Blood methylation biomarkers are associated with diabetic kidney disease progression in type 1 diabetes.

Background: DNA methylation differences are associated with kidney function and diabetic kidney disease (DKD), but prospective studies are scarce. Therefore, we aimed to study DNA methylation in a prospective setting in the Finnish Diabetic Nephropathy Study type 1 diabetes (T1D) cohort.

Methods: We analysed baseline blood sample-derived DNA methylation (Illumina's EPIC array) of 403 individuals with normal albumin excretion rate (early progression group) and 373 individuals with severe albuminuria (late progression group) and followed-up their DKD progression defined as decrease in eGFR to <60 mL/min/1.

Whole-exome and whole-genome sequencing of 1064 individuals with type 1 diabetes reveals novel genes for diabetic kidney disease.

Aims/hypothesis: Diabetic kidney disease (DKD) is a severe diabetic complication that affects one third of individuals with type 1 diabetes. Although several genes and common variants have been shown to be associated with DKD, much of the predicted inheritance remains unexplained. Here, we performed next-generation sequencing to assess whether low-frequency variants, extending to a minor allele frequency (MAF) ≤10% (single or aggregated) contribute to the missing heritability in DKD.

Whole-genome sequencing identifies variants in ANK1, LRRN1, HAS1, and other genes and regulatory regions for stroke in type 1 diabetes.

Individuals with type 1 diabetes (T1D) carry a markedly increased risk of stroke, with distinct clinical and neuroimaging characteristics as compared to those without diabetes. Using whole-exome or whole-genome sequencing of 1,051 individuals with T1D, we aimed to find rare and low-frequency genomic variants associated with stroke in T1D. We analysed the genome comprehensively with single-variant analyses, gene aggregate analyses, and aggregate analyses on genomic windows, enhancers and promoters.

Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes.

Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up.

Residual insulin secretion in individuals with type 1 diabetes in Finland: longitudinal and cross-sectional analyses.

Background: Contrary to the presumption that type 1 diabetes leads to an absolute insulin deficiency, many individuals with type 1 diabetes have circulating C-peptide years after the diagnosis. We studied factors affecting random serum C-peptide concentration in individuals with type 1 diabetes and the association with diabetic complications.

Methods: Our longitudinal analysis included individuals newly diagnosed with type 1 diabetes from Helsinki University Hospital (Helsinki, Finland) with repeated random serum C-peptide and concomitant glucose measurements from within 3 months of diagnosis and at least once later.

Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes.

Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome-wide methylation patterns are poorly defined.

Telomeres in clinical diabetes research - Moving towards precision medicine in diabetes care?

The early prediction of health outcomes for people with diabetes mellitus is desirable, as are adjunct therapies to reduce the related chronic complications and risk of premature death. The length of telomeres, protective caps on chromosome ends, is influenced by genetic and acquired factors, and shorter telomeres have been associated with and predictive of adverse cardiometabolic outcomes. Many studies have shown associations between telomere length in white blood cells (WBC) and diabetes per se and its chronic complications, and some studies show that telomeres do not always progressively shorten in people with diabetes.

Whole-exome sequencing identifies novel protein-altering variants associated with serum apolipoprotein and lipid concentrations.

Background: Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism.

Haptoglobin Genotype Does Not Confer a Risk of Stroke in Type 1 Diabetes.

The exon copy number variant in the haptoglobin gene is associated with cardiovascular and kidney disease. For stroke, previous research is inconclusive. We aimed to study the relationship between the haptoglobin Hp1/2 genotype and stroke in individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study.

Telomeres do not always shorten over time in individuals with type 1 diabetes.

Aims: We aimed to determine how white blood cell (WBC) telomeres and telomere length change over time are associated with health status in type 1 diabetes.

Methods: Relative telomere length (rTL) was measured in WBC DNA from two time-points (median 6.8 years apart) in 618 individuals from the Finnish Diabetic Nephropathy Study by quantitative PCR, with interassay CV ≤ 4%.

Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus.

Aims: Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied.

Is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes.

Diabetic retinopathy is a common diabetes complication that threatens the eyesight and may eventually lead to acquired visual impairment or blindness. While a substantial heritability has been reported for proliferative diabetic retinopathy (PDR), only a few genetic risk factors have been identified. Using genome-wide sib pair linkage analysis including 361 individuals with type 1 diabetes, we found suggestive evidence of linkage with PDR at chromosome 10p12 overlapping the gene (logarithm of odds = 2.

Genetic Determinants of Glycated Hemoglobin in Type 1 Diabetes.

Glycated hemoglobin (HbA) is an important measure of glycemia in diabetes. HbA is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA in a Finnish type 1 diabetes (T1D) cohort, FinnDiane.

Effects of a single bout of interval hypoxia on cardiorespiratory control in patients with type 1 diabetes.

Hypoxemia is common in diabetes, and reflex responses to hypoxia are blunted. These abnormalities could lead to cardiovascular/renal complications. Interval hypoxia (IH) (5-6 short periods of hypoxia each day over 1-3 weeks) was successfully used to improve the adaptation to hypoxia in patients with chronic obstructive pulmonary disease.

New susceptibility loci associated with kidney disease in type 1 diabetes.

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN.

Association testing of previously reported variants in a large case-control meta-analysis of diabetic nephropathy.

We formed the GEnetics of Nephropathy-an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K.

Genetic examination of SETD7 and SUV39H1/H2 methyltransferases and the risk of diabetes complications in patients with type 1 diabetes.

Objective: Hyperglycemia plays a pivotal role in the development and progression of vascular complications, which are the major sources of morbidity and mortality in diabetes. Furthermore, these vascular complications often persist and progress despite improved glucose control, possibly as a result of prior episodes of hyperglycemia. Epigenetic modifications mediated by histone methyltransferases are associated with gene-activating events that promote enhanced expression of key proinflammatory molecules implicated in vascular injury.