Polygenic risk scores predict diabetes complications and their response to intensive blood pressure and glucose control.
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ABSTRACT: Aims/hypothesis
Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk.Methods
We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 individuals with type 2 diabetes in the UK Biobank study.Results
The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events (p = 6.3 × 10-21 and p = 9.6 × 10-31, respectively) and a 4.4-fold (p = 6.8 × 10-33) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk individuals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years.Conclusions/interpretation
This novel multiPRS model stratified individuals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy.
SUBMITTER: Tremblay J
PROVIDER: S-EPMC8382653 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThere is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events.MethodsA total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.ResultsAfter 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001).ConclusionsIn patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.)
| S-EPMC4123215 | biostudies-literature
Project description:BackgroundPrevious studies indicated that intensive blood pressure (BP) control (systolic BP < 120 mm·Hg) compared with standard BP control (<140 mm·Hg) was associated with an increased risk of type 2 diabetes (T2D) and impaired fasting glucose (IFG) among hypertensive patients with normoglycemia. However, the impact of intensive BP control on the incidence of T2D for those with IFG is still unknown.MethodsThis was a secondary analysis of the SPRINT (Systolic Blood Pressure Intervention Trial) of the study. We included participants with IFG at randomization, which was defined as fasting blood glucose (FBG) between 100 and 125 mg/dL. The primary outcome was incident T2D, defined as events of reaching FBG ≥ 126 mg/dL, participant self-report T2D at annual examination, or a record of hypoglycemic medications at follow-up. The secondary outcome was incident IFG reversion (IFGR), defined as the time to first FBG back to normoglycemia (<100 mg/dl) among participants without incident T2D. Cox proportional hazards models were used to compare the cumulative incidence of outcomes between the two BP control groups. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated.ResultsA total of 3310 participants were included in our primary outcome analysis (median age 67 years, 29% female). There were 293 participants who developed T2D among the intensive BP control group and 256 participants who developed T2D among the standard BP control group, resulting in 56.87 (50.36-63.39) versus 49.33 (43.29-55.37) events per 1000 person-years of treatment (HR 1.18 [95% CI, 1.00-1.40], P=0.052). After excluding 549 participants who developed T2D, 2761 participants were included in our secondary outcome analysis with 559 participants who developed IFGR among the intensive BP control group and 632 participants who developed IFGR among the standard BP control group, resulting in 141.20 (129.50-152.91) versus 158.20 (145.86,170.53) events per 1000 person-years of treatment (HR 0.9 [95% CI, 0.8-1.01], P=0.067).ConclusionsOur study found that in comparison to the standard BP control for hypertensive patients with IFG, intensive BP control was associated with a small increased risk of new-onset T2D, though it did not reach statistical significance. This kind of impact should be considered when implementing the strategy, especially for those with high risks of developing T2D. This trial is registered with NCT01206062.
| S-EPMC10036175 | biostudies-literature
Project description:Maternal blood pressure (BP) is associated with variations in fetal weight, an important determinant of neonatal and adult health. However, the association of BP-raising genetic risk with fetal weight is unknown. We tested the associations of maternal BP-raising polygenic risk scores (PRS) with estimated fetal weights (EFWs) at 13, 20, 27, and 40 weeks of gestation. This study included 622 White, 637 Black, 568 Hispanic, and 238 Asian pregnant women with genotype data from the NICHD Fetal Growth Studies. PRS of systolic (SBP) and diastolic BP (DBP) were calculated for each participant based on summary statistics from a recent genome-wide association study. Linear regression models were used to compare mean EFW differences between the highest versus lowest tertile of PRS, adjusting for maternal age, education, parity, genetic principal components and fetal sex. Hispanics in the highest DBP PRS tertile, compared to those in the lowest, had 8.1 g (95% CI: -15.1, -1.1), 32.4 g (-58.4, -6.4) and 119.4 g (-218.1, -20.7) lower EFW at 20, 27 and 40 weeks, respectively. Similarly, Asians in the highest DBP PRS tertile had 137.2 g (-263.5, -10.8) lower EFW at week 40, and those in the highest tertile of SBP PRS had 3.2 g (-5.8, -0.7), 12.9 g (-23.5, -2.4), and 39.8 g (-76.9, -2.7) lower EFWs at 13, 20, and 27 weeks. The findings showed that pregnant women's genetic susceptibility to high BP contributes to reduced fetal growth, suggesting a potential future clinical application in perinatal health.
