Diabetes Genetic Risk Score Research Articles

Random C-Peptide and Islet Antibodies at Onset Predict β Cell Function Trajectory and Insulin Dependence in Pediatric Diabetes

ContextIdentification of prognostic biomarkers in pediatric diabetes is important for precision medicine. ObjectiveWe assessed whether C-peptide and islet autoantibodies are useful to predict the natural history of children with new-onset diabetes. MethodsWe prospectively studied 72 children with new-onset diabetes (median follow-up: 8 months) by applying the Aβ classification system (“A+”: islet autoantibody positive, “β+”: random serum C-peptide≥1.3 ng/mL at diagnosis). Beta-cell function was assessed longitudinally with 2h post-prandial/stimulated urinary C-peptide-to-creatinine ratio (UCPCR) 3-12 weeks (V1) and 6-12 months after diagnosis (V2). We obtained a type 1 diabetes genetic risk score (T1D GRS2) for each participant, and compared characteristics at baseline, and clinical outcomes at V2. ResultsThe cohort was 50% male. Racial distribution was 76.4% White, 20.8% Black and 2.8% Asian or other races. A total of 46.5% participants were Hispanic. Median age (Q1-Q3) was 12.4 (8.3-14.5) years. The Aβ subgroup frequencies were 46 A+β-(63.9%), 1 A-β-(1.4%), 4 A+β+(5.6%), and 21 A-β+(29.2%). Baseline serum C-peptide correlated with UCPCR at both V1 (r=0.36, p=0.002) and V2 (r=0.47, p<0.001). There were significant subgroup differences in age, race, frequency of diabetic ketoacidosis and T1D GRS2 (p<0.01). At V2, the two β- subgroups had lower UCPCR and higher HbA1c compared with the two β+ subgroups (p<0.001 and p=0.02, respectively). Thirty-eight percent of A-β+ but none of the other subgroups were insulin-independent at V2 (p<0.001). ConclusionsC-peptide and islet autoimmunity at diagnosis define distinct phenotypes and predict beta-cell function and insulin dependence 6-12 months later in racially/ethnically diverse children with new-onset diabetes.

Autoantibodies to truncated GAD(96-585) antigen stratify risk of early insulin requirement in adult-onset diabetes.

We investigated whether characterisation of full-length (f-)GADA responses could identify early insulin requirement in adult-onset diabetes. In 179 f-GADA positive participants diagnosed with type 2 diabetes, we assessed associations of truncated (t-)GADA positivity, f-GADA IgG subclasses, and f-GADA affinity with early insulin requirement (<5 years), type 1 diabetes genetic risk score (T1D GRS), and C-peptide. t-GADA positivity was lower in f-GADA positive without early insulin in comparison to f-GADA positive type 2 diabetes requiring insulin within 5 years, and type 1 diabetes (75% vs. 91% and 95% respectively, p<0.0001). t-GADA positivity (in those f-GADA positive) identified a group with a higher type 1 diabetes genetic susceptibility (mean T1D GRS 0.248 vs. 0.225, p=0.003), lower C-peptide (1156 pmol/L vs. 4289 pmol/L, p=1x10-7), and increased IA-2A positivity (23% vs. 6%, p=0.03). In survival analysis, t-GADA positivity was associated with early insulin requirement compared with those only positive for f-GADA, independently from age of diagnosis, f-GADA titre and duration of diabetes [adjusted HR 5.7 (95% CI 1.4, 23.5), p=0.017]. The testing of t-GADA in f-GADA positive individuals with type 2 diabetes identifies those who have genetic and clinical characteristics comparable to type 1 diabetes and stratifies those at higher risk of early insulin requirement.

Islet autoantibody frequency in relatives of children with type 1 diabetes who have a type 2 diabetes diagnosis.

This study aimed to evaluate characteristics of autoimmunity in individuals who have a type 2 diagnosis and are relatives of children with type 1 diabetes. Pre-diagnosis samples (median 17 months before onset) from relatives who were later diagnosed with type 2 diabetes were measured for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) as well as the type 1 diabetes genetic risk score (GRS2). Associations between islet autoantibodies, insulin treatment and GRS2 were analysed using Fisher's exact and t-tests. Among 226 relatives (64% men; mean age at sampling 41 years; mean age 54 years at diagnosis), 32 (14%) were islet autoantibody-positive for at least one autoantibody more than a decade before diagnosis. Approximately half of these (n = 15) were treated with insulin. GADA-positivity was higher in insulin-treated relatives than in non-insulin-treated relatives (12/18 [67%] vs. 6/18 [33%], p < 0.001). IAA-positivity was observed in 13/32 (41%) of relatives with autoantibodies. GRS2 scores were increased in autoantibody-positive relatives (p = 0.032), but there was no clear evidence for a difference according to treatment (p = 0.072). This study highlights the importance of measuring islet autoantibodies, including IAA, in relatives of people with type 1 diabetes to avoid misdiagnosis.

