We assessed the effects of non-HLA gene polymorphisms on the risk of islet autoimmunity (IA) and progression to type 1 diabetes in the Diabetes Autoimmunity Study in the Young. A total of 1,743 non-Hispanic, white children were included: 861 first-degree relatives and 882 general population children identified as having high-risk HLA-DR/DQ genotypes for type 1 diabetes. Of those, 109 developed IA and 61 progressed to diabetes. Study participants were genotyped for 20 non-HLA polymorphisms, previously confirmed as type 1 diabetes susceptibility loci. PTPN22 and UBASH3A predicted both IA and diabetes in regression models controlling for family history of type 1 diabetes and presence of HLA-DR3/4-DQB1*0302 genotype. In addition, PTPN2 predicted IA whereas INS predicted type 1 diabetes. The final multivariate regression models for both IA and type 1 diabetes included PTPN22, UBASH3A, and INS, in addition to family history of type 1 diabetes and HLA-DR3/4. In general population children, the most frequent combinations including these five significant predictors conferred hazard ratio of up to 13 for IA and >40 for type 1 diabetes. Non-HLA susceptibility alleles may help estimate risk for development of type 1 diabetes in the general population. These findings require replication in different populations.
We investigated whether omega-3 fatty acid intake and erythrocyte membrane omega-3 fatty acid levels are associated with conversion to type 1 diabetes in children with islet autoimmunity (IA).
The Diabetes Autoimmunity Study in the Young is following children at increased genetic risk for type 1 diabetes for the development of persistent IA, as defined as being positive for glutamic acid decarboxylase 65, i, or insulin autoantibodies on two consecutive visits, and then for the development of type 1 diabetes, as diagnosed by a physician. One hundred and sixty-seven children with persistent IA were followed for a mean of 4.8 yr, and 45 of these developed type 1 diabetes at a mean age of 8.7 yr. Erythrocyte membrane fatty acids (as a percent of total lipid) and dietary fatty acid intake (estimated via food frequency questionnaire) were analyzed as time-varying covariates in proportional hazards survival analysis, with follow-up time starting at detection of the first autoantibody.
Neither dietary intake of omega-3 fatty acids nor omega-6 fatty acids were associated with conversion to type 1 diabetes, adjusting for human leukocyte antigen (HLA)-DR, family history of type 1 diabetes, age at first IA positivity, maternal age, maternal education, and maternal ethnicity. Adjusting for HLA-DR, family history of type 1 diabetes and age at first IA positivity, omega-3 and omega-6 fatty acid levels of erythrocyte membranes were not associated with conversion to type 1 diabetes.
In this observational study, omega-3 fatty acid intake and status are not associated with conversion to type 1 diabetes in children with IA.
dietary intake; IA; omega-3 fatty acids; type 1 diabetes mellitus
To examine whether oral contraceptive use is associated with the presence of serum rheumatoid factor in women of reproductive age without rheumatoid arthritis.
304 women selected from parents of children who were at increased risk of developing type 1 diabetes were studied, because they were enriched with the human leucocyte antigen‐DR4 allele, a susceptibility marker for both type 1 diabetes and rheumatoid arthritis. Participants visited a clinic where blood was drawn for rheumatoid factor testing, and exposure data were collected via questionnaires. A medical history and joint examination were performed to rule out rheumatoid arthritis. Participants and examiners were unaware of the participants' rheumatoid factor status at the time of examination and questionnaire.
Use of oral contraceptives at any time was inversely associated with rheumatoid factor positivity (adjusted odds ratio (OR) 0.2, 95% confidence interval (CI) 0.07 to 0.52) independent of age, education and smoking. Smoking ⩾20 pack‐years was also associated with rheumatoid factor positivity (adjusted OR 56.38, 95% CI 4.31 to 736.98) compared with never smoking. Smoking 1–19 pack‐years was not associated with a positive rheumatoid factor.
Our results suggest that oral contraceptive use, and possibly cigarette smoking, act early in the development of the immune dysregulation that occurs in rheumatoid arthritis.
A recent meta-analysis of 13 prospective studies reported that higher levels of adiponectin were significantly associated with lower risk of type 2 diabetes. Most previous studies, however, were limited in their ability to adjust for appropriate confounding variables. Our objective, therefore, was to study this association after adjustment for directly measured adiposity and insulin sensitivity, expressed as the insulin sensitivity index (SI).