| S-EPMC8329099 | biostudies-literature
Project description:Glaucoma, a leading cause of blindness, has multifactorial causes, including environmental and genetic factors. We evaluated genetic risk factors of glaucoma with gene-gene interaction and explored modifications of genetic risk with gene-lifestyles interaction in adults >40 years. The present study included 377 subjects with glaucoma and 47,820 subjects without glaucoma in a large-scale hospital-based cohort study from 2004 to 2013. The presence of glaucoma was evaluated by a diagnostic questionnaire evaluated by a doctor. The genome-wide association study was performed to identify genetic variants associated with glaucoma risk. Food intake was assessed using a semiquantitative food frequency questionnaire. We performed generalized multifactor dimensionality reduction analysis to construct polygenetic-risk score (PRS) and explored gene × nutrient interaction. PRS of the best model included LIM-domain binding protein-2 (LDB2) rs3763969, cyclin-dependent kinase inhibitor 2B (CDKN2B) rs523096, ABO rs2073823, phosphodiesterase-3A (PDE3A) rs12314390, and cadherin 13 (CDH13) rs12449180. Glaucoma risk in the high-PRS group was 3.02 times that in the low-PRS group after adjusting for confounding variables. For those with low serum glucose levels (<126 mg/dL), but not for those with high serum glucose levels, glaucoma risk in the high-PRS group was 3.16 times that in the low-PRS group. In those with high carbohydrate intakes (?70%), but not in those with low carbohydrate intakes, glaucoma risk was 3.74 times higher in the high-PRS group than in the low-PRS group. The glaucoma risk was 3.87 times higher in the high-PRS group than in the low-PRS group only in a low balanced diet intake. In conclusion, glaucoma risk increased by three-fold in adults with a high PRS, and it can be reduced by good control of serum glucose concentrations and blood pressure (BP) with a balanced diet intake. These results can be applied to precision nutrition to reduce glaucoma risk.
| S-EPMC7693735 | biostudies-literature
Project description:UnlabelledLeft ventricular hypertrophy (LVH), a marker of cardiac end-organ damage, is a common complication of hypertension. Regression of LVH is achievable by sustained lowering of systolic blood pressure (BP). However, it is unknown whether a strategy aimed at lowering BP beyond that recommended would lower the risk of LVH. We examined the effect of intensive (systolic BP<120 mm Hg), compared with standard (systolic BP<140 mm Hg), BP lowering on the risk of LVH in 4331 patients with diabetes mellitus from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) BP trial, a randomized controlled trial. The outcome measures were electrocardiographic LVH defined by Cornell voltage (binary variable) and mean Cornell index (continuous variable). The baseline prevalence of LVH (5.3% versus 5.4%; P=0.91) and the mean Cornell index (1456 versus 1470 µV; P=0.45) were similar in the intensive (n=2154) and standard (n=2177) BP-lowering arms, respectively. However, after median follow-up of 4.4 years, intensive, compared with standard, BP lowering was associated with a 39% lower risk of LVH (odds ratio [95% confidence interval], 0.61[0.43, 0.88]; P=0.008) and a significantly lower adjusted mean Cornell index (1352 versus 1447 µV; P<0.001). The lower risk of LVH associated with intensive BP lowering during follow-up was because of more regression of baseline LVH and lower rate of developing new LVH, compared with standard BP lowering. No interactions by age, sex, or race were observed. These results provide evidence that targeting a systolic BP of <120 mm Hg when compared with <140 mm Hg in patients with hypertension and diabetes mellitus produces a greater reduction in LVH.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00000620.
| S-EPMC4644090 | biostudies-literature
Project description:BACKGROUND:In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients. METHODS:We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years. RESULTS:During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P=0.27). However, the effects differed according to the baseline level of proteinuria (P=0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P=0.01). CONCLUSIONS:In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)
| S-EPMC3662974 | biostudies-literature
Project description:In the Systolic Blood Pressure Intervention Trial (SPRINT), adults at high risk for cardiovascular disease who received intensive systolic blood-pressure control (target, <120 mm Hg) had significantly lower rates of death and cardiovascular disease events than did those who received standard control (target, <140 mm Hg). On the basis of these data, we wanted to determine the lifetime health benefits and health care costs associated with intensive control versus standard control.We used a microsimulation model to apply SPRINT treatment effects and health care costs from national sources to a hypothetical cohort of SPRINT-eligible adults. The model projected lifetime costs of treatment and monitoring in patients with hypertension, cardiovascular disease events and subsequent treatment costs, treatment-related risks of serious adverse events and subsequent costs, and quality-adjusted life-years (QALYs) for intensive control versus standard control of systolic blood pressure.We determined that the mean number of QALYs would be 0.27 higher among patients who received intensive control than among those who received standard control and would cost approximately $47,000 more per QALY gained if there were a reduction in adherence and treatment effects after 5 years; the cost would be approximately $28,000 more per QALY gained if the treatment effects persisted for the remaining lifetime of the patient. Most simulation results indicated that intensive treatment would be cost-effective (51 to 79% below the willingness-to-pay threshold of $50,000 per QALY and 76 to 93% below the threshold of $100,000 per QALY), regardless of whether treatment effects were reduced after 5 years or persisted for the remaining lifetime.In this simulation study, intensive systolic blood-pressure control prevented cardiovascular disease events and prolonged life and did so at levels below common willingness-to-pay thresholds per QALY, regardless of whether benefits were reduced after 5 years or persisted for the patient's remaining lifetime. (Funded by the National Heart, Lung, and Blood Institute and others; SPRINT ClinicalTrials.gov number, NCT01206062 .).
