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1.
Artigo em Inglês | MEDLINE | ID: mdl-31688074
2.
Am J Hum Genet ; 105(4): 706-718, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564435

RESUMO

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

3.
Fertil Steril ; 112(4): 655-656, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351701
4.
Diabetes Care ; 42(9): 1675-1683, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31227582

RESUMO

OBJECTIVE: There are no specific treatment guidelines for diabetes of the exocrine pancreas. High-quality studies are warranted to investigate whether the use of antidiabetic medications has survival benefit in individuals with diabetes of the exocrine pancreas. The objective was to determine the risk of mortality associated with the use of antidiabetic medications in individuals with pancreatic cancer-related diabetes (PCRD) and postpancreatitis diabetes mellitus (PPDM). RESEARCH DESIGN AND METHODS: Nationwide pharmaceutical dispensing data (2006-2015) linked to hospital discharge data were used to identify 1,862 individuals with PCRD or PPDM. Multivariable Cox regression analysis was conducted, and the risk was expressed as hazard ratios and 95% CIs. A 6-month lag was used to minimize reverse causality. RESULTS: In individuals with PCRD, ever users of metformin (adjusted hazard ratio 0.54; 95% CI 0.46-0.63) and ever users of insulin (adjusted hazard ratio 0.46; 95% CI 0.39-0.55) had significantly lower risks of mortality compared with never users of antidiabetic medications. These associations attenuated toward the null with the use of a 6-month lag. In individuals with PPDM, ever users of metformin had a significantly lower risk of mortality (adjusted hazard ratio 0.51; 95% CI 0.36-0.70), whereas ever-users of insulin did not have a significantly changed risk of mortality (adjusted hazard ratio 0.75; 95% CI 0.49-1.14) compared with never users of antidiabetic medications. The former association remained significant with the use of a 6-month lag. CONCLUSIONS: Metformin promotes a survival benefit in individuals with PPDM but not PCRD. Reverse causality may play a role in the association between insulin use and mortality in PCRD.

5.
Obesity (Silver Spring) ; 27(8): 1331-1337, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31219225

RESUMO

OBJECTIVE: Populations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma-glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry. METHODS: Levels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort GWAS of individuals of Mexican American ancestry was performed. Single-nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta-analysis. RESULTS: In the PNPLA3 gene, rs4823173 (P = 3.44 × 10-10 ), rs2896019 (P = 7.29 × 10-9 ), and rs2281135 (P = 8.73 × 10-9 ) were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10-8 , P = 1.98 × 10-7 , and P = 1.81 × 10-7 , respectively). The strong correlation (r2 = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT. CONCLUSIONS: PNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry.

6.
Clin Transl Gastroenterol ; 10(7): e00057, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31232720

RESUMO

INTRODUCTION: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM. We approached this question from a unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. METHODS: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. RESULTS: The mean GRS was identical between 321 subjects with CP-DM and 423 subjects with T2DM (66.53 vs 66.42, P = 0.95), and the GRS of both diabetic groups was significantly higher than that of nondiabetic controls (n = 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreas-specific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. DISCUSSION: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.

7.
J Transl Med ; 17(1): 176, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126299

RESUMO

BACKGROUND: Lifestyle intervention may have a critical effect on the association between genetics and obesity. This study aimed to investigate changes in FTO and IRX3 gene expression in obese and overweight male adolescents undergoing a lifestyle intervention and the role of FTO genotype in this interaction. METHODS: This study was a field trial of 62 adolescents from boys' high schools in Tehran, Iran. Two schools were randomly allocated as the intervention (n = 30) and control (n = 32) schools. The rs9930506 SNP in FTO was genotyped at baseline and the level of FTO and IRX3 expression in peripheral blood mononuclear cells (PBMCs). Anthropometric measurements were assessed at baseline and after 18 weeks of intensive lifestyle intervention. RESULTS: Our results showed that IRX3 expression in the intervention group was significantly up-regulated compared to baseline (P = 0.007) and compared to the control group (P = 0.011).The intervention group had significantly up-regulated transcripts of IRX3 only in rs9930506 risk allele carriers of the intervention group compared to risk allele carriers of the control group (P = 0.017). Moreover, our data showed that the FTO expression was up-regulated in AA genotype carriers and down-regulated in AG/GG genotype carriers (P = 0.017). CONCLUSION: Lifestyle modification may exert its effects on obesity through changes in the expression level of the FTO and IRX3 genes. However, FTO genotype plays a role in the extent of the effect of lifestyle changes on gene expression. Further studies are crucial to have a better understanding of the interaction between lifestyle, genetics and anthropometric measurements. Trial registration This paper reports a comprehensive intervention study (Interactions of Genetics, Lifestyle and Anthropometrics study or IGLA study), which is retrospectively registered in the Iranian Registry of Clinical Trials as IRCT2016020925699N2. Date registered: April 24, 2016. ( https://www.irct.ir/searchresult.php?id=25699&number=2 ).