RESEARCH DESIGN AND METHODS
The study included 1,096 Hispanic and African American participants free of diabetes at baseline (2000–2002) who returned for follow-up after 5 years. SI was determined from frequently sampled intravenous glucose tolerance tests with minimal model analysis. Visceral adipose tissue (VAT) area was determined by computed tomography. Diabetes and impaired fasting glucose (IFG) were defined using American Diabetes Association criteria. Multivariate generalized estimating equation logistic regression models were used to account for correlations within families.
A total of 82 subjects met criteria for incident diabetes. After adjustment for age, sex, ethnicity, and smoking, adiponectin was significantly inversely associated with diabetes (odds ratio [OR] 0.54 per 1 SD difference [95% CI 0.38–0.76]). The association remained significant after additional adjustment in individual models for BMI, homeostasis model assessment of insulin resistance, or VAT (all P < 0.05). However, adiponectin was no longer associated in separate models adjusted for SI or IFG (OR 0.81 [0.56–1.16] and 0.75 [0.53–1.06], respectively).
Adiponectin was inversely associated with incident diabetes after adjustment for conventional anthropometric and metabolic variables or VAT. Adjustment for detailed measures of SI attenuated this relationship, however, suggesting that the link between adiponectin and diabetes may operate at least in part through insulin resistance.
To examine associations between exposure to maternal diabetes in utero and body mass index (BMI) growth trajectories from birth through 13 years of age among a diverse cohort of youth.
Mixed linear effects models were constructed to assess differences in BMI and BMI growth velocity from birth through 13 years of age for 95 subjects exposed to diabetes in utero and 409 unexposed subjects enrolled in a retrospective cohort study.
The overall BMI growth trajectory (adjusted for sex and race/ethnicity) was not significantly different for exposed and unexposed subjects from birth through 26 months of age (p=0.48). However, the overall growth trajectory from 27 months of age through 13 years differed by exposure status (p=0.008), adjusted for sex and race/ethnicity. The difference was primarily due to a significantly higher BMI growth velocity among exposed youth between 10–13 years, increasing by 4.56 kg/m2 compared to 3.51 kg/m2 in the unexposed (p=0.005). Control for demographic variables, socioeconomic factors and maternal pre-pregnancy BMI did not alter the observed associations.
Exposure to maternal diabetes in utero accelerates BMI growth in late childhood thus increasing long-term obesity risk.
Gestational diabetes; fetal overnutrition; fetal exposure to diabetes; childhood obesity; childhood BMI; growth trajectory
To evaluate whether breastfeeding attenuates increased childhood adiposity associated with exposure to diabetes in utero.
RESEARCH DESIGN AND METHODS
Retrospective cohort study of 89 children exposed to diabetes in utero and 379 unexposed youth with measured BMI, waist circumference, skinfolds, visceral (VAT) and subcutaneous (SAT) abdominal fat. A measure of breast milk–months was derived from maternal self-report and used to categorize breastfeeding status as low (<6) and adequate (≥6 breast milk–months). Multiple linear regression was used to model the relationship between exposure to diabetes in utero and offspring adiposity outcomes among youth stratified according to breastfeeding status.
Adequate (vs. low) breastfeeding status was associated with significantly lower BMI, waist circumference, SAT, and VAT at ages 6–13 years. Among youth in the low breastfeeding category, exposure to diabetes in utero was associated with a 1.7 kg/m2 higher BMI (P = 0.03), 5.8 cm higher waist circumference (P = 0.008), 6.1 cm2 higher VAT (P = 0.06), 44.6 cm2 higher SAT (P = 0.03), and 0.11 higher ratio of subscapular-to-triceps skinfold ratio (P = 0.008). Among those with adequate breastfeeding in infancy, the effect of prenatal exposure to diabetes on childhood adiposity outcomes was not significant.
Adequate breastfeeding protects against childhood adiposity and reduces the increased adiposity levels associated with exposure to diabetes in utero. These data provide support for mothers with diabetes during pregnancy to breastfeed their infants in order to reduce the risk of childhood obesity.
To investigate whether enterovirus infections predict progression to type 1 diabetes in genetically predisposed children repeatedly positive for islet autoantibodies.