| S-EPMC5708850 | biostudies-literature
Project description:Compared with standard glycemic control, intensive glycemic control caused increased mortality in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Preliminary data from several studies suggest that intensive glycemic control is associated with QT prolongation, which may lead to ventricular arrhythmias as a possible explanation of this increased mortality. We sought to assess the effects of intensive glycemic control and intensive blood pressure control on the risk of incident QT prolongation. Cox proportional hazards models were used to compare the risk of incident QT prolongation (>460 ms in women or >450 ms in men) in the intensive versus standard glycemic control arms. Over a combined 48,634 person-years of follow-up (mean 4.9), 634 participants (6.4%) developed a prolonged QTc. Participants in the intensive glycemic control arm did not have an increased risk of QT prolongation. Similarly, a strategy of intensive blood pressure control did not result in a significant change in risk of prolonged QTc. Sensitivity analyses using alternative QT correction formulas (Hodges and Bazett) yielded overall similar findings. In conclusion, the increased mortality observed in the intensive glycemic control arm in the ACCORD trial is not likely to be explained by QT prolongation leading to lethal ventricular arrhythmias.
| S-EPMC7809716 | biostudies-literature
Project description:BackgroundThere are few rigorous studies to confirm or refute the commonly cited concern that control of blood pressure to lower thresholds may result in an increased risk of falls and fractures.ObjectiveTo compare falls and fractures in participants with type 2 diabetes in the intensive (targeting a systolic blood pressure of < 120 mmHg) and standard (targeting a systolic blood pressure of < 140 mmHg) blood pressure control arms of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) randomized trial (N = 4,733).ParticipantsA subset of 3,099 participants self-reported annually on the occurrence of falls and non-spine fractures. Fractures were centrally adjudicated.Main measuresThe incidence of falls in the two treatment groups was compared using a random-effects negative binomial model, and fracture risk was compared using Cox proportional hazards models.Key resultsAt enrollment in both groups, the mean age was 62 years, 44% were women, 25% were Black, and mean blood pressure was 138/75 mmHg. During follow-up, all classes of medications, particularly thiazide diuretics, were more commonly prescribed in the intensive group. After 1 year of follow-up, the mean systolic blood pressure was 133 ± 15 mmHg in the standard group and 119 ± 14 mmHg in the intensive group. The adjusted rate of falls did not differ in the intensive and standard groups (62.2/100 person-years vs. 74.1/100 person-years, RR = 0.84, 95% CI 0.54-1.29, p = 0.43). The risk of non-spine fractures was nonsignificantly lower in the intensive than in the standard blood pressure group (HR 0.79, 95% CI 0.62-1.01, p = 0.06).ConclusionsWe conclude that intensive antihypertensive treatment that lowered mean systolic blood pressure to below 120 mmHg was not associated with an increased risk of falls or non-spine fractures in patients age 40 to 79 years with type 2 diabetes.
| S-EPMC4242873 | biostudies-literature
Project description:BackgroundControversy over blood pressure (BP) treatment targets for individuals with diabetes is in part due to conflicting perspectives about generalizability of available trial data.ObjectiveThe authors sought to estimate how results from the largest clinical trial of intensive BP treatment among adults with diabetes would generalize to the U.S.PopulationMethodsThe authors used transportability methods to reweight individual patient data from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) BP trial (N = 4,507) of intensive (goal systolic BP <120 mm Hg) versus standard (goal systolic BP <140 mm Hg) treatment to better represent the demographic and clinical risk factors of the U.S. population of adults with diabetes (data from NHANES [National Health and Nutrition Examination Survey] 2005 to 2014, n = 1,943). The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Analysis used weighted Cox proportional hazards regression models with robust standard errors.ResultsThe ACCORD BP sample had less racial/ethnic diversity and more elevated cardiovascular risk factors than the NHANES participants. Weighted results significantly favored intensive BP treatment, unlike unweighted results (hazard ratio for primary outcome in intensive versus standard treatment in weighted analyses: 0.67, 95% confidence interval: 0.49 to 0.91; in unweighted analyses: hazard ratio: 0.88, 95% confidence interval: 0.73 to 1.07). Over 5 years, the weighted results estimate a number needed to treat of 34, and number needed to harm of 55.ConclusionsAfter reweighting to better reflect the U.S. adult population with diabetes, intensive BP therapy was associated with significantly lower risk for cardiovascular events. However, data were limited among racial/ethnic minorities and those with lower cardiovascular risk.
| S-EPMC6358208 | biostudies-literature