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Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank.

ABSTRACT: Although hyperlipidemia is traditionally considered a risk factor for type 2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL cholesterol (LDL-C) increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (odds ratio 0.41 [95% CI 0.39, 0.43] per mmol/L unit of LDL-C), despite positive associations of circulating LDL-C with HbA_1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower circulating LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n = 431,167) and the Global Lipids Genetics Consortium (n = 188,577), and data on T2D from the Diabetes Genetics Replication and Meta-Analysis consortium (n = 898,130). We identified 31 loci associated with lower circulating LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this dual phenotype, and nine have previously been implicated in nonalcoholic fatty liver disease. These findings extend our current understanding of the higher T2D risk among individuals with low circulating LDL-C and of the underlying mechanisms, including those responsible for the diabetogenic effect of LDL-C-lowering medications.

SUBMITTER: Klimentidis YC

PROVIDER: S-EPMC7506834 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank.

Klimentidis Yann C YC Arora Amit A Newell Michelle M Zhou Jin J Ordovas Jose M JM Renquist Benjamin J BJ Wood Alexis C AC

Diabetes 20200603 10

Although hyperlipidemia is traditionally considered a risk factor for type 2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL cholesterol (LDL-C) increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (odds ratio 0.41 [95% CI 0.39, 0.43] ...[more]

PMID: 32493714

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Project description:ContextIndividuals with diabetes are at increased risk for cardiovascular disease (CVD), but more aggressive targets for risk factor control have not been tested.ObjectiveTo compare progression of subclinical atherosclerosis in adults with type 2 diabetes treated to reach aggressive targets of low-density lipoprotein cholesterol (LDL-C) of 70 mg/dL or lower and systolic blood pressure (SBP) of 115 mm Hg or lower vs standard targets of LDL-C of 100 mg/dL or lower and SBP of 130 mm Hg or lower.Design, setting, and participantsA randomized, open-label, blinded-to-end point, 3-year trial from April 2003-July 2007 at 4 clinical centers in Oklahoma, Arizona, and South Dakota. Participants were 499 American Indian men and women aged 40 years or older with type 2 diabetes and no prior CVD events.InterventionsParticipants were randomized to aggressive (n=252) vs standard (n=247) treatment groups with stepped treatment algorithms defined for both.Main outcome measuresPrimary end point was progression of atherosclerosis measured by common carotid artery intimal medial thickness (IMT). Secondary end points were other carotid and cardiac ultrasonographic measures and clinical events.ResultsMean target LDL-C and SBP levels for both groups were reached and maintained. Mean (95% confidence interval) levels for LDL-C in the last 12 months were 72 (69-75) and 104 (101-106) mg/dL and SBP levels were 117 (115-118) and 129 (128-130) mm Hg in the aggressive vs standard groups, respectively. Compared with baseline, IMT regressed in the aggressive group and progressed in the standard group (-0.012 mm vs 0.038 mm; P < .001); carotid arterial cross-sectional area also regressed (-0.02 mm(2) vs 1.05 mm(2); P < .001); and there was greater decrease in left ventricular mass index (-2.4 g/m(2.7) vs -1.2 g/m(2.7); P = .03) in the aggressive group. Rates of adverse events (38.5% and 26.7%; P = .005) and serious adverse events (n = 4 vs 1; P = .18) related to blood pressure medications were higher in the aggressive group. Clinical CVD events (1.6/100 and 1.5/100 person-years; P = .87) did not differ significantly between groups.ConclusionsReducing LDL-C and SBP to lower targets resulted in regression of carotid IMT and greater decrease in left ventricular mass in individuals with type 2 diabetes. Clinical events were lower than expected and did not differ significantly between groups. Further follow-up is needed to determine whether these improvements will result in lower long-term CVD event rates and costs and favorable risk-benefit outcomes.Trial registrationclinicaltrials.gov Identifier: NCT00047424.

Project description:BackgroundPhenylketonuria (PKU; OMIM#261600) is a rare metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene resulting in high phenylalanine (Phe) in blood and brain. If not treated early this results in intellectual disability, behavioral and psychiatric problems, microcephaly, motor deficits, eczematous rash, autism, seizures, and developmental problems. There is a controversial discussion of whether patients with PKU have an additional risk for atherosclerosis due to interference of Phe with cholesterol synthesis and LDL-cholesterol regulation. Since cholesterol also plays a role in membrane structure and myelination, better insight into the clinical significance of the impact of Phe on lipoprotein metabolism is desirable. In 22 treated PKU patients (mean age 38.7 years) and 14 healthy controls (mean age 35.2 years), we investigated plasma with NMR spectroscopy and quantified 105 lipoprotein parameters (including lipoprotein subclasses) and 24 low molecular weight parameters. Analysis was performed on a 600 MHz Bruker AVANCE IVDr spectrometer as previously described.ResultsConcurrent plasma Phe in PKU patients showed a wide range with a mean of 899 μmol/L (50-1318 μmol/L). Total cholesterol and LDL-cholesterol were significantly lower in PKU patients versus controls: 179.4 versus 200.9 mg/dL (p < 0.02) and 79.5 versus 104.1 mg/dL (p < 0.0038), respectively. PKU patients also had lower levels of 22 LDL subclasses with the greatest differences in LDL2 Apo-B, LDL2 Particle Number, LDL2-phospholipids, and LDL2-cholesterol (p < 0.0001). There was a slight negative correlation of total cholesterol and LDL-cholesterol with concurrent Phe level. VLDL5-free cholesterol, VLDL5-cholesterol, VLDL5-phospholipids, and VLDL4-free cholesterol showed a significant (p < 0.05) negative correlation with concurrent Phe level. There was no difference in HDL and their subclasses between PKU patients and controls. Tyrosine, glutamine, and creatinine were significantly lower in PKU patients compared to controls, while citric and glutamic acids were significantly higher.ConclusionsUsing NMR spectroscopy, a unique lipoprotein profile in PKU patients can be demonstrated which mimics a non-atherogenic profile as seen in patients treated by statins.

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Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank.

Publications

Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank.

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