RESEARCH DESIGN AND METHODS
Since 1993, the Diabetes and Autoimmunity Study in the Young (DAISY) has followed 2,365 genetically predisposed children for islet autoimmunity and type 1 diabetes. Venous blood and rectal swabs were collected every 3–6 months after seroconversion for islet autoantibodies (against GAD, insulin, or insulinoma-associated antigen-2 [IA-2]) until diagnosis of diabetes. Enteroviral RNA in serum or rectal swabs was detected using reverse transcriptase PCR with primers specific for the conserved 5′ noncoding region, detecting essentially all enterovirus serotypes.
Of 140 children who seroconverted to repeated positivity for islet autoantibodies at a median age of 4.0 years, 50 progressed to type 1 diabetes during a median follow-up of 4.2 years. The risk of progression to clinical type 1 diabetes in the sample interval following detection of enteroviral RNA in serum (three diabetes cases diagnosed among 17 intervals) was significantly increased compared with that in intervals following a negative serum enteroviral RNA test (33 cases diagnosed among 1,064 intervals; hazard ratio 7.02 [95% CI 1.95–25.3] after adjusting for number of autoantibodies). Results remained significant after adjustment for ZnT8-autoantibodies and after restriction to various subgroups. Enteroviral RNA in rectal swabs was not predictive of progression to type 1 diabetes. No evidence for viral persistence was found.
This novel observation suggests that progression from islet autoimmunity to type 1 diabetes may increase after an enterovirus infection characterized by the presence of viral RNA in blood.
Pre-clinical rheumatoid arthritis (RA) biomarker elevations were evaluated and utilized to develop a model for the prediction of time to future diagnosis of seropositive RA.
Stored samples from 73 military seropositive RA cases (and controls) from pre-RA diagnosis (mean 2.9 samples per case; samples collected a mean of 6.6 years prior-to-diagnosis) were tested for rheumatoid factor (RF) isotypes, anti-cyclic citrullinated peptide (anti-CCP) antibodies, 14 cytokines/chemokines (bead-based assay) and C-reactive protein (CRP).
Pre-clinical positivity of anti-CCP and/or 2 or more RF isotypes was >96% specific for future RA. In pre-clinical RA, levels of the following were positive in a significantly greater proportion of RA cases versus controls: interleukin (IL)-1α, IL-1β, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, fibroblast growth factor-2, Flt-3 ligand, tumor necrosis factor-α, interferon gamma induced protein-10, granulocyte macrophage colony-stimulating factor, and CRP. Also, increasing numbers of elevated cytokines/chemokines were present in cases nearer to the time of diagnosis. RA cases ≥40 years-old at diagnosis had a higher proportion of samples positive for cytokines/chemokines 5-10 years prior-to-diagnosis, compared to cases <40 at diagnosis (p<0.01). In regression modeling using only case samples positive for autoantibodies highly specific for future RA, increasing numbers of cytokines/chemokines predicted decreased time-to-diagnosis, and the predicted time-to-diagnosis based on cytokines/chemokines was longer in older compared to younger cases.
Autoantibodies, cytokines/chemokines and CRP are elevated in the pre-clinical period of RA development. In pre-clinical autoantibody positive cases, the number of elevated cytokines/chemokines predicts the time of diagnosis of future RA in an age-dependent manner.
pre-clinical rheumatoid arthritis; rheumatoid arthritis; cytokines; chemokines; prediction model
Family-based linkage analysis has been a powerful tool for identification of genes contributing to traits with monogenic patterns of inheritance. These approaches have been of limited utility in identification of genes underlying complex traits. In contrast, searches for common genetic variants associated with complex traits have been highly successful. It is now widely recognized that common variations frequently explain only part of the inter-individual variation in populations. ‘Rare’ genetic variants have been hypothesized to contribute significantly to phenotypic variation in the population. We have developed a combination of family-based linkage, whole-exome sequencing, direct sequencing and association methods to efficiently identify rare variants of large effect. Key to the successful application of the method was the recognition that only a few families in a sample contribute significantly to a linkage signal. Thus, a search for mutations can be targeted to a small number of families in a chromosome interval restricted to the linkage peak. This approach has been used to identify a rare (1.1%) G45R mutation in the gene encoding adiponectin, ADIPOQ. This variant explains a strong linkage signal (LOD > 8.0) and accounts for ∼17% of the variance in plasma adiponectin levels in a sample of 1240 Hispanic Americans and 63% of the variance in families carrying the mutation. Individuals carrying the G45R mutation have mean adiponectin levels that are 19% of non-carriers. We propose that rare variants may be a common explanation for linkage peaks observed in complex trait genetics. This approach is applicable to a wide range of family studies and has potential to be a discovery tool for identification of novel genes influencing complex traits.
