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1.
Diabetes Care ; 42(2): 208-214, 2019 02.
Article in English | MEDLINE | ID: mdl-30352895

ABSTRACT

OBJECTIVE: Progression to insulin therapy in clinically diagnosed type 2 diabetes is highly variable. GAD65 autoantibodies (GADA) are associated with faster progression, but their predictive value is limited. We aimed to determine if a type 1 diabetes genetic risk score (T1D GRS) could predict rapid progression to insulin treatment over and above GADA testing. RESEARCH DESIGN AND METHODS: We examined the relationship between T1D GRS, GADA (negative or positive), and rapid insulin requirement (within 5 years) using Kaplan-Meier survival analysis and Cox regression in 8,608 participants with clinical type 2 diabetes (onset >35 years and treated without insulin for ≥6 months). T1D GRS was both analyzed continuously (as standardized scores) and categorized based on previously reported centiles of a population with type 1 diabetes (<5th [low], 5th-50th [medium], and >50th [high]). RESULTS: In GADA-positive participants (3.3%), those with higher T1D GRS progressed to insulin more quickly: probability of insulin requirement at 5 years (95% CI): 47.9% (35.0%, 62.78%) (high T1D GRS) vs. 27.6% (20.5%, 36.5%) (medium T1D GRS) vs. 17.6% (11.2%, 27.2%) (low T1D GRS); P = 0.001. In contrast, T1D GRS did not predict rapid insulin requirement in GADA-negative participants (P = 0.4). In Cox regression analysis with adjustment for age of diagnosis, BMI, and cohort, T1D GRS was independently associated with time to insulin only in the presence of GADA: hazard ratio per SD increase was 1.48 (1.15, 1.90); P = 0.002. CONCLUSIONS: A T1D GRS alters the clinical implications of a positive GADA test in patients with clinical type 2 diabetes and is independent of and additive to clinical features.


Subject(s)
Autoantibodies/blood , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/drug therapy , Glutamate Decarboxylase/immunology , Insulin/therapeutic use , Adult , Aged , Aged, 80 and over , Autoantibodies/genetics , Cohort Studies , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/immunology , Disease Progression , Female , Genetic Predisposition to Disease , Glutamate Decarboxylase/genetics , Humans , Male , Middle Aged , Prognosis , Research Design , Risk Factors , Survival Analysis
3.
Am J Hum Genet ; 100(6): 954-959, 2017 Jun 01.
Article in English | MEDLINE | ID: mdl-28528868

ABSTRACT

Most genetic variants identified in genome-wide association studies (GWASs) of complex traits are thought to act by affecting gene regulation rather than directly altering the protein product. As a consequence, the actual genes involved in disease are not necessarily the most proximal to the associated variants. By integrating data from GWAS analyses with those from genetic studies of regulatory variation, it is possible to identify variants pleiotropically associated with both a complex trait and measures of gene regulation. In this study, we used summary-data-based Mendelian randomization (SMR), a method developed to identify variants pleiotropically associated with both complex traits and gene expression, to identify variants associated with complex traits and DNA methylation. We used large DNA methylation quantitative trait locus (mQTL) datasets generated from two different tissues (blood and fetal brain) to prioritize genes for >40 complex traits with robust GWAS data and found considerable overlap with the results of SMR analyses performed with expression QTL (eQTL) data. We identified multiple examples of variable DNA methylation associated with GWAS variants for a range of complex traits, demonstrating the utility of this approach for refining genetic association signals.


Subject(s)
DNA Methylation/genetics , Genetic Pleiotropy , Genetic Variation , Genome-Wide Association Study , Quantitative Trait Loci/genetics , Quantitative Trait, Heritable , Basic Helix-Loop-Helix Transcription Factors/genetics , Brain/embryology , Crohn Disease/genetics , Fetus/metabolism , Humans , Mendelian Randomization Analysis , Migraine Disorders/blood , Migraine Disorders/genetics , Repressor Proteins/genetics
4.
J Crohns Colitis ; 10(2): 149-58, 2016 02.
Article in English | MEDLINE | ID: mdl-26619893

ABSTRACT

BACKGROUND AND AIMS: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients. METHODS: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, ≥50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls. RESULTS: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixty-eight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1×10(-7)) with 5-ASA-induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4×10(-9), odds ratio 3.1). CONCLUSIONS: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury.


Subject(s)
Acute Kidney Injury/chemically induced , DNA/analysis , Genome-Wide Association Study/methods , HLA Antigens/genetics , Inflammatory Bowel Diseases/drug therapy , Kidney/pathology , Mesalamine/adverse effects , Acute Kidney Injury/pathology , Adolescent , Adult , Aged , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Child , Female , Genotype , HLA Antigens/metabolism , Humans , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/immunology , Kidney/drug effects , Male , Mesalamine/therapeutic use , Middle Aged , Phenotype , Young Adult
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