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Statin Use Associates With Risk of Type 2 Diabetes via Epigenetic Patterns at ABCG1.

ABSTRACT: Statin is the medication most widely prescribed to reduce plasma cholesterol levels. Yet, how the medication contributes to diabetes risk and impaired glucose metabolism is not clear. This study aims to examine the epigenetic mechanisms of ABCG1 through which statin use associates with risk of type 2 diabetes. We determined the association between the statin use, DNA methylation at ABCG1 and type 2 diabetes/glycemic traits in the Framingham Heart Study Offspring (FHS, n = 2741), with validation in the Women's Health Initiative Study (WHI, n = 2020). The causal effect of statin use on the risk of type 2 diabetes was examined using a two-step Mendelian randomization approach. Next, based on transcriptome analysis, we determined the links between the medication-associated epigenetic status of ABCG1 and biological pathways on the pathogenesis of type 2 diabetes. Our results showed that DNA methylation levels at cg06500161 of ABCG1 were positively associated with the use of statin, type 2 diabetes and related traits (fasting glucose and insulin) in FHS and WHI. Two-step Mendelian randomization suggested a causal effect of statin use on type 2 diabetes and related traits through epigenetic mechanisms, specifically, DNA methylation at cg06500161. Our results highlighted that gene expression of ABCG1, ABCA1 and ACSL3, involved in both cholesterol metabolism and glycemic pathways, was inversely associated with statin use, CpG methylation, and diabetic signatures. We concluded that DNA methylation site cg06500161 at ABCG1 is a mediator of the association between statins and risk of type 2 diabetes.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7308584 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Statin Use Associates With Risk of Type 2 Diabetes via Epigenetic Patterns at ABCG1.

Liu Yuwei Y Shen Yu Y Guo Tao T Parnell Laurence D LD Westerman Kenneth E KE Smith Caren E CE Ordovas Jose M JM Lai Chao-Qiang CQ

Frontiers in genetics 20200616

Statin is the medication most widely prescribed to reduce plasma cholesterol levels. Yet, how the medication contributes to diabetes risk and impaired glucose metabolism is not clear. This study aims to examine the epigenetic mechanisms of ABCG1 through which statin use associates with risk of type 2 diabetes. We determined the association between the statin use, DNA methylation at ABCG1 and type 2 diabetes/glycemic traits in the Framingham Heart Study Offspring (FHS, n = 27 ...[more]

PMID: 32612641

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Project description:To test associations between statin use and cognitive impairment in adults with childhood-onset type 1 diabetes (T1D).In 2010-13, n = 108 middle-aged participants from ongoing observational Pittsburgh Epidemiology of Diabetes Complications Study underwent neurocognitive assessment (mean age and T1D duration of 49 and 41 years, respectively). All were diagnosed with childhood-onset (i.e., prior to age 18) T1D between 1950 and 1980 and were seen within one year of diagnosis at Children's Hospital of Pittsburgh. Self-reported statin use (yes/no and if yes, name of statin) was collected biennially from parent study baseline (1986-1988) to time of neurocognitive testing. Logistic regression models tested associations between statin use groups and cognitive impairment (defined as having two or more cognitive test scores 1.5SD or worse than published norms) while linear regression models tested associations between statin use groups and cognitive domain z-scores (domains: Verbal IQ, memory, executive function, psychomotor speed, and visuo-construction). All models controlled for education and age. To address confounding by indication, models were repeated using a propensity score for statin use.Of the 108 participants, 51 reported never using statins. Median duration of statin use among the 57 ever users was 6 years. These 57 ever statin users were split to create two groups (≤ or > median years of statin use): 1-6 years (n = 25), and 7-12 years (n = 32). Compared with never users, using statins 1-6 years tripled the odds of cognitive impairment (OR = 3.16; 95%CI: 0.93-10.72; P = 0.06) and using statins 7-12 years almost quintupled the odds of cognitive impairment (OR = 4.84; 95%CI: 1.63-14.44; P = 0.005). Compared with never users, using statins 1-6 or 7-12 years was related to worse performance in the memory domain (β = -0.52; P = 0.003, and -0.39; P = 0.014, respectively). Adjusting for coronary artery disease, low density lipoprotein cholesterol, and Apo E4 status did not substantially alter results, and none of these covariates were significantly related to cognitive outcomes (all P > 0.05). Propensity score analyses support that associations between poor cognitive outcomes and statin use were not due merely to confounding by indication.Statin use was associated with cognitive impairment, particularly affecting memory, in these middle-aged adults with childhood-onset T1D, whom at this age, should not yet manifest age-related memory deficits.