68-OR: Influence of the Type 1 Diabetes Genetic Risk Score on Response to Immunotherapies for Type 1 Diabetes Prevention

68-OR: Influence of the Type 1 Diabetes Genetic Risk Score on Response to Immunotherapies for Type 1 Diabetes Prevention

Clinical Prediction Models Combining Routine Clinical Measures Have High Accuracy in Identifying Youth-Onset Type 2 Diabetes Defined by Maintained Endogenous Insulin Secretion: The SEARCH for Diabetes in Youth Study.

With high prevalence of obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D). We studied 2,966 youth with diabetes in the prospective SEARCH for Diabetes in Youth study (diagnosis age ≤19 years) to develop prediction models to identify participants with fasting C-peptide ≥250 pmol/L (≥0.75 ng/mL) after >3 years' (median 74 months) diabetes duration. Models included clinical measures at the baseline visit, at a mean diabetes duration of 11 months (age, BMI, sex, waist circumference, HDL cholesterol), with and without islet autoantibodies (GADA, IA-2A) and a Type 1 Diabetes Genetic Risk Score (T1DGRS). Models using routine clinical measures with or without autoantibodies and T1DGRS were highly accurate in identifying participants with C-peptide ≥0.75 ng/mL (17% of participants; 2.3% and 53% of those with and without positive autoantibodies) (area under the receiver operating characteristic curve [AUCROC] 0.95-0.98). In internal validation, optimism was very low, with excellent calibration (slope 0.995-0.999). Models retained high performance for predicting retained C-peptide in older youth with obesity (AUCROC 0.88-0.96) and in subgroups defined by self-reported race/ethnicity (AUCROC 0.88-0.97), autoantibody status (AUCROC 0.87-0.96), and clinically diagnosed diabetes types (AUCROC 0.81-0.92). Prediction models combining routine clinical measures at diabetes diagnosis, with or without islet autoantibodies or T1DGRS, can accurately identify youth with diabetes who maintain endogenous insulin secretion in the range associated with T2D.

1829-PUB: Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes Randomised Controlled Trial (PRISM-RCT) in Chinese Patients with Young-Onset Diabetes—Study Design and Baseline Profile

Background: Young-onset diabetes (YOD) is heterogenous in aetiologies and clinical phenotypes. The PRISM study is a 3-year randomised controlled trial to evaluate the effect of precision treatment algorithm guided by biogenetic information on clinical outcomes in Chinese with YOD. Methods: In 2020-2021, we randomized 884 Chinese (18-50 years) with non-type 1 diabetes diagnosed ≤40 years to PRISM (n=443) or usual care (n=441). The PRISM group underwent assessment including biogenetic markers (anti-glutamic acid decarboxylase antibody [GADA], C-peptide, monogenic diabetes gene mutations and genetic risk scores predicting YOD, insulin requirement and complications) for issue of a personalized report to guide multidisciplinary care comprising endocrinologist consultation, counselling, empowerment on self-care, and reminders by supporting staff for 1 year at the Diabetes Research Centre before return to usual care. All patients return for assessment at year 3 for ascertainment of all-diabetes related endpoints. Results: Amongst 884 patients (mean±SD: age 40.7±6.5 years, median [IQR] age at diagnosis 34 [29,38] years, disease duration 7 [3,12] years, HbA1c 7.5±1.7%, 96.2% on glucose-lowering drugs, 27.7% on insulin), 74.7% had family history (19.7% both parents affected), 66.7% hypertension, 76.4% dyslipidaemia, 83% overweight and 35.4% albuminuria. Median fasting C-peptide was 0.6 (0.4, 0.9) nmol/L, 9.5% had C-peptide &amp;lt;0.2 nmol/L, 5.1% were GADA positive. In the PRISM group, 21.9% had low birthweight, 50.7%, childhood obesity, 5.7%, steroid exposure in childhood, 1.8-17.3%, co-existing endocrinopathies (thyroid disease, Cushing’s syndrome, polycystic ovarian syndrome), 7.5%, thalassaemia trait, 7.1%, chronic hepatitis B infection and 10.3%, mental illness. Conclusions: Lifecourse factors, endocrinopathies and mental illnesses are prevalent in YOD. Disclosure A.Luk: Research Support; Novo Nordisk, Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; Eli Lilly and Company. E.Chow: Research Support; Medtronic, Merck KGaA, Speaker's Bureau; Novartis, Bayer Inc., Sanofi. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Speaker's Bureau; Abbott, AstraZeneca, Lilly, Bayer Inc., Boehringer Ingelheim Inc. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. Y.Fan: None. B.Fan: None. C.K.P.Lim: Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. E.W.M.Poon: None. S.T.F.Tsoi: None. R.Ozaki: None. R.C.Ma: Advisory Panel; AstraZeneca, Merck &amp; Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. Funding Health and Medical Research Fund (CFS-CUHK2)

Genetic determinants of type 1 diabetes in individuals with weak evidence of islet autoimmunity at disease onset.

