Enabling reproducible type 1 diabetes polygenic risk scoring for clinical and translational applications.

Objective: Type 1 diabetes polygenic risk scores (PRS) offer a promising tool for identifying diabetes subtypes in adults with new-onset disease. We aimed to develop a pipeline for the clinical translation of type 1 diabetes PRS to support clinical decision-making within a large health system and to provide publicly available code for applying these methods to future PRS models.

Research Design And Methods: We adapted two established type 1 diabetes PRS models: a 67-SNP (GRS2) and a 7-SNP (AA7) score for a clinical genotyping platform and applied them to 73,346 participants in the biobank at the Colorado Center for Personalized Medicine (CCPM).

DNA Methylation Smoking Scores and Risk of Islet Autoimmunity and Type 1 Diabetes.

Objective: Multiple studies have reported an inverse association between self-reported smoking during pregnancy and offspring type 1 diabetes (T1D) risk. We investigated the association between DNA methylation (DNAm) smoke exposure scores, parental self-reported smoking, and islet autoimmunity (IA) and T1D risk in children at high risk of T1D.

Research Design And Methods: We used longitudinal data from the Diabetes Autoimmunity Study in the Young cohort, including 205 IA case and 206 control participants (87 and 88 were T1D case and control participants, respectively), matched by age, race/ethnicity, and sample availability.

Differences in immune cell profiles around the time of islet autoimmunity seroconversion in children with and without type 1 diabetes: Immune cell changes around islet autoimmunity.

Seroconversion (SV) marks the initiation of islet autoimmunity (IA) and pre-clinical phase of type 1 diabetes, yet the contributions of immune cells beyond cytotoxic T cells remain unclear. We applied high-resolution immune cell-type deconvolution using peripheral blood DNA methylation data from nested case-control samples of the Diabetes Autoimmunity Study in the Young (DAISY; n=151) and The Environmental Determinants of Diabetes in the Young (TEDDY; n=166) to estimate immune cell proportions across pre-SV and SV timepoints and construct functional ratios, such as the neutrophil-to-lymphocyte ratio (NLR). Using linear models, we evaluated differences between type 1 diabetes cases and controls at pre-SV, SV, and the change across timepoints.

A rapid accurate approach to inferring pedigrees in endogamous populations.

Accurate reconstruction of pedigrees from genetic data remains a challenging problem. Many relationship categories (e.g.

Prediction and Characterization of Genetically Regulated Expression of Target Tissues in Asthma.

Background: Genetic control of gene expression in asthma-related tissues is not well-characterized, particularly for African-ancestry populations, limiting advancement in our understanding of the increased prevalence and severity of asthma in those populations.

Objective: To create novel transcriptome prediction models for asthma tissues (nasal epithelium and CD4+ T cells) and apply them in transcriptome-wide association study (TWAS) to discover candidate asthma genes.

Methods: We developed and validated gene expression prediction databases for unstimulated CD4+ T cells (CD4+T) and nasal epithelium using an elastic net framework.

Longitudinal changes in DNA methylation during the onset of islet autoimmunity differentiate between reversion versus progression of islet autoimmunity.

Background: Type 1 diabetes (T1D) is preceded by a heterogenous pre-clinical phase, islet autoimmunity (IA). We aimed to identify pre vs. post-IA seroconversion (SV) changes in DNAm that differed across three IA progression phenotypes, those who lose autoantibodies (reverters), progress to clinical T1D (progressors), or maintain autoantibody levels (maintainers).

Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review.

Background: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification.

Methods: To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.

Investigating iron intake in risk of progression from islet autoimmunity to type 1 diabetes: The diabetes autoimmunity study in the young.

Background: Studies of the role of iron in the risk of type 1 diabetes (T1D) have been inconsistent. Given that iron generates reactive oxygen radicals, which can lead to oxidative damage and apoptosis in the beta cells of the pancreas, we examined whether iron intake was associated with the risk of progressing to T1D in individuals with islet autoimmunity (IA), the pre-clinical phase of T1D.

Methods: DAISY is a prospective cohort following 2,547 children at increased risk for IA and progression to T1D.

An Oxylipin-Related Nutrient Pattern and Risk of Type 1 Diabetes in the Diabetes Autoimmunity Study in the Young (DAISY).

Oxylipins, pro-inflammatory and pro-resolving lipid mediators, are associated with the risk of type 1 diabetes (T1D) and may be influenced by diet. This study aimed to develop a nutrient pattern related to oxylipin profiles and test their associations with the risk of T1D among youth. The nutrient patterns were developed with a reduced rank regression in a nested case-control study ( = 335) within the Diabetes Autoimmunity Study in the Young (DAISY), a longitudinal cohort of children at risk of T1D.