8.
Obesity (Silver Spring) ; 27(3): 434-443, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30801985

RESUMO

OBJECTIVE: Aging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-associated insulin resistance is due to increased adiposity or other age-related factors. To address this question, the impact of aging on insulin sensitivity was investigated independently of changes in body composition. METHODS: Cohorts of mice aged 4 to 8 months ("young") and 18 to 27 months ("aged") exhibiting similar body composition were characterized for glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analyses. The relationship between aging and insulin resistance in humans was investigated in 1,250 nondiabetic Mexican Americans who underwent hyperinsulinemic-euglycemic clamps. RESULTS: In mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. While aging did not diminish glucose tolerance, hyperinsulinemic-euglycemic clamps demonstrated impaired insulin sensitivity and reduced insulin clearance in aged mice on chow and high-fat diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican American males. CONCLUSIONS: This study demonstrates that in addition to altered body composition, adiposity-independent mechanisms also contribute to aging-associated insulin resistance in mice and humans.

9.
Fertil Steril ; 111(3): 535-546, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30611556

RESUMO

OBJECTIVE: To identify differences in the transcriptomic profiles during placentation from pregnancies conceived spontaneously vs. those with infertility using non-in vitro fertilization (IVF) fertility treatment (NIFT) or IVF. DESIGN: Cohort study. SETTING: Academic medical center. PATIENT(S): Women undergoing chorionic villus sampling at gestational age 11-13 weeks (n = 141), with pregnancies that were conceived spontaneously (n = 74), with NIFT (n = 33), or with IVF (n = 34), resulting in the delivery of viable offspring. INTERVENTION(S): Collection of chorionic villus samples from women who conceived spontaneously, with NIFT, or with IVF for gene expression analysis using RNA sequencing. MAIN OUTCOME MEASURE(S): Baseline maternal, paternal, and fetal demographics, maternal medical conditions, pregnancy complications, and outcomes. Differential gene expression of first-trimester placenta. RESULT(S): There were few differences in the transcriptome of first-trimester placenta from NIFT, IVF, and spontaneous pregnancies. There was one protein-coding differentially expressed gene (DEG) between the spontaneous and infertility groups, CACNA1I, one protein-coding DEG between the spontaneous and IVF groups, CACNA1I, and five protein-coding DEGs between the NIFT and IVF groups, SLC18A2, CCL21, FXYD2, PAEP, and DNER. CONCLUSION(S): This is the first and largest study looking at transcriptomic profiles of first-trimester placenta demonstrating similar transcriptomic profiles in pregnancies conceived using NIFT or IVF and spontaneous conceptions. Gene expression differences found to be highest in the NIFT group suggest that the underlying infertility, in addition to treatment-related factors, may contribute to the observed gene expression profiles.


Assuntos
Infertilidade/genética , Infertilidade/terapia , Placentação/genética , Técnicas de Reprodução Assistida , Transcriptoma , Adulto , Feminino , Fertilidade/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Infertilidade/diagnóstico , Infertilidade/fisiopatologia , Nascimento Vivo , Masculino , Pessoa de Meia-Idade , Gravidez , Resultado do Tratamento
10.
PLoS Genet ; 14(12): e1007813, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30566500

RESUMO

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.


Assuntos
Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo
11.
Artigo em Inglês | MEDLINE | ID: mdl-30445606

