Genetic risk factors affecting mitochondrial function are associated with kidney disease in people with Type 1 diabetes

Abstract Type 1 diabetes arises from the autoimmune destruction of insulin-producing beta-cells of the pancreas, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis. In this study, our aim was to identify genetic risk factors that contribute to progression from islet autoimmunity to clinical type 1 diabetes. We analyzed 6.8 million variants derived from whole genome sequencing of 160 islet autoantibody positive subjects, including 87 who had progressed to type 1 diabetes. The Cox proportional-hazard model for survival analysis was used to identify genetic variants associated with progression. We identified one novel region, 20p12.1 (TASP1; genome-wide P < 5 × 10–8) and three regions, 1q21.3 (MRPS21–PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 × 10–8) with progression from islet autoimmunity to type 1 diabetes. Once islet autoimmunity is initiated, functional mapping identified two critical pathways, response to viral infections and interferon signaling, as contributing to disease progression. These results provide evidence that genetic pathways involved in progression from islet autoimmunity differ from those pathways identified once disease has been established. These results support the need for further investigation of genetic risk factors that modulate initiation and progression of subclinical disease to inform efforts in development of novel strategies for prediction and intervention of type 1 diabetes.

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Genetic risk factors for type 1 diabetes

The Lancet ◽

10.1016/s0140-6736(16)30582-7 ◽

2016 ◽

Vol 387 (10035) ◽

pp. 2331-2339 ◽

Cited By ~ 196

Author(s):

Flemming Pociot ◽

Åke Lernmark

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Genetic Risk ◽

Genetic Risk Factors

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General population screening for childhood type 1 diabetes: is it time for a UK strategy?

Archives of Disease in Childhood ◽

10.1136/archdischild-2021-321864 ◽

2021 ◽

pp. archdischild-2021-321864

Author(s):

Rachel Elizabeth Jane Besser ◽

Sze May Ng ◽

John W Gregory ◽

Colin M Dayan ◽

Tabitha Randell ◽

...

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Population Based ◽

Screening Strategy ◽

Smooth Transition ◽

Islet Autoantibodies ◽

Awareness Campaigns

Type 1 diabetes (T1D) is a chronic autoimmune disease of childhood affecting 1:500 children aged under 15 years, with around 25% presenting with life-threatening diabetic ketoacidosis (DKA). While first-degree relatives have the highest risk of T1D, more than 85% of children who develop T1D do not have a family history. Despite public health awareness campaigns, DKA rates have not fallen over the last decade. T1D has a long prodrome, and it is now possible to identify children who go on to develop T1D with a high degree of certainty. The reasons for identifying children presymptomatically include prevention of DKA and related morbidities and mortality, reducing the need for hospitalisation, time to provide emotional support and education to ensure a smooth transition to insulin treatment, and opportunities for new treatments to prevent or delay progression. Research studies of population-based screening strategies include using islet autoantibodies alone or in combination with genetic risk factors, both of which can be measured from a capillary sample. If found during screening, the presence of two or more islet autoantibodies has a high positive predictive value for future T1D in childhood (under 18 years), offering an opportunity for DKA prevention. However, a single time-point test will not identify all children who go on to develop T1D, and so combining with genetic risk factors for T1D may be an alternative approach. Here we discuss the pros and cons of T1D screening in the UK, the different strategies available, the knowledge gaps and why a T1D screening strategy is needed.

