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Population ancestry and genetic risk for diabetes and kidney, cardiovascular, and bone disease: modifiable environmental factors may produce the cures.

ABSTRACT: Variable rates of disease observed between members of different continental population groups may be mediated by inherited factors, environmental exposures, or their combination. This article provides evidence in support of differential allele frequency distributions that underlie the higher rates of nondiabetic kidney disease in the focal segmental glomerulosclerosis spectrum of disease and lower rates of coronary artery calcified atherosclerotic plaque and osteoporosis in populations of African ancestry. With recognition that these and other common complex diseases are affected by biological factors comes the realization that targeted manipulation of environmental exposures and pharmacologic treatments will have different effects based on genotype. The present era of precision medicine will couple one's genetic makeup with specific therapies to reduce rates of disease based on the presence of disease-specific alleles.

SUBMITTER: Freedman BI

PROVIDER: S-EPMC3840048 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Population ancestry and genetic risk for diabetes and kidney, cardiovascular, and bone disease: modifiable environmental factors may produce the cures.

Freedman Barry I BI Divers Jasmin J Palmer Nicholette D ND

American journal of kidney diseases : the official journal of the National Kidney Foundation 20130726 6

Variable rates of disease observed between members of different continental population groups may be mediated by inherited factors, environmental exposures, or their combination. This article provides evidence in support of differential allele frequency distributions that underlie the higher rates of nondiabetic kidney disease in the focal segmental glomerulosclerosis spectrum of disease and lower rates of coronary artery calcified atherosclerotic plaque and osteoporosis in populations of Africa ...[more]

PMID: 23896482

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Project description:AimsType 2 diabetes mellitus (T2DM) is associated with increased cardiovascular disease (CVD) risk, but whether T2DM directly causes adverse cardiac remodelling is uncertain. We performed a comprehensive Mendelian randomization (MR) analysis to investigate the causal relevance of T2DM to CVD outcomes and cardiac structure/function.Methods and resultsBidirectional two-sample MR was conducted using summary-level data from European-ancestry genome-wide association studies. The T2DM GWAS data included 80 154 cases and 853 816 controls from the DIAGRAM consortium. Outcomes included coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure, atrial fibrillation, and various quantitative cardiac imaging traits assessed by magnetic resonance imaging. MR analysis revealed causal associations between genetic predisposition to T2DM and increased risk of CAD (odds ratio [OR] 1.104, 95% confidence interval [CI] 1.078-1.130, P = 2.59e-16), MI (OR 1.129, 95% CI 1.094-1.166, P = 6.02e-14) and stroke (OR 1.086, 95% CI 1.064-1.109, P = 1.02e-14). These associations were validated in the FinnGen cohort (CAD: OR 1.117, 95% CI 1.075-1.158, P = 1.56e-9; MI: OR 1.132, 95% CI 1.083-1.184, P = 4.27e-8; stroke: OR 1.138, 95% CI 1.107-1.170, P = 3.52e-20). Multivariable MR show consistent findings (CAD: OR 1.063, 95% CI 1.031-1.097, P = 1.11e-4; MI: OR 1.088, 95% CI 1.042-1.135, P = 1.12e-4; stroke: OR 1.066, 95% CI 1.032-1.101, P = 1.18e-4) after adjusting for cardiometabolic traits. T2DM was causally associated with higher left ventricular mass index (β = 0.473, 95% CI 0.193 to 0.752, P = 0.001), lower indexed right atrial minimum (β = -0.048, 95% CI -0.073 to -0.022, P = 2.1e-5), and maximum (β = -0.042, 95% CI -0.065 to -0.019, P = 4.12e-5) areas. The effects on right atrial size remained significant after adjusting for risk factors (minimum area: β = -0.041, 95% CI -0.072 to -0.010, P = 0.009; maximum area: β = -0.039, 95% CI -0.069 to -0.008, P = 0.012). Both apolipoprotein A1 and SBP are important mediators in the causal relationship between T2DM and left ventricular mass index. No reverse causal associations were identified.ConclusionsOur MR study demonstrates that genetic liability to T2DM plays causal roles in CAD, MI, stroke, and cardiac structure changes including left ventricular hypertrophy and reduced right atrial dimensions. These findings provide genetic evidence supporting glycaemic control in T2DM to mitigate cardiovascular complications and adverse cardiac remodelling.