RESUMO

Context: Maternal metabolic status reflects underlying physiological changes in the maternal-placental-fetal unit, which can identify contributors to adverse pregnancy outcomes associated with infertility and treatments utilized. Objective: To determine if maternal metabolomic profiles are different between spontaneous pregnancies and pregnancies conceived with fertility treatments, including in vitro fertilization (IVF) and non-IVF fertility treatments (NIFT) that may explain differences in pregnancy outcomes. Design: Metabolon® metabolomic analysis and ELISA assays for 17-ß-estradiol and progesterone were performed during the late first trimester from spontaneous conceptions and those conceived through fertility treatments, including NIFT and IVF. Setting: Academic institution. Subjects: The SMAART (Spontaneous/Medically Assisted/ART) cohort which consisted of 409 women, 208 conceived spontaneously, 201 with infertility that used fertility treatments (90 NIFT, 111 IVF). Intervention(s): Mode of conception (Spontaneous, NIFT and IVF). Main Outcome Measure(s): 806 metabolites within 8 super pathways, 17-ß-estradiol and progesterone levels in maternal plasma in the late first trimester. Results: Metabolomic differences in the lipid super pathway (steroid metabolites, lipids with DHA acyl chains, acyl cholines), xanthine and benzoate metabolites (p<0.05) were significantly different among the Spontaneous and Infertility groups, with greatest differences between Spontaneous and IVF groups. 17-ß-estradiol and progesterone were significantly elevated in the Infertility group, with greatest differences among the Spontaneous and IVF groups. Conclusions: Metabolomic profiles differ between spontaneous and infertility pregnancies, likely driven by IVF. Elevated steroids and their metabolites are likely due to increased hormone production from placenta reprogrammed from fertility treatments which may contribute to adverse outcomes associated with infertility and treatments utilized.

12.
Am J Mens Health ; : 1557988318808119, 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30373434

RESUMO

The role of FTO genotype in the effect of FTO gene expression level on change in body mass index and body composition has not been studied. This study aimed to investigate the role of FTO genotype in the association between change in the expression level of the FTO gene with changes in anthropometric measurements in obese and overweight adolescent boys. Eighty-four boys aged 12 to 16 years participated in this longitudinal study. A bioimpedance analyzer (BIA) was used to estimate percentage of body fat (%body fat) and percentage of skeletal muscle (%skeletal muscle). The FTO gene expression level in peripheral blood mononuclear cells (PBMCs) was assessed using quantitative Real Time PCR (qPCR). The DNA samples were genotyped for the FTO gene polymorphisms by DNA sequencing. All measurements were performed at baseline and after intervention. A significant association was observed between the level of gene expression and %skeletal muscle. The gene expression fold change was significantly associated with change in %skeletal muscle in AA or AG genotype carriers (ß = 0.34, p = .02). No significant association was detected between the change in FTO gene expression with change in anthropometric indices in GG genotype carriers. In conclusion, the association between FTO gene expression and body composition can be influenced by FTO genotype. Future studies are required to assess the interactions between FTO genotype, FTO gene expression in different tissues, and body composition.

13.
Pancreas ; 47(10): 1239-1243, 2018 Nov/Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30325863

RESUMO

Pancreatogenic diabetes mellitus is most commonly the result of chronic pancreatitis but can also occur secondary to pancreatic cancer. The early identification of pancreatogenic diabetes and distinction from the more prevalent type 2 diabetes are clinically significant; however, currently, there is no validated method to differentiate these diabetes subtypes. We describe a study, "Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: the DETECT study," that seeks to address this knowledge gap. The DETECT study is a multicenter study that will examine differences in hormone and glucose excursions after a mixed meal test. The study will also create a biorepository that will be used to evaluate novel diagnostic biomarkers for differentiating these diabetes subtypes.

14.
Clin Endocrinol (Oxf) ; 88(6): 848-855, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29575061

RESUMO

OBJECTIVE: Patients with type 2 diabetes mellitus have an increased risk of fracture despite normal or increased bone mineral density (BMD). Studies on the relationship of glucose homeostasis with BMD phenotypes have been inconclusive because distinguishing the roles of insulin resistance and hyperglycaemia in bone remodelling is challenging. In this study, we sought to define the relationship of site-specific BMD with glucose homeostasis traits and anthropometric traits. DESIGN/PATIENTS/MEASUREMENTS: In a cross-sectional study, we examined 787 subjects from the Mexican-American Coronary Artery Disease (MACAD) cohort who had undergone euglycaemic-hyperinsulinaemic clamps, oral glucose tolerance testing and dual X-ray absorptiometry. Glucose homeostasis traits included insulinogenic index (IGI30), insulin sensitivity (M value), insulin clearance (MCRI), fasting insulin, fasting glucose and 2-hour glucose. Univariate and multivariate analyses were performed to assess the association of glucose homeostasis and anthropometric traits with site-specific BMD. RESULTS: Two-hour glucose was negatively associated with arm BMD in women, which remained significant in multivariate analysis (ß = -.15, P = .0015). Positive correlations between fasting insulin and BMD at weight-bearing sites, including pelvis (ß = .22, P < .0001) and legs (ß = .17, P = .001) in women and pelvis (ß = .33, P < .0001) in men, lost significance after multivariate adjustment. Lean mass exhibited strong independent positive associations with BMD at multiple sites in both sexes. CONCLUSION: Our findings suggest that (i) anabolic effects of insulin might work via mechanical loading from lean mass; (ii) a direct negative effect of increasing glucose might be more prominent at cortical-bone-rich sites in women; and (iii) lean mass is a strong positive predictor of bone mass.