Islet autoantibodies (AAbs) are detected in >90% of individuals with clinically suspected type 1 diabetes at disease onset. A single AAb, sometimes at low titre, is often detected in some individuals, making their diagnosis uncertain. Type 1 diabetes genetic risk scores (GRS) are a useful tool for discriminating polygenic autoimmune type 1 diabetes from other types of diabetes, particularly the monogenic forms, but testing is not routinely performed in the clinic. Here, we used a type 1 diabetes GRS to screen for monogenic diabetes in individuals with weak evidence of autoimmunity, i.e. with a single AAb at disease onset. In a pilot study, we genetically screened 142 individuals with suspected type 1 diabetes, 42 of whom were AAb-negative, 27 of whom had a single AAb (single AAb-positive) and 73 of whom had multiple AAbs (multiple AAb-positive) at disease onset. Next-generation sequencing (NGS) was performed in 41 AAb-negative participants, 26 single AAb-positive participants and 60 multiple AAb-positive participants using an analysis pipeline of more than 200 diabetes-associated genes. The type 1 diabetes GRS was significantly lower in AAb-negative individuals than in those with a single and multiple AAbs. Pathogenetic class 4/5 variants in MODY or monogenic diabetes genes were identified in 15/41 (36.6%) AAb-negative individuals, while class 3 variants of unknown significance were identified in 17/41 (41.5%). Residual C-peptide levels at diagnosis were higher in individuals with mutations compared to those without pathogenetic variants. Class 3 variants of unknown significance were found in 11/26 (42.3%) single AAb-positive individuals, and pathogenetic class 4/5 variants were present in 2/26 (7.7%) single AAb-positive individuals. No pathogenetic class 4/5 variants were identified in multiple AAb-positive individuals, but class 3 variants of unknown significance were identified in 19/60 (31.7%) patients. Several patients across the three groups had more than one class 3 variant. These findings provide insights into the genetic makeup of patients who show weak evidence of autoimmunity at disease onset. Absence of islet AAbs or the presence of a single AAb together with a low type 1 diabetes GRS may be indicative of a monogenic form of diabetes, and use of NGS may improve the accuracy of diagnosis.

The relationship between islet autoantibody status and the genetic risk of type 1 diabetes in adult-onset type 1 diabetes

Aims/hypothesisThe reason for the observed lower rate of islet autoantibody positivity in clinician-diagnosed adult-onset vs childhood-onset type 1 diabetes is not known. We aimed to explore this by assessing the genetic risk of type 1 diabetes in autoantibody-negative and -positive children and adults.MethodsWe analysed GAD autoantibodies, insulinoma-2 antigen autoantibodies and zinc transporter-8 autoantibodies (ZnT8A) and measured type 1 diabetes genetic risk by genotyping 30 type 1 diabetes-associated variants at diagnosis in 1814 individuals with clinician-diagnosed type 1 diabetes (1112 adult-onset, 702 childhood-onset). We compared the overall type 1 diabetes genetic risk score (T1DGRS) and non-HLA and HLA (DR3-DQ2, DR4-DQ8 and DR15-DQ6) components with autoantibody status in those with adult-onset and childhood-onset diabetes. We also measured the T1DGRS in 1924 individuals with type 2 diabetes from the Wellcome Trust Case Control Consortium to represent non-autoimmune diabetes control participants.ResultsThe T1DGRS was similar in autoantibody-negative and autoantibody-positive clinician-diagnosed childhood-onset type 1 diabetes (mean [SD] 0.274 [0.034] vs 0.277 [0.026], p=0.4). In contrast, the T1DGRS in autoantibody-negative adult-onset type 1 diabetes was lower than that in autoantibody-positive adult-onset type 1 diabetes (mean [SD] 0.243 [0.036] vs 0.271 [0.026], p<0.0001) but higher than that in type 2 diabetes (mean [SD] 0.229 [0.034], p<0.0001). Autoantibody-negative adults were more likely to have the more protective HLA DR15-DQ6 genotype (15% vs 3%, p<0.0001), were less likely to have the high-risk HLA DR3-DQ2/DR4-DQ8 genotype (6% vs 19%, p<0.0001) and had a lower non-HLA T1DGRS (p<0.0001) than autoantibody-positive adults. In contrast to children, autoantibody-negative adults were more likely to be male (75% vs 59%), had a higher BMI (27 vs 24 kg/m2) and were less likely to have other autoimmune conditions (2% vs 10%) than autoantibody-positive adults (all p<0.0001). In both adults and children, type 1 diabetes genetic risk was unaffected by the number of autoantibodies (p>0.3). These findings, along with the identification of seven misclassified adults with monogenic diabetes among autoantibody-negative adults and the results of a sensitivity analysis with and without measurement of ZnT8A, suggest that the intermediate type 1 diabetes genetic risk in autoantibody-negative adults is more likely to be explained by the inclusion of misclassified non-autoimmune diabetes (estimated to represent 67% of all antibody-negative adults, 95% CI 61%, 73%) than by the presence of unmeasured autoantibodies or by a discrete form of diabetes. When these estimated individuals with non-autoimmune diabetes were adjusted for, the prevalence of autoantibody positivity in adult-onset type 1 diabetes was similar to that in children (93% vs 91%, p=0.4).Conclusions/interpretationThe inclusion of non-autoimmune diabetes is the most likely explanation for the observed lower rate of autoantibody positivity in clinician-diagnosed adult-onset type 1 diabetes. Our data support the utility of islet autoantibody measurement in clinician-suspected adult-onset type 1 diabetes in routine clinical practice.Graphical abstract