Project description:BACKGROUND:Cardiovascular disease (CVD) mortality is substantially higher in Russia than in neighbouring Norway. We aimed to compare blood pressure- and lipid-lowering medication use and proportion meeting treatment targets between general population samples in the two countries in those with CVD and diabetes. METHODS:The study population was adults aged 40-69 years reporting a diagnosis of myocardial infarction (MI), stroke and/or diabetes participating in cross-sectional population-based studies in Russia (Know Your Heart (KYH) 2015-18 N = 626) and Norway (The Tromsø Study 2015-16 (Tromsø 7) N = 1353). Reported medications were coded according to the 2016 WHO Anatomical Therapeutic Chemical Classification system. Treatment targets were defined using the Joint European Societies guidelines for CVD prevention in clinical practice (2016). RESULTS:Age- and sex-standardized prevalence of use of lipid-lowering medications was higher in Tromsø 7 for all three conditions with a disproportionately large difference in those reporting MI (+ 48% (95% CI 39, 57%)). Proportion meeting treatment targets for LDL cholesterol was poor in both studies (age- and sex-standardized prevalence of control KYH vs Tromsø 7: MI 5.1% vs 10.1%; stroke 11.6% vs 5.8%; diabetes 24.9% vs 23.3%). Use of antihypertensive medication was higher in KYH for stroke (+ 40% (95% CI 30, 50%)) and diabetes (+ 27% (95% CI 19, 34%)) groups but approximately equal for the MI group (- 1% (95% CI -1, 1%)). Proportion meeting blood pressure targets was lower in KYH vs Tromsø 7 (MI 51.8% vs 76.3%; stroke 49.5% vs 69.6%; diabetes 51.9% vs 63.9%). CONCLUSIONS:We identified different patterns of medication use in people with CVD and diabetes. However despite higher use of lipid-lowering medication in the Norwegian study treatment to target for total cholesterol was poor in both Russian and Norwegian studies. In contrast we found higher levels of use of antihypertensive medications in the Russian study but also that less participants met treatment targets for blood pressure. Further work should investigate what factors are responsible for this seeming paradox and how management of modifiable risk factors for secondary prevention could be improved.

Project description:BackgroundCardiovascular disease (CVD) remains a paramount contemporary health challenge. This study examined age-specific effects of 14 risk factors on CVD and mortality in different age groups.MethodsWe analyzed data from 226,759 CVD-free participants aged 40 years and older in the UK Biobank during the period from baseline time (2006-2010) to September 30, 2021. The primary CVD outcome was a composite of incident coronary artery disease, heart failure, and stroke. We calculated age-specific hazard ratios (HRs) and population-attributable fractions (PAF) for CVD and mortality associated with 14 potentially modifiable risk factors.FindingsDuring 12.17-year follow-up, 23,838 incident CVD cases and 11,949 deaths occurred. Age-specific disparities were observed in the risk factors contributing to CVD, and the overall PAF declined with age (PAF of 56.53% in middle-age; 49.78% in quinquagenarian; 42.45% in the elderly). Metabolic factors had the highest PAF in each age group, with hypertension (14.04% of the PAF) and abdominal obesity (9.58% of the PAF) being prominent. Behavioral factors had the highest PAF in the middle-aged group (10.68% of the PAF), and smoking was the leading behavioral factor in all age groups. In socioeconomic and psychosocial risk clusters, low income contributed most among middle-aged (3.74% of the PAF) and elderly groups (3.66% of the PAF), while less education accounted more PAF for quinquagenarian group (4.46% of the PAF). Similar age-specific patterns were observed for cardiovascular subtypes and mortality.InterpretationA large fraction of CVD cases and deaths were associated with modifiable risk factors in all age groups. Targeted efforts should focus on the most impactful risk factors, as well as age-specific modifiable risk factors. These findings may inform the development of more precise medical strategies to prevent and manage CVD and related mortality.FundingThe work was supported by the Bill & Melinda Gates Foundation (grant number: INV-016826 to Hualiang Lin) and the National Natural Science Foundation of China (grant number: 82373534 to Hualiang Lin).

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Population ancestry and genetic risk for diabetes and kidney, cardiovascular, and bone disease: modifiable environmental factors may produce the cures.

Publications

Population ancestry and genetic risk for diabetes and kidney, cardiovascular, and bone disease: modifiable environmental factors may produce the cures.

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