Vitamin D deficiency is associated with many adverse health outcomes. There are several well established environmental predictors of vitamin D concentrations, yet studies of the genetic determinants of vitamin D concentrations are in their infancy. Our objective was to conduct a pilot genome-wide association (GWA) study of 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) concentrations in a subset of 229 Hispanic subjects, followed by replication genotyping of 50 single nucleotide polymorphisms (SNPs) in the entire sample of 1,190 Hispanics from San Antonio, Texas and San Luis Valley, Colorado. Of the 309,200 SNPs that met all quality control criteria, three SNPs in high linkage disequilibrium (LD) with each other were significantly associated with 1,25[OH]2D (rs6680429, rs9970802, and rs10889028) at a Bonferroni corrected P-value threshold of 1.62 × 10−7, however none met the threshold for 25[OH]D. Of the 50 SNPs selected for replication genotyping, five for 25[OH]D (rs2806508, rs10141935, rs4778359, rs1507023, and rs9937918) and eight for 1,25[OH]2D (rs6680429, rs1348864, rs4559029, rs12667374, rs7781309, rs10505337, rs2486443, and rs2154175) were replicated in the entire sample of Hispanics (P < 0.01). In conclusion, we identified several SNPs that were associated with vitamin D metabolite concentrations in Hispanics. These candidate polymorphisms merit further investigation in independent populations and other ethnicities.
Vitamin D; 25-hydroxyvitamin D; 1,25-dihydroxyvitamin D; genome-wide association study; Hispanic
In this observational study, we compared erythrocyte membrane fatty acids in infants consuming formula supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA) with those consuming other types of milks. In 110 infants who were participants in a cohort study of otherwise healthy children at risk for developing type 1 diabetes, erythrocytes were collected at approximately 9 months of age, and fatty acid content was measured as a percent of total lipids. Parents reported the type of milk the infants consumed in the month of and prior to erythrocyte collection – infant formula supplemented with ARA and DHA (supplemented formula), formula with no ARA and DHA supplements (non-supplemented formula), breast-milk, or non-supplemented formula plus breast-milk. Membrane DHA (4.42 versus 1.79, p < 0.001) and omega-3 fatty acid (5.81 versus 3.43, p < 0.001) levels were higher in infants consuming supplemented versus non-supplemented formula. Omega-6 fatty acids were lower in infants consuming supplemented versus non-supplemented formula (26.32 versus 29.68, p = 0.023); ARA did not differ between groups. Infants given supplemented formula had higher DHA (4.42 versus 2.81, p < 0.001) and omega-3 fatty acids (5.81 versus 4.45, p = 0.008) than infants drinking breast-milk. In infants whose mothers did not receive any dietary advice, use of supplemented formula is associated with higher omega-3 and lower omega-6 fatty acid status.
Arachidonic Acid; Docosahexaenoic Acid; Breastfeeding; Infant Feeding; Infant Formula; Infant Feeding Behavior
To determine if antibodies against peptidyl arginine deiminase Type 4 (PAD-4) are present in the pre-clinical phase of rheumatoid arthritis (RA), and to compare their appearance to other pre-clinical autoantibodies.
Prediagnosis serum samples from 83 subjects with RA were evaluated for presence of anti-PAD-4 antibody, anti-cyclic citrullinated peptide (anti-CCP) antibody, and rheumatoid factor (RF). In addition, a control cohort (N = 83) matched on age, gender, race, number of samples, and duration of serum storage were tested for antibody against PAD-4 to determine its sensitivity and specificity for future RA.
Fifteen of 83 (18.1%) subjects with RA had at least one prediagnosis sample positive for anti-PAD-4. One of 83 (1.2%) control subjects had at least one sample positive, resulting in a sensitivity and specificity of anti-PAD-4 for the future development of RA of 18.1% and 98.8%, respectively. The mean time of first positivity for anti-PAD-4 was ~4.6 years prior to diagnosis. Anti-PAD-4 positivity was associated with anti-CCP positivity (OR 5.13, 95%CI 1.07–24.5, p = 0.04). In subjects with prediagnosis samples positive for both antibodies, anti-CCP positivity predated anti-PAD-4 in 9 of 13 (69%) cases.