Immunophenotype and genetic risk scores to improve autoantibody negative type 1 diabetes classification: study protocol

&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;An estimated 10-30% of type 1 diabetes (T1D) individuals do not have detectable autoantibodies at diagnosis, thus are classified as “idiopathic” or “non-immune.” Given the non-pathogenic role of islet autoantibodies, the validity of excluding an immune basis for disease in such individuals needs to be questioned. The pan-autoantibody negative type 1 diabetes in adults (PANDA) study aims to characterise the immune, clinical and metabolic phenotype of autoantibody negative T1D individuals.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This is a two-part, multi-centre study which is recruiting 100 participants: autoantibody positive T1D (N=25), autoantibody negative T1D (N=25), latent autoimmune diabetes in adults (N=25) and age- and sex-matched normoglycaemic control (N=25) individuals. Study 1 involves baseline pathology collection and high dimensional immune-phenotyping using flow cytometry. DNA will be extracted from saliva samples to calculate type 1 diabetes genetic risk scores (T1DGRS). Autoantibody negative individuals will undergo monogenic diabetes testing. Study 2 is a prospective, longitudinal sub-study of study 1 participants within 5 years of diagnosis. Beta cell function will be assessed using glucagon stimulated C-peptide at 0, 9 and 18 months. The primary outcome of study 1 is to determine the phenotype of immune cells in autoantibody positive and negative T1D compared to healthy controls. Secondary outcomes of study 1 include clinical and metabolic characteristics and the T1DGRS. The primary outcome of study 2 is the rate of decline of stimulated C-peptide over time. &lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The PANDA study is the first study of its kind which aims to improve diagnosis and characterisation of autoantibody negative T1D.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;

Routine Islet Autoantibody Testing in Clinically Diagnosed Adult-Onset Type 1 Diabetes Can Help Identify Misclassification and the Possibility of Successful Insulin Cessation.

Recent joint American Diabetes Association and European Association for the Study of Diabetes guidelines recommend routine islet autoantibody testing in all adults newly diagnosed with type 1 diabetes. We aimed to assess the impact of routine islet autoantibody testing in this population. We prospectively assessed the relationship between islet autoantibody status (GADA, IA-2A, and ZNT8A), clinical and genetic characteristics, and progression (annual change in urine C-peptide-to-creatinine ratio [UCPCR]) in 722 adults (≥18 years old at diagnosis) with clinically diagnosed type 1 diabetes and diabetes duration <12 months. We also evaluated changes in treatment and glycemia over 2 years after informing participants and their clinicians of autoantibody results. Of 722 participants diagnosed with type 1 diabetes, 24.8% (179) were autoantibody negative. This group had genetic and C-peptide characteristics suggestive of a high prevalence of nonautoimmune diabetes: lower mean type 1 diabetes genetic risk score (islet autoantibody negative vs. positive: 10.85 vs. 13.09 [P < 0.001] [type 2 diabetes 10.12]) and lower annual change in C-peptide (UCPCR), -24% vs. -43% (P < 0.001).After median 24 months of follow-up, treatment change occurred in 36.6% (60 of 164) of autoantibody-negative participants: 22.6% (37 of 164) discontinued insulin, with HbA1c similar to that of participants continuing insulin (57.5 vs. 60.8 mmol/mol [7.4 vs. 7.7%], P = 0.4), and 14.0% (23 of 164) added adjuvant agents to insulin. In adult-onset clinically diagnosed type 1 diabetes, negative islet autoantibodies should prompt careful consideration of other diabetes subtypes. When routinely measured, negative antibodies are associated with successful insulin cessation. These findings support recent recommendations for routine islet autoantibody assessment in adult-onset type 1 diabetes.

Proteomic analysis of diabetes genetic risk scores identifies complement C2 and neuropilin-2 as predictors of type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) Study.