15.
J Clin Endocrinol Metab ; 103(5): 1877-1888, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29546329

RESUMO

Context: Metabolomics provides a biochemical fingerprint that, when coupled with clinical phenotypes, can provide insight into physiological processes. Objective: Survey metabolites associated with dynamic and basal measures of glucose homeostasis. Design: Analysis of 733 plasma metabolites from the Insulin Resistance Atherosclerosis Family Study. Setting: Community based. Participants: One thousand one hundred eleven Mexican Americans. Main Outcome: Dynamic measures were obtained from the frequently sampled intravenous glucose tolerance test and included insulin sensitivity and acute insulin response to glucose. Basal measures included homeostatic model assessment of insulin resistance and ß-cell function. Results: Insulin sensitivity was associated with 99 metabolites (P < 6.82 × 10-5) explaining 28% of the variance (R2adj) beyond 28% by body mass index. Beyond branched chain amino acids (BCAAs; P = 1.85 × 10-18 to 1.70 × 10-5, R2adj = 8.1%) and phospholipids (P = 3.51 × 10-17 to 3.00 × 10-5, R2adj = 14%), novel signatures of long-chain fatty acids (LCFAs; P = 4.49 × 10-23 to 4.14 × 10-7, R2adj = 11%) were observed. Conditional analysis suggested that BCAA and LCFA signatures were independent. LCFAs were not associated with homeostatic model assessment of insulin resistance (P > 0.024). Acute insulin response to glucose was associated with six metabolites; glucose had the strongest association (P = 5.68 × 10-16). Homeostatic model assessment of ß-cell function had significant signatures from the urea cycle (P = 9.64 × 10-14 to 7.27 × 10-6, R2adj = 11%). Novel associations of polyunsaturated fatty acids (P = 2.58 × 10-13 to 6.70 × 10-5, R2adj = 10%) and LCFAs (P = 9.06 × 10-15 to 3.93 × 10-7, R2adj = 10%) were observed with glucose effectiveness. Assessment of the hyperbolic relationship between insulin sensitivity and secretion through the disposition index revealed a distinctive signature of polyunsaturated fatty acids (P = 1.55 × 10-12 to 5.81 × 10-6; R2adj = 3.8%) beyond that of its component measures. Conclusions: Metabolomics reveals distinct signatures that differentiate dynamic and basal measures of glucose homeostasis and further identifies new metabolite classes associated with dynamic measures, providing expanded insight into the metabolic basis of insulin resistance.

16.
J Pediatr Gastroenterol Nutr ; 66(5): 789-796, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29470286

RESUMO

BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) disproportionately affects Hispanic boys. Further, obesity and insulin resistance are major risk factors for NAFLD. No gene localization studies had been performed on children with biopsy-proven NAFLD. This study aims to identify genomic variants associated with increased adiposity and insulin resistance in a population of children with varying histologic severity of NAFLD. METHODS: We conducted a genome-wide association scan (GWAS) including 624,297 single-nucleotide polymorphisms (SNPs) distributed among all 22 autosomal chromosomes in 234 Hispanic boys (up to 18 years of age) who were consecutively recruited in a prospective cohort study in the Nonalcoholic Steatohepatitis Clinical Research Network Studies. Traits were examined quantitatively using linear regression. SNPs with P value <10 and a minor allele frequency >5% were considered potentially significant. RESULTS: Evaluated subjects had a median age of 12.0 years, body mass index (BMI) of 31.4, and hemoglobin A1C (Hgb A1C) of 5.3. The prevalence of NAFL, borderline NASH, and definite NASH were 23%, 53%, and 22%, respectively. The GWAS identified 10 SNPs that were associated with BMI z score, 6 within chromosome 2, and 1 within CAMK1D, which has a potential role in liver gluconeogenesis. In addition, the GWAS identified 9 novel variants associated with insulin resistance: HOMA-IR (6) and HbA1c (3). CONCLUSIONS: This study of Hispanic boys with biopsy-proven NAFLD with increased risk for the metabolic syndrome revealed novel genetic variants that are associated with obesity and insulin resistance.