Autoantibodies to PAD-4 are present in the pre-clinical phase of RA in a subset of patients and are associated with anti-CCP positivity. Further exploration is needed regarding the timing of appearance and disease-related effects of PAD-4 autoimmunity.
Rheumatoid arthritis; pre-clinical; peptidyl arginine deiminase type 4; anti-citrullinated peptide antibodies
The purpose of this study was to conduct a scoping review of the literature about the establishment and impact of quality and safety team initiatives in acute care.
Studies were identified through electronic searches of Medline, Embase, CINAHL, PsycINFO, ABI Inform, Cochrane databases. Grey literature and bibliographies were also searched. Qualitative or quantitative studies that occurred in acute care, describing how quality and safety teams were established or implemented, the impact of teams, or the barriers and/or facilitators of teams were included. Two reviewers independently extracted data on study design, sample, interventions, and outcomes. Quality assessment of full text articles was done independently by two reviewers. Studies were categorized according to dimensions of quality.
Of 6,674 articles identified, 99 were included in the study. The heterogeneity of studies and results reported precluded quantitative data analyses. Findings revealed limited information about attributes of successful and unsuccessful team initiatives, barriers and facilitators to team initiatives, unique or combined contribution of selected interventions, or how to effectively establish these teams.
Not unlike systematic reviews of quality improvement collaboratives, this broad review revealed that while teams reported a number of positive results, there are many methodological issues. This study is unique in utilizing traditional quality assessment and more novel methods of quality assessment and reporting of results (SQUIRE) to appraise studies. Rigorous design, evaluation, and reporting of quality and safety team initiatives are required.
Rheumatoid arthritis (RA) likely develops in several phases, beginning with genetic risk, followed by asymptomatic autoimmunity, then finally, clinically-apparent disease. Investigating the phases of disease that exist prior to the onset of symptoms - i.e. the pre-clinical period of RA – will lead to understanding of the important relationships between genetic and environmental factors that may lead to disease, as well as allow for the development of predictive models for disease, and ultimately preventive strategies for RA.
Celiac Disease (CD) is an autoimmune disease triggered by exposure to gluten containing foods. IgA autoantibodies to tissue transglutaminase (TTG) are elevated in CD, but little is known about the gastrointestinal state prior to the appearance of TTG. Antibodies to wheat storage globulin Glo-3A have been studied in type 1 diabetes (T1D), and may be a marker of altered mucosal barrier and/or immune function. In this study, we investigated antibody responses to Glo-3A in CD.
In the Diabetes Autoimmunity Study in the Young (DAISY), children are followed prospectively from birth for the appearance of TTG and CD. 50 cases of CD were frequency-matched with 50 controls on age (of TTG seroconversion in the case), gender, ethnicity, presence of a first degree relative with T1D, and HLA-DR3 genotype. In cases and controls, IgG antibodies to Glo-3A were analyzed in a blinded manner in the sample collected at the time of seroconversion to TTG positivity (or the matched sample in controls) and in all previous samples since birth (mean: 4.5 samples). The association between Glo-3A antibody levels and CD case status was explored using t-tests at the TTG positive visit and when Glo-3A levels were highest and mixed modeling to describe Glo-3A over time.
At the time of first elevated TTG (mean 4.9 years), CD cases had higher Glo-3A antibody levels than controls (13.3±17.2 versus 7.6±11.7, p = 0.005). In both cases and controls, Glo-3A antibodies appear to peak at a mean age of 2.9 years, prior to mean age of initial TTG seroconversion. The peak Glo-3A antibody levels were higher in cases than controls a (25.5±21.8 versus 14.9±18.3 p = 0.0007). Using mixed modeling to account for multiple visits per person, cases had higher levels of Glo-3A antibodies than controls at all ages from birth to TTG seroconversion (β = 0.53, p = 0.002).
Compared to controls, CD cases have higher Glo-3A antibody responses beginning years prior to initial detection of TTG.
celiac disease; risk factors; transglutaminase autoantibodies; Glo-3A wheat globulin
Childhood obesity tracks into adulthood, and may increase diabetes and cardiovascular disease risk in adulthood. Prospective analyses may better define the pathways between early life factors and greater childhood body mass index (BMI), a measure of obesity.