Project description:BACKGROUND:We evaluated the effect of statin use on new-onset type 2 diabetes among individuals without atherosclerotic cardiovascular disease (ASCVD) using nationally representative South Korean claims data (2002-2013, N?=?1,016,820). METHODS:A total of 13,698 patients (statin users 5273, non-statin users 5273) aged 40-74 years, newly diagnosed with dyslipidemia but without any history of diabetes or ASCVD, were selected in 2005. We followed up the final sample until 2013 and evaluated the cumulative incidence of type 2 diabetes. We used extended Cox regression models to estimate the time-varying adjusted hazard ratios of statin use on new-onset type 2 diabetes. We performed further analyses based on the cumulative defined daily dose of statin received per year to evaluate the degree of risk compared to non-statin users. RESULTS:Over the mean follow-up period of 7.1 years, 3034 patients developed type 2 diabetes; the number of statin users exceeded that of non-users, demonstrating that statin use significantly increased the risk of new-onset type 2 diabetes. The risk of new-onset type 2 diabetes differed among statin users according to cDDD per year (adjusted HR?=?1.31 [95% CI 1.18-1.46] for less than 30 cDDD per year; 1.58 [1.43-1.75] for 30-120 cDDD per year; 1.83 [1.62-2.08] for 120-180 cDDD per year; and 2.83 [2.51-3.19] for more than 180 cDDD per year). The diabetogenic effect of pitavastatin was not statistically significant, but the risk was the largest for atorvastatin. Long-term exposure (??5 years) to statins was associated with a statistically significant increase in the risk of new onset type 2 diabetes in all statin subtypes explored, with the highest magnitude for simvastatin (HR?=?1.916, 95% CI 1.647-2.228) followed by atorvastatin (HR?=?1.830, 95% CI 1.487-2.252). CONCLUSIONS:Statin use was significantly associated with an increased risk of new-onset type 2 diabetes. We also found a dose-response relationship in terms of statin use duration and dose maintenance. Periodic screening and monitoring for incident type 2 diabetes may be warranted in long-term statin users.

Project description:Prenatal exposure to famine and adulthood obesity have been independently related to the risk of type 2 diabetes; however, little is known about the joint effects of these risk factors at different stages of life on adulthood diabetes risk.The analysis included 88 830 participants of the China Kadoorie Biobank, who were born around the time of the Chinese Great Famine and without diabetes, cardiovascular diseases, or cancer at baseline. We defined famine exposure subgroups as nonexposed (born between 1 October 1962 and 30 September 964), fetal-exposed (born between 1 October 1959 and 30 September 1961) and early-childhood exposed (born between 1 October 1956 and 30 September 1958). General obesity was assessed by body mass index (BMI: overweight???24.0, obesity???28.0) and abdominal obesity assessed by waist-to-hip ratio (WHR, men/women: moderate???0.90/0.85, high???0.95/0.90).During a median 7.3 years (642 552 person-years) of follow-up, we identified 1372 incident cases of type 2 diabetes. Compared with nonexposed and early-childhood exposed participants combined as a single comparison group, fetal-exposed participants showed an increased risk of diabetes in adulthood [hazard ratio (HR)?=?1.25; 95% confidence interval (CI): 1.07-1.45]. The association between general obesity and diabetes was consistent across subgroups according to famine exposure (P for interaction?>?0.05). A stronger association between abdominal obesity and diabetes was observed in the fetal-exposed subgroup than in other subgroups (P for interaction?=?0.025 in the whole population). This interaction was more obvious in women (P?=?0.013) but not in men (P?=?0.699). Compared with normal-BMI and -WHR participants, those with both general (BMI???24.0) and abdominal (WHR???0.90/0.85) obesity in adulthood had 5.32 (95% CI: 3.81-7.43)-, 3.13 (2.48-3.94)- and 4.43 (3.45-5.68)-fold higher risks if these were carried during, before and after times of famine, respectively.Coexistence of prenatal experience of undernutrition and abdominal obesity in adulthood was associated with a higher risk of type 2 diabetes.

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Statin Use Associates With Risk of Type 2 Diabetes via Epigenetic Patterns at ABCG1.

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Statin Use Associates With Risk of Type 2 Diabetes via Epigenetic Patterns at <i>ABCG1</i>.

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