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Prediction of autoimmune diabetes and celiac disease in childhood by genes and perinatal environment: Design and initial aims of the PAGE study

Norsk Epidemiologi ◽

10.5324/nje.v24i1-2.1811 ◽

2014 ◽

Vol 24 (1-2) ◽

Author(s):

Lars C. Stene ◽

Geir Joner ◽

Ketil Størdal

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Celiac Disease ◽

Blood Plasma ◽

Genetic Risk ◽

Autoimmune Diabetes ◽

Genetic Risk Factors ◽

Host Cells ◽

Full Cohort

Type 1 diabetes and celiac disease result from misdirected immune mediated destruction of host cells, and are among the most common chronic diseases in children. Despite changes in incidence over the past 3 decades, little is known about non-genetic risk factors (except for dietary gluten for celiac disease). Norway is among the countries in the world with the highest incidence of these two diseases. We describe here plans and study design for the PAGE study (Prediction of Autoimmune diabetes and celiac disease in childhood by Genes and perinatal Environment). PAGE is a sub-study within the Norwegian Mother and Child Cohort study, including follow-up of more than 100,000 pregnancies. Children who develop type 1 diabetes or celiac disease are identified via linkage to the Norwegian Patient Register and the Norwegian Childhood Diabetes Registry, with complementing information from questionnaires. The overall aim is to test hypotheses about potential non-genetic risk factors for type 1 diabetes and for celiac disease, with focus on factors operating early in life. In addition to a full cohort analysis of factors registered in questionnaires, we will analyse biomarkers in maternal blood plasma and cord blood plasma. Mothers and children will be genotyped for well-established susceptibility polymorphisms. Biomarkers will be analysed in cases and controls within the cohort. Factors to be tested in the full cohort include infant feeding, diet and dietary supplements in the mother during pregnancy and in the child, and use of antibiotics and non-prescription drugs. Biomarkers to be tested include 25-hydroxyvitamin D, markers of immune activation, and small metabolites (metabolomics). We will also explore the potential role of maternal cells in the fetal circulation (maternal microchimerism) in later risk of celiac disease and type 1 diabetes.

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Risk Factors for Kidney Disease in Type 1 Diabetes

Diabetes Care ◽

10.2337/dc18-2062 ◽

2019 ◽

Vol 42 (5) ◽

pp. 883-890 ◽

Cited By ~ 13

Author(s):

Bruce A. Perkins ◽

Ionut Bebu ◽

Ian H. de Boer ◽

Mark Molitch ◽

William Tamborlane ◽

...

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Kidney Disease

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Presence and Determinants of Cardiovascular Disease and Mortality in Individuals With Type 1 Diabetes of Long Duration: The FinnDiane 50 Years of Diabetes Study

10.2337/figshare.14626908.v1 ◽

2021 ◽

Author(s):

Valma Harjutsalo ◽

Drazenka Pongrac Barlovic ◽

Daniel Gordin ◽

Carol Forsblom ◽

George King ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Type 1 Diabetes ◽

Kidney Disease ◽

Cumulative Incidence ◽

Diabetes Duration ◽

Baseline Visit ◽

Background Population ◽

Long Duration

Objective The aim of this study was to determine the incidence of cardiovascular disease (CVD) and mortality as well as their risk factors in type 1 diabetes (T1D) with more than 50-years duration. Methods From 5,396 individuals included in the Finnish Diabetic Nephropathy Study, 729 diagnosed in 1967 or earlier survived with T1D for more than 50 years. In this FinnDiane 50-year cohort, cumulative incidence of CVD events was assessed from the diagnosis of diabetes, and the excess CVD risk, compared to matched 12,710 individuals without diabetes, was calculated by Fine and Gray’s method. In addition, at the baseline visit (median duration of diabetes of 39 years) risk factors for different types of CVD (both non-fatal and fatal) and mortality were analyzed and cause-specific hazard ratios were estimated during a median follow-up of 16.6 years from the baseline visit. Results In individuals with diabetes duration of more than 50 years, the 60-year cumulative incidence of CVD from the diagnosis of diabetes was 64.3% (62.5-66.0). Compared to individuals without diabetes, the standardized incidence ratio for CVD was 7.4 (6.5-8.3) and was in persons with normoalbuminuria 4.9 (4.0-5.9). Mean HbA1c and HbA1c variability, dyslipidemia, BMI, kidney disease, age and diabetes duration were the variables associated with incident CVD. In particular, HbA1c was associated with peripheral artery disease (PAD). Standardized mortality ratio compared with the Finnish background population was 3.2 (2.8-3.7). The factors, associated with mortality were diabetes duration, increased HbA1c variability, inflammation, insulin resistance, kidney disease and PAD. Conclusions Individuals with T1D of very long duration are at a high risk of CVD. In addition, throughout the lifespan, optimal glycemic control remains central to CVD and excess mortality prevention.

