Comparison between two analytic strategies to detect linkage to obesity with genetically determined age of onset: the Framingham Heart Study

BACKGROUND: Genes have been found to influence the age of onset of several diseases and traits. The occurrence of many chronic diseases, obesity included, appears to be strongly age-dependent. However, an analysis of potential age of onset genes for obesity has yet to be reported. There are at least two analytic methods for determining an age of onset gene. The first is to consider a person affected if they possess the trait before a certain age (an early age of onset phenotype). The second is to define the phenotype based on the residual from a survival analysis. RESULTS: No regions provided evidence for linkage at the more stringent level of p < 0.001. However, five regions showed consistent suggestive evidence for linkage (one marker with p < 0.01 and a second contiguous marker at p < 0.05). These regions were chromosome 1 (280–294 cM) and chromosome 16 (56–64 cM) for overweight using the survival analysis residual method and chromosome 13 (102–122 cM), chromosome 17 (127–138 cM), and chromosome 19 (23–47 cM) for obese before age 35. CONCLUSION: Only one region (chromosome 19 at 23–47 cM) showed somewhat consistent results between the two analytic methods. Potential reasons for inconsistent results between the two methods, as well as their strengths and weaknesses, are discussed. The use of both methods together to explore the genetics of the age of onset of a trait may prove to be beneficial in determining a gene that is linked only to an early age of onset phenotype versus one that determines age of onset through all age groups

Insulin clearance and the incidence of type 2 diabetes in Hispanics and African Americans: the IRAS Family Study.

ObjectiveWe aimed to identify factors that are independently associated with the metabolic clearance rate of insulin (MCRI) and to examine the association of MCRI with incident type 2 diabetes in nondiabetic Hispanics and African Americans.Research design and methodsWe investigated 1,116 participants in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study with baseline examinations from 2000 to 2002 and follow-up examinations from 2005 to 2006. Insulin sensitivity (S(I)), acute insulin response (AIR), and MCRI were determined at baseline from frequently sampled intravenous glucose tolerance tests. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin. Incident diabetes was defined as fasting glucose ≥126 mg/dL or antidiabetic medication use by self-report.ResultsWe observed that S(I) and HDL cholesterol were independent positive correlates of MCRI, whereas fasting insulin, fasting glucose, subcutaneous adipose tissue, visceral adipose tissue, and AIR were independent negative correlates (all P &lt; 0.05) at baseline. After 5 years of follow-up, 71 (6.4%) participants developed type 2 diabetes. Lower MCRI was associated with a higher risk of incident diabetes after adjusting for demographics, lifestyle factors, HDL cholesterol, indexes of obesity and adiposity, and insulin secretion (odds ratio 2.01 [95% CI 1.30-3.10], P = 0.0064, per one-SD decrease in loge-transformed MCRI).ConclusionsOur data showed that lower MCRI predicts the incidence of type 2 diabetes

Environmental Trigger(s) of Type 1 Diabetes: Why Is It So Difficult to Identify?

Non peer reviewe

Plasma 25-Hydroxyvitamin D Concentration and Risk of Islet Autoimmunity

We examined the association between plasma 25-hydroxyvitamin D [25(OH)D] concentration and islet autoimmunity (IA) and whether vitamin D gene polymorphisms modify the effect of 25(OH)D on IA risk. We followed 8,676 children at increased genetic risk of type 1 diabetes at six sites in the U.S. and Europe. We defined IA as positivity for at least one autoantibody (GADA, IAA, or IA-2A) on two or more visits. We conducted a risk set sampled nested case-control study of 376 IA case subjects and up to 3 control subjects per case subject. 25(OH)D concentration was measured on all samples prior to, and including, the first IA positive visit. Nine polymorphisms in VDR, CYP24A, CYP27B1, GC, and RXRA were analyzed as effect modifiers of 25(OH)D. Adjusting for HLA-DR-DQ and ancestry, higher childhood 25(OH)D was associated with lower IA risk (odds ratio = 0.93 for a 5 nmol/L difference; 95% CI 0.89, 0.97). Moreover, this association was modified by VDR rs7975232 (interaction P = 0.0072), where increased childhood 25(OH)D was associated with a decreasing IA risk based upon number of minor alleles: 0 (1.00; 0.93, 1.07), 1 (0.92; 0.89, 0.96), and 2 (0.86; 0.80, 0.92). Vitamin D and VDR may have a combined role in IA development in children at increased genetic risk for type 1 diabetes.Peer reviewe

Effects of Gluten Intake on Risk of Celiac Disease: a case-control study on a Swedish birth cohort.

It is not clear how intake of gluten during infancy affects subsequent risk of celiac disease. We investigated whether gluten intake before 2 years of age increases risk for celiac disease in genetically susceptible children

Genome-Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium.

