78.9% for females) and specificity (90.2% for males and 69.8% for females) for the diagnosis of MetS, independent of BMI measurements. CONCLUSION: These data support the central role of adiponectin and leptin in MetS, and demonstrated that adiponectin/leptin can be used as a highly sensitive and specific biomarker for MetS.
Assuntos
Adiponectina/sangue , Leptina/sangue , Síndrome Metabólica/sangue , Adulto , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Americanos Mexicanos , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
OBJECTIVE: Previous studies in mice and humans observed down-regulation of the gene expression of ATP6V1H associated with type 2 diabetes. This study identified prospectively changes in ATP6V1H expression before and after overt diabetes. METHODS: Expression of ATP6V1H in peripheral blood was compared pre and post development of diabetes in nine individuals. RESULTS: Considerable variation of ATP6V1H mRNA levels was observed between different individuals. However, within each individual the decrease in expression of ATP6V1H with the development of diabetes was highly statistically significant. CONCLUSIONS: ATP6V1H may represent a critical molecular mechanism involved in the development of type 2 diabetes and its compilations through its important regulatory effect on vacuolar-ATPase activity.
Assuntos
Diabetes Mellitus Tipo 2/genética , Regulação para Baixo , Adulto , Idoso , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Masculino , Americanos Mexicanos , Pessoa de Meia-Idade , Projetos Piloto , RNA Mensageiro/biossíntese , Risco , Distribuição Tecidual , Transcriptoma , Estados Unidos/epidemiologia , Estados Unidos/etnologia , ATPases Vacuolares Próton-Translocadoras/sangue , ATPases Vacuolares Próton-Translocadoras/genéticaRESUMO
OBJECTIVE: The lack of standardized reference range for the homeostasis model assessment-estimated insulin resistance (HOMA-IR) index has limited its clinical application. This study defines the reference range of HOMA-IR index in an adult Hispanic population based with machine learning methods. METHODS: This study investigated a Hispanic population of 1854 adults, randomly selected on the basis of 2000 Census tract data in the city of Brownsville, Cameron County. Machine learning methods, support vector machine (SVM) and Bayesian Logistic Regression (BLR), were used to automatically identify measureable variables using standardized values that correlate with HOMA-IR; K-means clustering was then used to classify the individuals by insulin resistance. RESULTS: Our study showed that the best cutoff of HOMA-IR for identifying those with insulin resistance is 3.80. There are 39.1% individuals in this Hispanic population with HOMA-IR>3.80. CONCLUSIONS: Our results are dramatically different using the popular clinical cutoff of 2.60. The high sensitivity and specificity of HOMA-IR>3.80 for insulin resistance provide a critical fundamental for our further efforts to improve the public health of this Hispanic population.