Autoimmunity plays a role in the onset of diabetes after 40 years of age

Abstract Aims/hypothesis Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

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A Comprehensive Type 1 Diabetes Genetic Risk Score Is Associated with Type 2 Diabetes in the Framingham Heart Study

Diabetes ◽

10.2337/db18-1715-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1715-P

Author(s):

SHYLAJA SRINIVASAN ◽

AARON LEONG ◽

MIRIAM UDLER ◽

BIANCA C. PORNEALA ◽

JAMES B. MEIGS ◽

...

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Risk Score ◽

Genetic Risk ◽

Framingham Heart Study ◽

Genetic Risk Score ◽

Heart Study

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A Type 1 Diabetes Genetic Risk Score Can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults

Diabetes Care ◽

10.2337/dc15-1111 ◽

2015 ◽

Vol 39 (3) ◽

pp. 337-344 ◽

Cited By ~ 111

Author(s):

Richard A. Oram ◽

Kashyap Patel ◽

Anita Hill ◽

Beverley Shields ◽

Timothy J. McDonald ◽

...

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Young Adults ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score

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Next steps in the identification of gene targets for type 1 diabetes

Diabetologia ◽

10.1007/s00125-020-05248-8 ◽

2020 ◽

Vol 63 (11) ◽

pp. 2260-2269 ◽

Cited By ~ 1

Author(s):

Struan F. A. Grant ◽

Andrew D. Wells ◽

Stephen S. Rich

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Beta Cell ◽

Genetic Risk ◽

Genetic Risk Score ◽

Cell Types ◽

Total Risk ◽

Chromosome Conformation

Abstract The purpose of this review is to provide a view of the future of genomics and other omics approaches in defining the genetic contribution to all stages of risk of type 1 diabetes and the functional impact and clinical implementations of the associated variants. From the recognition nearly 50 years ago that genetics (in the form of HLA) distinguishes risk of type 1 diabetes from type 2 diabetes, advances in technology and sample acquisition through collaboration have identified over 60 loci harbouring SNPs associated with type 1 diabetes risk. Coupled with HLA region genes, these variants account for the majority of the genetic risk (~50% of the total risk); however, relatively few variants are located in coding regions of genes exerting a predicted protein change. The vast majority of genetic risk in type 1 diabetes appears to be attributed to regions of the genome involved in gene regulation, but the target effectors of those genetic variants are not readily identifiable. Although past genetic studies clearly implicated immune-relevant cell types involved in risk, the target organ (the beta cell) was left untouched. Through emergent technologies, using combinations of genetics, gene expression, epigenetics, chromosome conformation and gene editing, novel landscapes of how SNPs regulate genes have emerged. Furthermore, both the immune system and the beta cell and their biological pathways have been implicated in a context-specific manner. The use of variants from immune and beta cell studies distinguish type 1 diabetes from type 2 diabetes and, when they are combined in a genetic risk score, open new avenues for prediction and treatment.

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A Type 1 Diabetes Genetic Risk Score Can Identify Patients With GAD65 Autoantibody–Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy

Diabetes Care ◽

10.2337/dc18-0431 ◽

2018 ◽

Vol 42 (2) ◽

pp. 208-214 ◽

Cited By ~ 12

Author(s):

Anita L. Grubb ◽

Timothy J. McDonald ◽

Femke Rutters ◽

Louise A. Donnelly ◽

Andrew T. Hattersley ◽

...

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Insulin Therapy ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Positive Type

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Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105532 ◽

2018 ◽

Vol 56 (9) ◽

pp. 602-605 ◽

Cited By ~ 4

Author(s):

Andreas Beyerlein ◽

Ezio Bonifacio ◽

Kendra Vehik ◽

Markus Hippich ◽

Christiane Winkler ◽

...

Keyword(s):

Type 1 Diabetes ◽

Risk Score ◽

Genetic Risk ◽

Genetic Factors ◽

Genetic Risk Score ◽

Risk Scores ◽

Islet Autoimmunity ◽

Islet Autoantibody ◽

Clinical Type

BackgroundProgression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown.MethodsIn 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression.ResultsIslet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93).ConclusionsGenetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

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SNP-Based Genetic Risk Score Modeling Suggests No Increased Genetic Susceptibility of the Roma Population to Type 2 Diabetes Mellitus

Genes ◽

10.3390/genes10110942 ◽

2019 ◽

Vol 10 (11) ◽

pp. 942 ◽

Cited By ~ 7

Author(s):

Nardos Abebe Werissa ◽

Peter Piko ◽

Szilvia Fiatal ◽

Zsigmond Kosa ◽

Janos Sandor ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

General Population ◽

Genetic Risk ◽

Genetic Risk Score ◽

Risk Scores ◽

Unhealthy Lifestyle ◽

Roma Population

Background: In a previous survey, an elevated fasting glucose level (FG) and/or known type 2 diabetes mellitus (T2DM) were significantly more frequent in the Roma population than in the Hungarian general population. We assessed whether the distribution of 16 single nucleotide polymorphisms (SNPs) with unequivocal effects on the development of T2DM contributes to this higher prevalence. Methods: Genetic risk scores, unweighted (GRS) and weighted (wGRS), were computed and compared between the study populations. Associations between GRSs and FG levels and T2DM status were investigated in separate and combined study populations. Results: The Hungarian general population carried a greater genetic risk for the development of T2DM (GRSGeneral = 15.38 ± 2.70 vs. GRSRoma = 14.80 ± 2.68, p < 0.001; wGRSGeneral = 1.41 ± 0.32 vs. wGRSRoma = 1.36 ± 0.31, p < 0.001). In the combined population models, GRSs and wGRSs showed significant associations with elevated FG (p < 0.001) and T2DM (p < 0.001) after adjusting for ethnicity, age, sex, body mass index (BMI), high-density Lipoprotein Cholesterol (HDL-C), and triglyceride (TG). In these models, the effect of ethnicity was relatively strong on both outcomes (FG levels: βethnicity = 0.918, p < 0.001; T2DM status: ORethnicity = 2.484, p < 0.001). Conclusions: The higher prevalence of elevated FG and/or T2DM among Roma does not seem to be directly linked to their increased genetic load but rather to their environmental/cultural attributes. Interventions targeting T2DM prevention among Roma should focus on harmful environmental exposures related to their unhealthy lifestyle.