Genetic predisposition to type 2 diabetes is well-established, and genetic risk scores (GRS) have been developed that capture heritable liabilities for type 2 diabetes phenotypes. However, the proteins through which these genetic variants influence risk have not been thoroughly investigated. This study aimed to identify proteins and pathways through which type 2 diabetes risk variants may influence pathophysiology. Using a proteomics data-driven approach in a discovery sample of 7241 White participants in the Atherosclerosis Risk in Communities Study (ARIC) cohort and a replication sample of 1674 Black ARIC participants, we interrogated plasma levels of 4870 proteins and four GRS of specific type 2 diabetes phenotypes related to beta cell function, insulin resistance, lipodystrophy, BMI/blood lipid abnormalities and a composite score of all variants combined. Twenty-two plasma proteins were identified in White participants after Bonferroni correction. Of the 22 protein-GRS associations that were statistically significant, 10 were replicated in Black participants and all but one were directionally consistent. In a secondary analysis, 18 of the 22 proteins were found to be associated with prevalent type 2 diabetes and ten proteins were associated with incident type 2 diabetes. Two-sample Mendelian randomisation indicated that complement C2 may be causally related to greater type 2 diabetes risk (inverse variance weighted estimate: OR 1.65 per SD; p=7.0 × 10-3), while neuropilin-2 was inversely associated (OR 0.44 per SD; p=8.0 × 10-3). Identified proteins may represent viable intervention or pharmacological targets to prevent, reverse or slow type 2 diabetes progression, and further research is needed to pursue these targets.

A Diabetes Genetic Risk Score Is Associated With All-Cause Dementia and Clinically Diagnosed Vascular Dementia in the Million Veteran Program.

Diabetes and dementia are diseases of high health care burden worldwide, and studies have shown that diabetes is associated with an increased relative risk of dementia. We set out to examine whether type 2 diabetes-associated genetic variants were associated with dementia and whether they differed by race/ethnicity or clinical dementia diagnosis. We evaluated associations of two type 2 diabetes genetic risk scores (GRS and GRS-nonAPOE: a score without rs429358, a variant associated with Alzheimer disease [AD]) with three classifications of clinical dementia diagnoses in the Million Veteran Program (MVP): all-cause dementia, vascular dementia (VaD), and AD. We conducted our analysis stratified by European (EUR), African (AFR), and Hispanic (HIS) races/ethnicities. In EUR, we found associations of the GRS with all-cause dementia (odds ratio [OR] 1.06, P = 1.60e-07) and clinically diagnosed VaD (OR 1.12, P = 5.2e-05) but not with clinically diagnosed AD (OR 1.02, P = 0.43). The GRS was not associated with any dementia outcome in AFR or HIS. When testing with GRS-nonAPOE, we found that effect size estimates in EUR increased and P values decreased for all-cause dementia (OR 1.08, P = 2.6e-12), for VaD (OR 1.14, P = 7.2e-07), and for AD (OR 1.06, P = 0.018). For AFR, the association of GRS-nonAPOE and clinically diagnosed VaD (OR 1.15, P = 0.016) was statistically significant. There were no significant findings for HIS. We found evidence suggesting shared genetic pathogenesis of diabetes with all-cause dementia and clinically diagnosed VaD.

Combined effects of bisphenol A and diabetes genetic risk score on incident type 2 diabetes: A nested case-control study

Observational studies reported inconsistent results on the association between bisphenol A (BPA) and type 2 diabetes (T2D) risk. Whether genetic factors modified the association remains unclear. The present nested case-control study prospectively investigated the association of BPA with T2D risk, and the interaction and combined effects of diabetes genetic risk score (GRS) and serum BPA on T2D risk. Based on the Dongfeng-Tongji cohort study, 995 incident diabetes cases and 1:1 age- and gender-matched controls were included. T2D was diagnosed based on the American Diabetes Association criteria. Serum BPA concentration was measured at baseline. Diabetes GRS was constructed by 88 diabetes-related SNPs selected from large-scale GWASs. A U-shaped association was observed between serum BPA levels and T2D risk, with the lowest odds of T2D at the serum BPA levels of 1.00 ng/mL (P = 0.001 for nonlinearity). Compared with the middle group, the multivariate-adjusted ORs of T2D in the lowest group and the highest group of serum BPA were 1.52 (95% CI: 1.04, 2.22) and 1.40 (95% CI: 1.08, 1.81), respectively. Both serum BPA levels (β = 0.107, P = 0.001) and weighted-GRS (w-GRS) (β = 0.072, P = 0.02) were significantly associated with baseline FPG levels. Participants with both highest w-GRS and serum BPA levels had highest risk of T2D (OR = 2.53, 95%CI: 1.49, 4.31, P = 0.001) and higher baseline FPG levels (β = 0.218, P = 0.01), compared with those with both lowest w-GRS and serum BPA levels. Non modified effects of serum BPA levels and w-GRS on T2D, baseline FPG levels, and 5-y changes of FPG levels were detected (All Pinteraction > 0.05). Our results suggested a U-shaped association between serum BPA levels and T2D risk. Participants with higher serum BPA levels and diabetes genetic risk had higher FPG levels and higher risk of T2D.