The Diabetes Autoimmunity Study in the Young (DAISY) prospectively follows children from birth that are at increased genetic risk for type 1 diabetes. We examined longitudinal data for 1,178 DAISY subjects (mean age at last follow-up: 6.59 years (range: 2.0–11.5 years). Birth size and diabetes exposure in utero were collected in the enrollment interview. Infant diet information was collected via interviews throughout infancy. Infant weight gain and childhood BMI were measured at clinic visits.
Female gender, diabetes exposure in utero, larger size for gestational age, shorter breastfeeding duration, and more rapid infant weight gain predicted higher childhood BMI. Formal mediation analysis suggests the effect of shorter breastfeeding duration on childhood BMI may be mediated by more rapid infant weight gain. Also, the effect of diabetes exposure in utero on childhood BMI may be mediated by larger size for gestational age.
We identified strong interrelationships between early life factors and childhood BMI. Understanding these pathways may aid childhood obesity prevention efforts.
Breastfeeding duration; Infant weight gain; Diabetes exposure in utero; Birth size; Mediator
Gene–environment interactions are likely to be involved in the susceptibility to multifactorial diseases but are difficult to detect. Available methods usually concentrate on some particular genetic and environmental factors. In this paper, we propose a new method to determine whether a given exposure is susceptible to interact with unknown genetic factors. Rather than focusing on a specific genetic factor, the degree of familial aggregation is used as a surrogate for genetic factors. A test comparing the recurrence risks in sibs according to the exposure of indexes is proposed and its power is studied for varying values of model parameters. The Exposed versus Unexposed Recurrence Analysis (EURECA) is valuable for common diseases with moderate familial aggregation, only when the role of exposure has been clearly outlined. Interestingly, accounting for a sibling correlation for the exposure increases the power of EURECA. An application on a sample ascertained through one index affected with type 2 diabetes is presented where gene–environment interactions involving obesity and physical inactivity are investigated. Association of obesity with type 2 diabetes is clearly evidenced and a potential interaction involving this factor is suggested in Hispanics (P=0.045), whereas a clear gene–environment interaction is evidenced involving physical inactivity only in non-Hispanic whites (P=0.028). The proposed method might be of particular interest before genetic studies to help determine the environmental risk factors that will need to be accounted for to increase the power to detect genetic risk factors and to select the most appropriate samples to genotype.
diabetes mellitus; type 2; epidemiologic research design; familial aggregation; genetic predisposition to disease; environmental exposure
To describe a large, multi-center prospective cohort study of first-degree relatives (FDRs) of probands with rheumatoid arthritis (RA), and outline the utility of such a study in investigating the natural history of RA development.
1058 FDRs, none of whom met the American College of Rheumatology (ACR) criteria for RA, have been enrolled into a prospective study investigating genetic and environmental influences on the development of RA-related autoimmunity. Demographic, epidemiologic, genetic, autoantibody, and physical examination data from the initial study enrollment visit is described for these FDRs, and the relationship is examined between genetic factors, autoantibodies, inflammation, and joint disease.
Fifty-five percent of FDRs have ≥1 copy of the shared epitope (SE); 20% have ≥1 copy of PTPN22 polymorphism; ~16% are positive for rheumatoid factor (RF, including isotypes), and/or anti-cyclic citrullinated peptide (anti-CCP) antibody. RF-IgM positivity is associated with ≥1 tender joint/s on examination (OR 2.50, 95% CI 1.27 to 4.89, p<0.01), and elevated levels of CRP (OR 5.31, 95% CI 1.45 to 19.52, p = 0.01).
FDRs without RA demonstrate high prevalence of genetic risk factors and RA-related autoantibodies. Additionally, RF association with tender joints and elevated CRP suggests autoantibodies are a valid intermediate marker of RA-related autoimmunity in this cohort. This prospective FDR cohort will be a valuable resource for evaluating the relationship between genetic, epidemiologic factors and the development of RA-related autoimmunity.
rheumatoid arthritis; epidemiology; environmental factors; first-degree relatives; pre-clinical rheumatoid arthritis
The primary goals of this study were: 1) to identify individuals with undiagnosed inflammatory arthritis (IA) and rheumatoid arthritis (RA) in a community health-fair screen, and 2) to establish in a health-fair setting the diagnostic accuracy of combinations of the Connective Tissue Disease Screening Questionnaire (CSQ) and autoantibody testing for IA.