17.
Biol Sex Differ ; 9(1): 4, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29335024

RESUMO

BACKGROUND: Development of the placenta during the late first trimester is critical to ensure normal growth and development of the fetus. Developmental differences in this window such as sex-specific variation are implicated in later placental disease states, yet gene expression at this time is poorly understood. METHODS: RNA-sequencing was performed to characterize the transcriptome of 39 first trimester human placentas using chorionic villi following genetic testing (17 females, 22 males). Gene enrichment analysis was performed to find enriched canonical pathways and gene ontologies in the first trimester. DESeq2 was used to find sexually dimorphic gene expression. Patient demographics were analyzed for sex differences in fetal weight at time of chorionic villus sampling and birth. RESULTS: RNA-sequencing analyses detected 14,250 expressed genes, with chromosome 19 contributing the greatest proportion (973/2852, 34.1% of chromosome 19 genes) and Y chromosome contributing the least (16/568, 2.8%). Several placenta-enriched genes as well as histone-coding genes were identified to be unique to the first trimester and common to both sexes. Further, we identified 58 genes with significantly different expression between males and females: 25 X-linked, 15 Y-linked, and 18 autosomal genes. Genes that escape X inactivation were highly represented (59.1%) among X-linked genes upregulated in females. Many genes differentially expressed by sex consisted of X/Y gene pairs, suggesting that dosage compensation plays a role in sex differences. These X/Y pairs had roles in parallel, ancient canonical pathways important for eukaryotic cell growth and survival: chromatin modification, transcription, splicing, and translation. CONCLUSIONS: This study is the first characterization of the late first trimester placenta transcriptome, highlighting similarities and differences among the sexes in ongoing human pregnancies resulting in live births. Sexual dimorphism may contribute to pregnancy outcomes, including fetal growth and birth weight, which was seen in our cohort, with males significantly heavier than females at birth. This transcriptome provides a basis for development of early diagnostic tests of placental function that can indicate overall pregnancy heath, fetal-maternal health, and long-term adult health.

18.
Lancet Diabetes Endocrinol ; 6(3): 223-236, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28919064

RESUMO

Genome-wide association studies (GWAS) for BMI, waist-to-hip ratio, and other adiposity traits have identified more than 300 single-nucleotide polymorphisms (SNPs). Although there is reason to hope that these discoveries will eventually lead to new preventive and therapeutic agents for obesity, this will take time because such developments require detailed mechanistic understanding of how an SNP influences phenotype (and this information is largely unavailable). Fortunately, absence of functional information has not prevented GWAS findings from providing insights into the biology of obesity. Genes near loci regulating total body mass are enriched for expression in the CNS, whereas genes for fat distribution are enriched in adipose tissue itself. Gene by environment and lifestyle interaction analyses have revealed that our increasingly obesogenic environment might be amplifying genetic risk for obesity, yet those at highest risk could mitigate this risk by increasing physical activity and possibly by avoiding specific dietary components. GWAS findings have also been used in mendelian randomisation analyses probing the causal association between obesity and its many putative complications. In supporting a causal association of obesity with diabetes, coronary heart disease, specific cancers, and other conditions, these analyses have clinical relevance in identifying which outcomes could be preventable through weight loss interventions.


Assuntos
Interação Gene-Ambiente , Estudos de Associação Genética , Predisposição Genética para Doença , Genética Populacional , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Humanos , Obesidade/epidemiologia
19.
J Acad Nutr Diet ; 118(4): 555-567, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28919082

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person-years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined.

20.
Pregnancy Hypertens ; 10: 7-9, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29153693

RESUMO

MicroRNA (miRNA) expression has not been studied during placentation in pregnancies that develop preeclampsia, when it likely manifests. In this pilot study, miRNA expression in late first trimester placenta from four pregnancies that developed severe preeclampsia matched to controls using the Affymetrix GeneChip® miRNA 3.0 Array identified 9 miRNAs differentially expressed, with miR-202-3p the most significantly overexpressed in severe preeclampsia. Real-time reverse transcription polymerase chain reaction (qRT-PCR) confirmed overexpression of miR-202-3p in a validation cohort, with a 7-fold increase in pregnancies that developed severe preeclampsia (p≤0.05). Differential miRNA expression, specifically miR-202-3p, is seen in first trimester placenta in severe preeclampsia.


Assuntos
MicroRNAs/genética , Placenta/metabolismo , Pré-Eclâmpsia/genética , Primeiro Trimestre da Gravidez , Regulação para Cima , Adulto , Estudos de Casos e Controles , Amostra da Vilosidade Coriônica , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , MicroRNAs/metabolismo , Projetos Piloto , Pré-Eclâmpsia/metabolismo , Gravidez , Reação em Cadeia da Polimerase em Tempo Real , Índice de Gravidade de Doença
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