1285-P: Differentiating between Diabetic and Idiopathic Gastroparesis: A Genetic Perspective

Gastroparesis is a serious medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. An innate immune dysregulation and injury to the interstitial cells of Cajal and other components of the enteric nervous system is likely central to the pathogenesis of gastroparesis. Most common etiologies include diabetes, post-surgical but most cases are idiopathic. Thus far, little is known about the underlying genetic risk factors for gastroparesis. We have done a genome-wide association study comparing idiopathic and diabetic cases with controls as well as contrasting idiopathic versus diabetic cases. We report a novel genetic association of SLC15A4 locus with idiopathic gastroparesis. This signal is driven by multiple variants with top missense variant SLC15A4:NM145648:exon2:c.T716C:p.V239A, rs33990080. Altogether, among EUR cohort we report 69 carriers out of 214 versus controls 165 out of 896 (MAF: cases 0.18; MAF: controls 0.09) and OR: 1.9 (p-value&amp;lt;10^-6) . We furthermore differentiate idiopathic from diabetic gastroparesis with an established diabetes genetic risk score, - result that is statistically significant (p-value&amp;lt;0.0004) . We also delineate a number of significant loci implicated in diabetes risk including (HLA-DQB1,HLA-DQA2, EXOC6B) in the idiopathic versus diabetic gastroparesis analysis. Of particular interest are the Exocyst complex component, 6 (EXOC6/6B) with lead variant rs41420. previously identified to play a role in insulin signaling through its interaction with the glucose transporter GLUT4. Current genetic findings suggest that a mechanism directly connected to macrophage polarization may be implicated in the etiology gastroparesis. The GWAS picture that is emerging implicates novels loci implicated in the pathophysiology of gastroparesis differentiating those of diabetic versus idiopathic etiology. Disclosure S.P.Smieszek: None.

243-OR: Integrating Genetic Risk Score and Islet Autoantibody Characteristics in the Predictive Model for Type 1 Diabetes in the TrialNet Study

Background: Type 1 diabetes (T1D) genetic risk score (GRS) and islet autoantibody (AAb) specificity and titers influence T1D risk; however, these factors collected at baseline in cross sectional studies have not been effectively incorporated in the current models for prediction of progression along pre-clinical stages of T1D. Our aim was to develop an updated model of T1D prediction for research and clinical practice. Methods: AAb-positive relatives of individuals with T1D (n=1,233, 52% female, 88% European ancestry, age mean 15 yrs [SD 12.2]) from the TrialNet Pathway to Prevention were followed for a median of 3.1 years (IQR 1.1 -7.1). T1D developed in 498/1,233 (40.4%). T1D GRS, AAb number, AAb combination, AAb titer, age and sex were evaluated on the combined T1D prediction model, estimating its performance using 3-fold cross-validation (10x repeated). Results: Machine learning (survival random forest) and traditional methods (Cox models, extended Cox model) performed equivalently as measured by 5 yr horizon time-dependent AUC ROC (respectively 0.74, 0.74, 0.72), on calibration by integrated Brier score (respectively 0.15, 0.15, 0.16), and by calibration plots. AAb combinations with specific variables predicted T1D. In multivariate analysis, T1D GRS was a significant predictor of T1D in individuals positive for GADA, IAA or both. For any autoantibody combination including IA2A, the IA2A titer was predictive while the T1D GRS was not. Variable importance analyses showed that T1D was predicted by IA2A titer level, followed by T1D GRS and combinations of specific AAbs. Conclusion: We modeled individual estimates of T1D risk with T1D GRS, AAb characteristics, age, and sex. T1D prediction improved by adding T1D GRS and AAb characteristics to other variables, and was similar using machine learning or traditional models. T1D GRS was a significant predictor only in the absence of IA2A. In the presence of IA2A, IA2A titer was the most influential factor. Disclosure L. A. Ferrat: None. M. J. Redondo: Advisory Panel; Self; Provention Bio, Inc. A. Steck: None. H. M. Parikh: None. L. You: None. S. Onengut-gumuscu: None. P. Gottlieb: Advisory Panel; Self; Janssen Research &amp; Development, LLC, Tolerion, Inc., Viacyte, Inc., Other Relationship; Self; ImmunoMolecular Therapeutics, Inc., Research Support; Self; Caladrius Biosciences, Inc., Immune Tolerance Network, Mercia Pharma Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Precigen, Inc., Tolerion, Inc. S. S. Rich: None. J. Krischer: None. R. A. Oram: Consultant; Self; Janssen Research &amp; Development, LLC. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK121843-01); JDRF (3-SRA-2019-827-S-B)

Interaction of diabetes genetic risk and successful lifestyle modification in the Diabetes Prevention Programme.