ObjectivePopulations 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.MethodsLevels 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.ResultsIn 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.ConclusionsPNPLA3, 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

Components of Metabolic Syndrome and 5-Year Chance in Insulin Clearance - The Resistance Atherosclerosis Study (IRAS)

Aims Cross-sectional evidence indicates that abdominal adiposity, hypertension, dyslipidaemia and glycaemia are associated with reduced metabolic clearance rate of insulin (MCRI). Little is known about the progression of MCRI and whether components of metabolic syndrome are associated with the change in MCRI. In this study, we examined the association between components of metabolic syndrome and the 5-year change of MCRI. Methods At baseline and 5-year follow-up, we measured fasting plasma triglycerides (TG), high-density lipoprotein (HDL) cholesterol, blood pressure (BP), waist circumference (WC) and fasting blood glucose (FBG) in 784 non-diabetic participants in the Insulin Resistance Atherosclerosis Study. MCRI, insulin sensitivity (SI) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests. Results We observed a 29% decline of MCRI at follow-up. TG, systolic BP and WC at baseline were inversely associated with a decline of MCRI regression models adjusted for age, sex, ethnicity, smoking, alcohol consumption, energy expenditure, family history of diabetes, BMI, SI and AIR [β = −0.057 (95% confidence interval, CI: −0.11, −0.0084) for TG, β = −0.0019 (95% CI: −0.0035, −0.00023) for systolic BP and β  = −0.0084 (95% CI: −0.013, −0.0039) for WC; all p \u3c 0.05]. Higher HDL cholesterol at baseline was associated with an increase in MCRI [multivariable-adjusted β = 0.0029 (95% CI: 0.0010, 0.0048), p = 0.002]. FBG at baseline was not associated with MCRI at follow-up [multivariable-adjusted β = 0.0014 (95% CI: −0.0026, 0.0029)]. Conclusions MCRI declined progressively over 5 years in a non-diabetic cohort. Components of metabolic syndrome at baseline were associated with a significant change in MCRI

Innovative Test Operations to Support Orion and Future Human Rated Missions

This paper describes how the Orion program is implementing new and innovative test approaches and strategies in an evolving development environment. The early flight test spacecraft are evolving in design maturity and complexity requiring significant changes in the ground test operations for each mission. The testing approach for EM-2 is planned to validate innovative Orion production acceptance testing methods to support human exploration missions in the future. Manufacturing and testing at Kennedy Space Center in the Neil Armstrong Operations and Checkout facility will provide a seamless transition directly to the launch site avoiding transportation and checkout of the spacecraft from other locations

Plasma adiponectin levels are associated with circulating inflammatory cytokines in autoantibody positive first-degree relatives of rheumatoid arthritis patients

Background Extra-articular manifestations of rheumatoid arthritis (RA), potentially due to systemic inflammation, include cardiovascular disease and sarcopenic obesity. Adiponectin, an adipose-derived cytokine, has been implicated in inflammatory processes in RA, but little is known regarding its association with inflammation in a pre-clinical period. Therefore, we investigated whether adiponectin was associated with inflammatory markers in individuals at risk for RA, and whether RA-related autoimmunity modifies these associations. Methods We analyzed samples from 144 first-degree relatives (FDRs) of RA probands, of whom 23 were positive for anti-cyclic citrullinated peptide antibody and/or ≥ 2 rheumatoid factor isotypes (IgM, IgG or IgA). We called this phenotype the ‘high risk autoantibody profile (HRP)’ as it has been shown in prior work to be >96% specific for future RA. We measured adiponectin, cytokines, and high-sensitivity C-reactive protein (hsCRP). Using linear mixed effects models, we evaluated interaction between HRP positivity and adiponectin on inflammatory markers, adjusting for age, sex, ethnicity, body mass index, pack-years smoking, and use of cholesterol-lowering medications. Results In everyone, adiponectin concentration was inversely associated with hsCRP and IL-1β in adjusted models, where a 1% higher adiponectin was associated with a 26% lower hsCRP (p = 0.04) and a 26% lower IL-1β (p = 0.04). Significant interactions between HRP and adiponectin for associations with GM-CSF, IL-6, and IL-9 were detected in fully adjusted models (p = 0.0006, p = 0.006, p = 0.01, respectively). In HRP positive FDRs but not HRP negative FDRs, a 1% higher adiponectin was associated with 97% higher GM-CSF, 73% higher IL-6, and 54% higher IL-9 concentrations. Conclusions Adiponectin associates with inflammatory markers, and these associations differ in individuals with a high-risk autoantibody profile compared with those without. The interaction between adiponectin and autoimmunity warrants further investigation into the potential systemic effects of RA-related autoantibodies and adiponectin on inflammation in the absence of clinically apparent RA

Prenatal Maternal Anxiety in South Asia: A Rapid Best-Fit Framework Synthesis

Background: Most research efforts toward prenatal maternal anxiety has been situated in high-income countries. In contrast, research from low- and middle-income countries has focused on maternal depression and prenatal maternal anxiety in low- and middle-income countries remains poorly understood.Objectives: To examine whether dimensions and attributes of current maternal anxiety assessment tools appropriately capture South Asia women's experiences of perinatal distress during pregnancy.Design: We conducted a rapid review with best fit framework synthesis, as we wished to map study findings to an a priori framework of dimensions measured by prenatal maternal anxiety tools.Data Sources: We searched MEDLINE, PsycINFO, and CINAHL and gray literature in November 2016. Studies were included if published in English, used any study design, and focused on women's experiences of prenatal/antenatal anxiety in South Asia.Review Methods: Study quality was assessed using the Effective Public Health Practice Project Quality Assessment Tool and Critical Appraisal Skills Programme Qualitative Checklist. Study findings were extracted to an a priori framework derived from pregnancy-related anxiety tools.Results: From 4,177 citations, 9 studies with 19,251 women were included. Study findings mapped to the a priori framework apart from body image. A new theme, gender inequality, emerged from the studies and was overtly examined through gender disparity, gender preference of fetus, or domestic violence.Conclusions: Gender inequality and societal acceptability of domestic violence in South Asian women contextualizes the experience of prenatal maternal anxiety. Pregnancy-related anxiety tools should include domains related to gender inequality to better understand their influence on pregnancy outcomes