Screening for IA/RA was performed at health-fair sites using a combination of CSQ, joint examination, rheumatoid factor (RF) and anti-cyclic citrullinated (anti-CCP) antibody testing. IA was defined as ≥1 swollen joint/s suggestive of synovitis on joint examination by a trained clinician.
Six-hundred one subjects were screened; 51.0% participating because of joint symptoms (pain, stiffness, or swelling). Eighty-four subjects (14.0%) had ≥1 swollen joint/s designated as IA on joint examination. Of the 601 subjects screened, 9 (1.5%) had IA and met ≥4 of 7 American College of Rheumatology criteria for RA but had no prior diagnosis of RA, and 15 (2.5%) had IA and RF and/or anti-CCP positivity, suggesting early RA. The diagnostic accuracy of combinations of CSQ and autoantibody testing for the identification of IA yielded maximal sensitivity, specificity, positive and negative predictive values of 95.3%, 99.2%, 71.4%, and 97.7%, respectively.
Health-fair screening may be an effective approach for the identification of individuals with undiagnosed IA/RA. A combination of CSQ and autoantibody testing alone has clinically useful diagnostic accuracy for the detection of IA. Decisions regarding which methodology to use for future health-fair IA/RA screening will depend on goals of screening and funding.
inflammatory arthritis; rheumatoid arthritis; health-fair screening; diagnostic accuracy
The genome-wide association study by Herbert and colleagues identified the INSIG2 single nucleotide polymorphism (SNP) rs7566605 as contributing to increased BMI in ethnically distinct cohorts. The present study sought to further clarify by testing whether SNPs of INSIG2 influenced quantitative adiposity or glucose homeostasis traits in Hispanics of the Insulin Resistance Atherosclerosis Family Study (IRASFS). Using a tagging SNP approach, rs7566605 and 31 additional SNPs were genotyped in 1425 IRASFS Hispanics. SNPs were tested for association with six adiposity measures: BMI, waist circumference (WAIST), waist to hip ratio (WHR), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and VAT to SAT ratio (VSR). SNPs were also tested for association with fasting glucose (GFAST), fasting insulin (FINS), and three measures obtained from the frequently sampled intravenous glucose tolerance test: insulin sensitivity (SI), acute insulin response (AIR), and disposition index (DI). Most prominent association was observed with direct CT-measured adiposity phenotypes, including VAT, SAT, and VSR (P-values range from 0.007 to 0.044 for rs17586756, rs17047718, rs17047731, rs9308762, rs12623648, and rs11673900). Multiple SNP associations were observed with all glucose homeostasis traits (P-values range from 0.001 to 0.031 for rs17047718, rs17047731, rs2161829, rs10490625, rs889904, and rs12623648). Using BMI as a covariate in evaluation of glucose homeostasis traits slightly reduced their association. However, association with adiposity and glucose homeostasis phenotypes is not significant following multiple comparisons adjustment. Trending association after multiple comparisons adjustment remains suggestive of a role for genetic variation of INSIG2 in obesity, but these results require validation.
Insulin-induced gene 2; single nucleotide polymorphism; genetic association; adiposity; glucose homeostasis
To describe the 5-year change in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas.
RESEARCH DESIGN AND METHODS
Absolute change in VAT and SAT measured by abdominal computed tomography scans has been obtained at a 5-year interval from African Americans (n = 389) and Hispanic Americans (n = 844), aged 20–69 years, in 10-year age-groups.
Mean 5-year increases in VAT areas in women were 18, 7, 4, 0.4, and −3 cm2 for African Americans and 13, 7, 3, 1, and −15 cm2 for Hispanics, across the 5 age decades (trend not significant). Mean 5-year increases in SAT areas in women were 88, 46, 19, 17, and 14 cm2 for African Americans and 53, 20, 17, 12, and 1 cm2 for Hispanics, across the 5 age decades (P < 0.05 for both). Similar trends have been observed in men.
Accumulation of abdominal fat is greatest in young adulthood. These data may be useful in identifying subgroups at risk of type 2 diabetes.
We conducted a dietary validation study in youth aged 1 to 11 years by comparing dietary intake of omega-3 and omega-6 polyunsaturated fatty acids (PUFA) as assessed by a parent-completed semi-quantitative food frequency questionnaire (FFQ) over time to erythrocyte membrane composition of the same fatty acids.