To test whether diabetes genetic risk modifies the association of successful lifestyle changes with incident diabetes. We studied 823 individuals randomized to the intensive lifestyle intervention (ILS) arm of the Diabetes Prevention Programme who were diabetes-free 1 year after enrolment. We tested additive and multiplicative interactions of a 67-variant diabetes genetic risk score (GRS) with achievement of three ILS goals at 1 year (≥7% weight loss, ≥150 min/wk of moderate leisure-time physical activity, and/or a goal for self-reported total fat intake) on the primary outcome of incident diabetes over 3 years of follow-up. A lower GRS and achieving each or all three ILS goals were each associated with lower incidence of diabetes (all P < 0.05). Additive interactions were significant between the GRS and achievement of the weight loss goal (P < 0.001), physical activity goal (P = 0.02), and all three ILS goals (P < 0.001) for diabetes risk. Achievement of all three ILS goals was associated with 1.8 (95% CI 0.3, 3.4), 3.1 (95% CI 1.5, 4.7), and 3.9 (95% CI 1.6, 6.2) fewer diabetes cases/100-person-years in the first, second and third GRS tertiles (P < 0.001 for trend). Multiplicative interactions between the GRS and ILS goal achievement were significant for the diet goal (P < 0.001), but not for weight loss (P = 0.18) or physical activity (P = 0.62) goals. Genetic risk may identify high-risk subgroups for whom successful lifestyle modification is associated with greater absolute reduction in the risk of incident diabetes.

Genetic Composition and Autoantibody Titers Model the Probability of Detecting C-Peptide Following Type 1 Diabetes Diagnosis.

We and others previously demonstrated that a type 1 diabetes genetic risk score (GRS) improves the ability to predict disease progression and onset in at-risk subjects with islet autoantibodies. Here, we hypothesized that GRS and islet autoantibodies, combined with age at onset and disease duration, could serve as markers of residual β-cell function following type 1 diabetes diagnosis. Generalized estimating equations were used to investigate whether GRS along with insulinoma-associated protein-2 autoantibody (IA–2A), zinc transporter 8 autoantibody (ZnT8A), and GAD autoantibody (GADA) titers were predictive of C-peptide detection in a largely cross-sectional cohort of 401 subjects with type 1 diabetes (median duration 4.5 years [range 0–60]). Indeed, a combined model with incorporation of disease duration, age at onset, GRS, and titers of IA–2A, ZnT8A, and GADA provided superior capacity to predict C-peptide detection (quasi-likelihood information criterion [QIC] = 334.6) compared with the capacity of disease duration, age at onset, and GRS as the sole parameters (QIC = 359.2). These findings support the need for longitudinal validation of our combinatorial model. The ability to project the rate and extent of decline in residual C-peptide production for individuals with type 1 diabetes could critically inform enrollment and benchmarking for clinical trials where investigators are seeking to preserve or restore endogenous β-cell function.

The Absence of Islet Autoantibodies in Clinically Diagnosed Older-Adult Onset Type 1 Diabetes Suggests an Alternative Pathology, Advocating for Routine Testing in This Age Group

Objective: Islet autoantibodies at diagnosis are not well studied in older-adult onset (>30years) type 1 diabetes due to difficulties of accurate diagnosis. We used a type 1 diabetes genetic risk score (T1DGRS) to identify type 1 diabetes aiming to evaluate the prevalence and pattern of autoantibodies in older-adult onset type 1 diabetes. Methods: We used a 30 variant T1DGRS in 1866 white-European individuals to genetically confirm a clinical diagnosis of new onset type 1 diabetes. We then assessed the prevalence and pattern of GADA, IA2A and ZnT8A within genetically consistent type 1 diabetes across three age groups ( 30years (n=588)). Findings: In autoantibody positive cases T1DGRS was consistent with 100% type 1 diabetes in each age group. Conversely in autoantibody negative cases, T1DGRS was consistent with 93%(56/60) of 30years having type 1 diabetes. Restricting analysis to genetically consistent type 1 diabetes showed similar proportions of positive autoantibodies across age groups (92% 30years)[p=0.87]. GADA was the most common autoantibody in older-adult onset type 1 diabetes, identifying 95% of autoantibody positive cases versus 72% in those <18years. Interpretation: Older adult-onset type 1 diabetes has identical rates but different patterns of positive autoantibodies to childhood onset. In clinically suspected type 1 diabetes in older-adults, absence of autoantibodies strongly suggests non-autoimmune diabetes. Our findings suggest the need to change guidelines from measuring islet autoantibodies where there is diagnostic uncertainty to measuring at least GADA in all suspected adult type 1 diabetes cases. Funding Statement: NJT is funded by a Wellcome Trust funded GW4 PhD (220601/Z/20/Z). M.N.W. is supported by the Wellcome Trust Institutional Support Fund (WT097835MF). KAP is a Wellcome Trust fellow (219606/Z/19/Z) and the genetic risk score analysis in ADDRESS-2 was funded by Diabetes wellness Research foundation pump priming grant. ADDRESS-2 is co-funded by Diabetes UK (grant numbers 09-0003919, 15-005234 & 19/0006119) and the Juvenile Diabetes Research Foundation (grant numbers 9-2010-407 & 3-SRA-2015-35-A-N), supported by the NIHR Clinical Research Network and hosted by Imperial College London. S.M. is currently supported by a Future Leaders Mentorship award from the European Federation for the Study of Diabetes. NO is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College London. DJ is funded by the NIHR CRN. Declaration of Interests: We declare no competing interest. Ethics Approval Statement:Ethics for the ADDRESS2 study was granted by the South Central – Berkshire NHS Research Ethics Committee on the 03/10/2010, ref: 10/H0505/85. Ethics for monogenic testing in the ADDRESS2 cohort by the East of England – Essex Research Ethics Committee on the 14/7/2016, ref 16/EE/0306

