Showing papers by "Ronald Klein published in 2021"

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

Abstract: Background Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of end stage kidney disease (ESKD) in individuals with type 1 diabetes at advanced kidney disease stage. Methods Gene-based exome array analysis of 15,449 genes in 5 large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time-to-ESKD, testing the top gene in a 6th cohort (N=2,372/1,115 events all cohorts) and replicating in two retrospective case-control studies (N=1,072 cases, 752 controls). Deep resequencing of the top associated gene in 5 cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. Results Protein coding variants in the hydroxysteroid 17-beta dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (N=4,196; p-value=3.3x10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other chronic kidney disease-associated renal pathologies. Conclusions HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.

Metformin and carotid intima-media thickness in never-smokers with type 1 diabetes: The REMOVAL trial

Abstract: Aim: To determine whether metformin's effects on carotid artery intima‐media thickness (cIMT) in type 1 diabetes differ according to smoking status. Methods: Regression model effect estimates for the effect of metformin versus placebo (double‐blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial. Results: In 428 randomized participants (227 never‐smokers, 201 ever‐smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never‐smokers (−0.012 mm, 95% CI −0.021 to −0.002; p = .0137) but not in ever‐smokers (0.003 mm, 95% CI −0.008 to 0.014; p = .5767); and similarly in non‐current smokers (−0.008 mm, 95% CI −0.015 to −0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI −0.007 to 0.032; p = .1887). Three‐way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non‐current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never‐smokers (−0.020 mm, 95% CI −0.034 to −0.006; p = .0067) but not in ever‐smokers (−0.006 mm, 95% CI −0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three‐way interaction term. Conclusions: This subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes.

Incidence and progression of diabetic retinopathy in a multi-ethnic US cohort: the Multi-Ethnic Study of Atherosclerosis.

Abstract: Aim To provide contemporary longitudinal data on the incidence and progression of diabetic retinopathy (DR) in a multi-ethnic population of whites, African Americans, Chinese and Hispanics in the United States. Methods A prospective, multi-region, multi-ethnic population-based cohort study that included 498 participants with diabetes, aged 45–84 years at baseline, from the Multi-Ethnic Study of Atherosclerosis with retinal images obtained twice, on average 8 years apart. Presence and severity of DR were graded from these retinal images according to the modified Airlie House classification system. Main outcome measures were 8-year incidence, progression and improvement of DR, and their associated risk factors. Results Over the 8 years, the cumulative rates were 19.2% for incident DR, 17.3% for DR progression, 23.3% for DR improvement, 2.7% for incident vision-threatening DR, 1.8% for incident proliferative DR and 2.2% for incident macular oedema. In multivariate analysis, significant risk factors associated with incident DR were higher glycosylated haemoglobin (relative risk (RR) 1.28; 95% CI: 1.16 to 1.41) and higher systolic blood pressure (RR 1.14; 95% CI: 1.04 to 1.25). Significant factors associated with DR progression were higher glycosylated haemoglobin (RR 1.20; 95% CI: 1.00 to 1.43) and higher low-density lipoprotein cholesterol (RR 1.01; 95% CI: 1.00 to 1.03). Conclusion Over an 8-year period, approximately one in five participants with diabetes developed DR, while almost a quarter of those with DR at baseline showed improvement, possibly reflecting the positive impact of clinical and public health efforts in improving diabetes care in the United States over the last two decades.

Diabetes subgroups and risk for complications: The Multi-Ethnic Study of Atherosclerosis (MESA).

Abstract: Aims To characterize diabetes subgroups among a multi-ethnic cohort and assess risk for incident complications. Methods We included 1587 participants from the Multi-Ethnic Study of Atherosclerosis with diabetes. We characterized eight diabetes subgroups according to absolute thresholds for disease characteristics: age at diabetes diagnosis (≤45 years), fasting glucose (FG ≥7.7 mmol/L; ≥140 mg/dL), and waist circumference (women ≥105 cm; men ≥110 cm). We estimated risk for mortality, incident cardiovascular disease, chronic kidney disease, heart failure, dementia, and retinopathy, respectively, over 17 years after adjustment for demographics, behavioral, clinical risk factors, and cohort attrition. Results The subgroup with both high FG and early age at onset was associated with higher risk for death, CVD, heart failure, CKD, and retinopathy and the subgroup with both early age at onset and high waist circumference was associated CVD, heart failure, CKD, and retinopathy. The subgroup that met all three high-risk thresholds had greater risk for death, heart failure, CKD, and retinopathy. We did not observe evidence for synergistic or antagonistic joint effects of the high-risk characteristics for any outcome. Conclusions Our work supports differential risk for various diabetes complications among exclusive subgroups defined by age at diabetes onset, fasting glucose, and central adiposity.

Relation between Retinopathy and Progression of Coronary Artery Calcium in Individuals with Versus Without Diabetes Mellitus (From the Multi-Ethnic Study of Atherosclerosis).

Abstract: Retinopathy is a microvascular complication of diabetes mellitus (DM); however, it is also increasingly recognized in persons without DM. The microvascular diseases may play a prominent role in coronary heart disease (CHD) development in individuals with DM. We performed the study to evaluate the relation between non-DM retinopathy and CHD and also the association between baseline retinopathy and incidence and progression of CHD in individuals with and without DM. We included 5709 subjects with and without DM from the Multi-Ethnic Study of Atherosclerosis, who had retinal photos and coronary artery calcium score (CACS) available. We studied the association between baseline retinopathy and incidence and progression of coronary artery calcification (CAC) in subjects with and without DM. In DM group, the presence of retinopathy was significantly associated with an increased rate of CAC (RR 1.3 (95% CI [1.02, 1.66]) after adjusting for age, sex, race, follow-up time, and CHD risk factors. In non-DM group, the presence of retinopathy was not significantly associated with increased risk of CAC, however, the interaction between presence of retinopathy and DM status was not statistically significant. Within the DM group with CAC present at baseline, the presence of retinopathy was significantly associated with greater CAC progression (113 Agatson units (AU) greater, (95% CI [51-174]). In the non-DM group with present CAC at baseline; the presence of retinopathy was associated with 24 (95% CI [-0.69, 48.76]) AU higher CAC progression. All findings were adjusted for CHD risk factors. In conclusion, after adjustment for major CHD risk factors, retinopathy was associated with progression of CAC in both DM and non-DM individuals. However, the association was stronger in those with DM.

Generational Differences in the 10-year Incidence of Impaired Contrast Sensitivity.

Abstract: To determine if incidence of contrast sensitivity (CS) impairment differs by generation and identify factors to explain these differences.The Beaver Dam Eye Study (BDES) and Beaver Dam Offspring St...

Diet and Age-Related Macular Degeneration

Abstract: Age-related macular degeneration (ARMD) is a degenerative condition of the outer layers of the region of the retina that is responsible for central vision. Lesions of ARMD occur between the layer of the retina that contains the rod and cone cells and the vascular layer in the choroid. Pigmentary disturbances that are observed in patients with ARMD include depigmentation of the retinal pigment epithelium cells (RPE) and hyperpigmentation, often around the periphery of depigmented zones. Oxidative stress is one mechanism that can lead to the accumulation and shedding of indigestible lipid-rich residues by the RPE. Evidence ol retinal damage caused by light exposure is also consistent with the notion that oxidative stress contributes to ARMD. The evidence to support possible roles of nutritional factors comes primarily from two types of scientific inquiry: experimental studies in animals and epidemiologic studies in people. Several recent studies suggest that diet can alter macular pigment density in people.