The study population included youth aged 1 to 11 years who were participants in the Diabetes Autoimmunity Study in the Young (DAISY), a longitudinal study in Denver, Colorado that is following a cohort of youth at risk for developing Type I diabetes. Four hundred four children who had erythrocyte membrane fatty acid data matched to an FFQ corresponding to the same time frame for a total of 917 visits (matches) were included. PUFA intake was expressed as both g/day (adjusted for total energy) and as percent of total fat intake. We used mixed models to test the association and calculate the correlation between the erythrocyte membrane estimates and PUFA intake using all records of data for each youth.
Intakes of total omega-3 fatty acids (β=0.52, p<0.0001, ρ=0.23) and marine PUFAs (β=1.62, p<0.0001, ρ=0.42), as a percent of total fat in the diet, were associated with percent of omega-3 and marine PUFAs in the erythrocyte membrane. Intakes of omega-6 PUFAs (β=0.04, p=0.418, ρ=0.05) and arachidonic acid (β=0.31, p=0.774, ρ=0.01) were not associated.
In these young children, a FFQ using parental report provided estimates of average long-term intakes of marine PUFAs that correlated well with their erythrocyte cell membrane fatty acid status.
This study evaluated the influence of somatostatin receptor type 2 (SSTR2) polymorphisms on measures of glucose homeostasis in the Insulin Resistance Atherosclerosis Family Study (IRASFS). SSTR2 is a G-protein–coupled receptor that, in response to somatostatin, mediates inhibition of insulin, glucagon, and growth hormone release and thus may affect glucose homeostasis.
RESEARCH DESIGN AND METHODS
Ten single nucleotide polymorphisms (SNPs) spanning the gene were chosen using a SNP density selection algorithm and genotyped on 1,425 Hispanic-American individuals from 90 families in the IRASFS. These families comprised two samples (set 1 and set 2), which were analyzed individually and as a combined set. Single SNP tests of association were performed for four glucose homeostasis measures—insulin sensitivity (SI), acute insulin response (AIR), disposition index (DI), and fasting blood glucose (FBG)—using generalized estimating equations.
The SSTR2 locus was encompassed by a single linkage disequilibrium (LD) block (D′ = 0.91–1.00; r2 = 0.09–0.97) that contained four of the ten SNPs evaluated. Within the SSTR2-containing LD block, evidence of association was observed in each of the two sets and in a combined analysis with decreased SI(βhomozygous = −0.16; Pmeta-analysis = 0.0024–0.0030), decreased DI (βhomozygous = −0.35 to −5.16; Pmeta-analysis = 0.0075–0.027), and increased FBG (βhomozygous = 2.30; Pmeta-analysis = 0.045). SNPs outside the SSTR2-containing LD block were not associated with measures of glucose homeostasis.
We observed evidence for association of SSTR2 polymorphisms with measures of glucose homeostasis. Thus, variants in SSTR2 may influence pathways of SIto modulate glucose homeostasis.
Multiple studies have identified FTO gene variants associated with measures of adiposity in European-derived populations. The study objective was to determine whether FTO variants were associated with adiposity, including visceral and subcutaneous adipose tissue (VAT; SAT), and glucose homeostasis measures in the Insulin Resistance Atherosclerosis Family Study (IRASFS). A total of 27 SNPs in FTO intron 1, including SNPs prominent in the literature (rs9939609, rs8050136, rs1121980, rs17817449, rs1421085, and rs3751812), were genotyped in 1,424 Hispanic Americans and 604 African Americans. Multiple SNPs were associated with BMI and SAT (p-values ranging from 0.001 to 0.033), and trending or associated with waist circumference (p-values ranging from 0.008 to 0.099) in the Hispanic Americans. No association was observed with VAT, illustrating that FTO variants are associated with overall fat mass instead of specific fat depots. For the glucose homeostasis measures, variants were associated with fasting insulin but, consistent with other studies, after BMI adjustment, no evidence of association remained. The lack of association of FTO SNPs with insulin sensitivity is consistent with the lack of association with VAT, since these traits are strongly correlated. In the African Americans, only rs8050136 and rs9939609 were associated with BMI and WAIST (p-values of 0.011 and 0.034), and associated or trending towards association with SAT (p-values of 0.038 and 0.058). These results confirm that FTO variants are associated with adiposity measures, predisposing individuals to obesity by increasing overall fat mass in Hispanic Americans and to a lesser degree in African Americans.
fat mass and obesity associated (FTO) gene; single nucleotide polymorphism; genetic association; adiposity; glucose homeostasis