Type 1 diabetes can present before the age of 6\xa0months and is characterised by autoimmunity and rapid loss of beta cells

Aims/hypothesisDiabetes diagnosed at <6 months of age is usually monogenic. However, 10–15% of affected infants do not have a pathogenic variant in one of the 26 known neonatal diabetes genes. We characterised infants diagnosed at <6 months of age without a pathogenic variant to assess whether polygenic type 1 diabetes could arise at early ages.MethodsWe studied 166 infants diagnosed with type 1 diabetes at <6 months of age in whom pathogenic variants in all 26 known genes had been excluded and compared them with infants with monogenic neonatal diabetes (n = 164) or children with type 1 diabetes diagnosed at 6–24 months of age (n = 152). We assessed the type 1 diabetes genetic risk score (T1D-GRS), islet autoantibodies, C-peptide and clinical features.ResultsWe found an excess of infants with high T1D-GRS: 38% (63/166) had a T1D-GRS >95th centile of healthy individuals, whereas 5% (8/166) would be expected if all were monogenic (p < 0.0001). Individuals with a high T1D-GRS had a similar rate of autoantibody positivity to that seen in individuals with type 1 diabetes diagnosed at 6–24 months of age (41% vs 58%, p = 0.2), and had markedly reduced C-peptide levels (median <3 pmol/l within 1 year of diagnosis), reflecting rapid loss of insulin secretion. These individuals also had reduced birthweights (median z score −0.89), which were lowest in those diagnosed with type 1 diabetes at <3 months of age (median z score −1.98).Conclusions/interpretationWe provide strong evidence that type 1 diabetes can present before the age of 6 months based on individuals with this extremely early-onset diabetes subtype having the classic features of childhood type 1 diabetes: high genetic risk, autoimmunity and rapid beta cell loss. The early-onset association with reduced birthweight raises the possibility that for some individuals there was reduced insulin secretion in utero. Comprehensive genetic testing for all neonatal diabetes genes remains essential for all individuals diagnosed with diabetes at <6 months of age.Graphical abstract

Type 1 diabetes in Africa: an immunogenetic study in the Amhara of North-West Ethiopia

Aims/hypothesisWe aimed to characterise the immunogenic background of insulin-dependent diabetes in a resource-poor rural African community. The study was initiated because reports of low autoantibody prevalence and phenotypic differences from European-origin cases with type 1 diabetes have raised doubts as to the role of autoimmunity in this and similar populations.MethodsA study of consecutive, unselected cases of recently diagnosed, insulin-dependent diabetes (n = 236, ≤35 years) and control participants (n = 200) was carried out in the ethnic Amhara of rural North-West Ethiopia. We assessed their demographic and socioeconomic characteristics, and measured non-fasting C-peptide, diabetes-associated autoantibodies and HLA-DRB1 alleles. Leveraging genome-wide genotyping, we performed both a principal component analysis and, given the relatively modest sample size, a provisional genome-wide association study. Type 1 diabetes genetic risk scores were calculated to compare their genetic background with known European type 1 diabetes determinants.ResultsPatients presented with stunted growth and low BMI, and were insulin sensitive; only 15.3% had diabetes onset at ≤15 years. C-peptide levels were low but not absent. With clinical diabetes onset at ≤15, 16–25 and 26–35 years, 86.1%, 59.7% and 50.0% were autoantibody positive, respectively. Most had autoantibodies to GAD (GADA) as a single antibody; the prevalence of positivity for autoantibodies to IA-2 (IA-2A) and ZnT8 (ZnT8A) was low in all age groups. Principal component analysis showed that the Amhara genomes were distinct from modern European and other African genomes. HLA-DRB1*03:01 (p = 0.0014) and HLA-DRB1*04 (p = 0.0001) were positively associated with this form of diabetes, while HLA-DRB1*15 was protective (p < 0.0001). The mean type 1 diabetes genetic risk score (derived from European data) was higher in patients than control participants (p = 1.60 × 10−7). Interestingly, despite the modest sample size, autoantibody-positive patients revealed evidence of association with SNPs in the well-characterised MHC region, already known to explain half of type 1 diabetes heritability in Europeans.Conclusions/interpretationThe majority of patients with insulin-dependent diabetes in rural North-West Ethiopia have the immunogenetic characteristics of autoimmune type 1 diabetes. Phenotypic differences between type 1 diabetes in rural North-West Ethiopia and the industrialised world remain unexplained.