COVID-19 Mortality in the Colorado Center for Personalized Medicine Biobank.

Over 6.37 million people have died from COVID-19 worldwide, but factors influencing COVID-19-related mortality remain understudied. We aimed to describe and identify risk factors for COVID-19 mortality in the Colorado Center for Personalized Medicine (CCPM) Biobank using integrated data sources, including Electronic Health Records (EHRs).

DNA Methylation Near May Mediate the Relationship between Family History of Type 1 Diabetes and Type 1 Diabetes Risk.

Given the differential risk of type 1 diabetes (T1D) in offspring of affected fathers versus affected mothers and our observation that T1D cases have differential DNA methylation near the imprinted gene compared to controls, we examined whether methylation near mediates the association between T1D family history and T1D risk. In a nested case-control study of 87 T1D cases and 87 controls from the Diabetes Autoimmunity Study in the Young, we conducted causal mediation analyses at 12 region CpGs to decompose the effect of family history on T1D risk into indirect and direct effects. These effects were estimated from two regression models adjusted for the human leukocyte antigen DR3/4 genotype: a linear regression of family history on methylation (mediator model) and a logistic regression of family history and methylation on T1D (outcome model).

Changes in the Coexpression of Innate Immunity Genes During Persistent Islet Autoimmunity Are Associated With Progression of Islet Autoimmunity: Diabetes Autoimmunity Study in the Young (DAISY).

Longitudinal changes in gene expression during islet autoimmunity (IA) may provide insight into biological processes that explain progression to type 1 diabetes (T1D). We identified individuals from Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, autoantibodies present on two or more visits. Illumina's NovaSeq 6000 was used to quantify gene expression in whole blood.

Lipid mediators are detectable in the nasal epithelium and differ by asthma status in female subjects.

Background: Lipid mediators, bioactive products of polyunsaturated fatty acid metabolism, contribute to inflammation initiation and resolution in allergic diseases; however, their presence in lung-related biosamples has not been fully described.

Objective: We aimed to quantify lipid mediators in the nasal airway epithelium and characterize preliminary associations with asthma.

Methods: Using liquid chromatography-mass spectrometry, we conducted a pilot study to quantify 56 lipid mediators from nasal epithelial samples collected from 11 female participants of an outpatient asthma clinic and community controls (aged 30-55 years).

Epigenome-Wide Association Study of Infant Feeding and DNA Methylation in Infancy and Childhood in a Population at Increased Risk for Type 1 Diabetes.

We assessed associations between infant diet (e.g., breastfeeding and introduction to solid foods) and DNA methylation in infancy and childhood.

Discovering metabolite quantitative trait loci in asthma using an isolated population.

Background: Integration of metabolomics with genetics may advance understanding of disease pathogenesis but has been underused in asthma genetic studies.

Objective: We sought to discover new genetic effects in asthma and to characterize the molecular consequences of asthma genetic risk through integration with the metabolome in a homogeneous population.

Methods: From fasting serum samples collected on 348 Tangier Island residents, we quantified 2612 compounds using untargeted metabolomics.

An effective processing pipeline for harmonizing DNA methylation data from Illumina's 450K and EPIC platforms for epidemiological studies.

Objective: Illumina BeadChip arrays are commonly used to generate DNA methylation data for large epidemiological studies. Updates in technology over time create challenges for data harmonization within and between studies, many of which obtained data from the older 450K and newer EPIC platforms. The pre-processing pipeline for DNA methylation is not trivial, and influences the downstream analyses.

A Mediation Approach to Discovering Causal Relationships between the Metabolome and DNA Methylation in Type 1 Diabetes.

Environmental factors including viruses, diet, and the metabolome have been linked with the appearance of islet autoimmunity (IA) that precedes development of type 1 diabetes (T1D). We measured global DNA methylation (DNAm) and untargeted metabolomics prior to IA and at the time of seroconversion to IA in 92 IA cases and 91 controls from the Diabetes Autoimmunity Study in the Young (DAISY). Causal mediation models were used to identify seven DNAm probe-metabolite pairs in which the metabolite measured at IA mediated the protective effect of the DNAm probe measured prior to IA against IA risk.

Phospholipid Levels at Seroconversion Are Associated With Resolution of Persistent Islet Autoimmunity: The Diabetes Autoimmunity Study in the Young.

Reversion of islet autoimmunity (IA) may point to mechanisms that prevent IA progression. We followed 199 individuals who developed IA during the Diabetes Autoimmunity Study in the Young. Untargeted metabolomics was performed in serum samples following IA.