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Angiotensin-converting enzyme insertion/deletion and angiotensin type 1 receptor A1166C polymorphisms as genetic risk factors in benign prostatic hyperplasia and prostate cancer

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320309352800 ◽

2009 ◽

Vol 10 (4) ◽

pp. 241-246 ◽

Cited By ~ 15

Author(s):

Erick Sierra Díaz ◽

José Sánchez Corona ◽

Roberto Carlos Rosales Gómez ◽

Susan Andrea Gutierrez Rubio ◽

José Gonzalo Vázquez Camacho ◽

...

Keyword(s):

Prostate Cancer ◽

Risk Factors ◽

Benign Prostatic Hyperplasia ◽

Angiotensin Converting Enzyme ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Prostatic Hyperplasia ◽

Converting Enzyme ◽

Angiotensin Type

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Elevated Urinary VEGF-A,Transferrin, and Angiotensinogen Levels in Normoalbuminuric Children and Adolescents with Type 1 Diabetes; Can They Be Early Markers of Diabetic Kidney Disease?

Hormone Research in Paediatrics ◽

10.1159/000521447 ◽

2021 ◽

Author(s):

Aydilek Dağdeviren Çakır ◽

Seha Kamil Saygılı ◽

Nur Canpolat ◽

Dildar Konukoğlu ◽

Hande Turan ◽

...

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Kidney Disease ◽

Children And Adolescents ◽

Diabetic Kidney Disease ◽

Disease Duration ◽

Healthy Children ◽

Diabetic Kidney ◽

The Mean

Objective: We hypothesized that diabetic kidney disease (DKD) begins early, before albuminuria occurs. We therefore aimed to assess potential early urinary biomarkers of (DKD) in normoalbuminuric and normotensive children and adolescents with Type 1 Diabetes (T1D) to evaluate the relationship between these markers and clinical and laboratory risk factors for DKD. Methods: This cross-sectional study included 75 children and adolescents with T1D (62% females, mean age 13.9 ± 3.2 years) with normoalbuminuria [an albumin/creatinine ratio (ACR) below 30 mg/g creatinine]. Fifty-five age- and sex-matched healthy children and adolescents served as controls. For the assessment of early DKD, urinary levels of angiotensinogen (AGT), transferrin, nephrin, vascular endothelial growth factor-A (VEGF-A), and kidney injury molecule-1 (KIM-1) were measured in adequately collected 24-h urine samples using enzyme-linked immunoassays. Results: The mean disease duration was 7.3± 3.2 (ranged 2.1 - 15.7) years and the mean HbA1c level was 8.8±1.4%. The median levels of urine VEGF-A/Cr, AGT/Cr, and Transferrin/Cr were significantly higher in normoalbuminuric patients with T1D, compared with those of controls (p<0.001, p=0.02, and p=0.001, respectively), but there was no difference in nephrin/Cr and KIM-1/Cr between the two groups. Although, none of the patients had albuminuria, the median level of urine ACR was significantly higher in the patient group than the control group (p=0.003). The ACR was positively correlated with glomerular filtration rate (GFR). Urinary transferrin/Cr, AGT/Cr, and VEGF-A/Cr were significantly correlated with ACR, but not with either GFR or diabetic risk factors including HbA1c or disease duration. Conclusion: Normoalbuminuric and normotensive children and adolescents with T1D have elevated urinary VEGF, AGT and transferrin levels, which may indicate the development of DKD before albuminuria occurs.

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