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Type 2 Diabetes Genetic Risk Scores Are Associated With Increased Type 2 Diabetes Risk Among African Americans by Cardiometabolic Status

Clinical Medicine Insights Endocrinology and Diabetes ◽

10.1177/1179551417748942 ◽

2018 ◽

Vol 11 ◽

pp. 117955141774894 ◽

Cited By ~ 7

Author(s):

Jill Layton ◽

Xiaochen Li ◽

Changyu Shen ◽

Mary de Groot ◽

Leslie Lange ◽

...

Keyword(s):

Type 2 Diabetes ◽

African Americans ◽

Genetic Risk ◽

Genetic Risk Score ◽

Diabetes Risk ◽

Risk Scores ◽

Genetic Risk Scores ◽

Normal Ranges ◽

Increased Risk

The relationship between genetic risk variants associated with glucose homeostasis and type 2 diabetes risk has yet to be fully explored in African American populations. We pooled data from 4 prospective studies including 4622 African Americans to assess whether β-cell dysfunction (BCD) and/or insulin resistance (IR) genetic variants were associated with increased type 2 diabetes risk. The BCD genetic risk score (GRS) and combined BCD/IR GRS were significantly associated with increased type 2 diabetes risk. In cardiometabolic-stratified models, the BCD and IR GRS were associated with increased type 2 diabetes risk among 5 cardiometabolic strata: 3 clinically healthy strata and 2 clinically unhealthy strata. Genetic risk scores related to BCD and IR were associated with increased risk of type 2 diabetes in African Americans. Notably, the GRSs were significant predictors of type 2 diabetes among individuals in clinically normal ranges of cardiometabolic traits.

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Ancestry-Matched and Cross-Ancestry Genetic Risk Scores of Type 2 Diabetes in Pregnant Women and Fetal Growth—A Study in an Ancestrally Diverse Cohort

10.2337/figshare.16999933 ◽

2021 ◽

Author(s):

Marion Ouidir ◽

Xuehuo Zeng ◽

Suvo Chatterjee ◽

Cuilin Zhang ◽

Fasil Tekola-Ayele

Keyword(s):

Type 2 Diabetes ◽

Birth Weight ◽

Pregnant Women ◽

Fetal Growth ◽

Genetic Risk ◽

Genetic Risk Score ◽

Challenge Test ◽

Fetal Weight ◽

Risk Scores

Maternal genetic variants associated with offspring birth weight and adult type 2 diabetes (T2D) risk loci show some overlap. Whether T2D genetic risk influences longitudinal fetal weight and the gestational timing when these relationships begin is unknown. We investigated the associations of T2D genetic risk score (GRS) with longitudinal fetal weight and birth weight among 1,513 pregnant women from four ancestral groups. Women had up to 5 ultrasonography. Ancestry-matched GRS were constructed separately using 380 European- (GRSeur), 104 African- (GRSafr), and 189 East Asian- (GRSeas) related T2D loci discovered in different population groups. Among European Americans, the highest quartile GRSeur was significantly associated with 53.8 g higher fetal weight (95% confidence interval [CI] 19.2-88.5 g) over the pregnancy. The associations began at gestational week 24 and continued through week 40, with a 106.8 g (95% CI: 6.5-207.1 g) increase in birth weight. The findings were similar in analysis further adjusted for maternal glucose challenge test results. No consistent association was found using ancestry-matched or cross-ancestry GRS in non-Europeans. In conclusion, T2D genetic susceptibility may influence fetal growth starting at mid-second trimester among Europeans. Absence of similar associations in non-Europeans urges the need for further genetic T2D studies in diverse ancestries.

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Genetic architecture of type 1 diabetes with low genetic risk score informed by 41 unreported loci

Communications Biology ◽

10.1038/s42003-021-02368-8 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Hui-Qi Qu ◽

Jingchun Qu ◽

Jonathan Bradfield ◽

Luc Marchand ◽

Joseph Glessner ◽

...

Keyword(s):

Type 1 Diabetes ◽

Genetic Risk ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Rare Variants ◽

Genetic Risk Score ◽

Autism Spectrum ◽

Risk Scores ◽

Interferon Α

AbstractType 1 diabetes (T1D) patients with low genetic risk scores (GRS) may be non-autoimmune or autoimmune mediated by other genetic loci. The T1D-GRS2 provides us an opportunity to look into the genetic architecture of these patients. A total of 18,949 European individuals were included in this study, including 6599 T1D cases and 12,323 controls. 957 (14.5%) T1D patients were identified with low GRS (GRS < 8.43). The genome-wide association study on these patients identified 41 unreported loci. Two loci with common variants and 39 loci with rare variants were identified in this study. This study identified common SNPs associated with both low GRS T1D and expression levels of the interferon-α-induced MNDA gene, indicating the role of viral infection in T1D. Interestingly, 16 of the 41 unreported loci have been linked to autism spectrum disorder (ASD) by previous studies, suggesting that genes residing at these loci may underlie both T1D and autism.

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