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Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants Influence on Health

Lotta, L. A., Sharp, S. J., Burgess, S., Perry, J. R., Stewart, I. D., Willems, S. M., & Wareham, N. J. (2016). Association between low-density lipoprotein cholesterol–lowering genetic variants and risk of type 2 diabetes: a meta-analysis. Jama, 316(13), 1383-1391.

General epidemiology of the issue

LDL is low-density lipoprotein, also called “bad” cholesterol. High LDL levels lead to a build-up of cholesterol in the arteries, which may be associated with an increased risk of type 2 diabetes. LDL levels depend on the diet, body weight, physical activity, smoking, age and gender, genetics, and medication intake. According to a study, LDL cholesterol-lowering alleles near the HMGCR gene are associated with a higher risk of type 2 diabetes. Noteworthy, an enzyme encoded by the HMGCR gene is normally suppressed by cholesterol derived from the internalization and degradation of LDL. The researchers also admit that it is unknown whether alleles near the NPC1L1 gene are associated with the risk of type 2 diabetes. Notably, a protein encoded by the NPCL1 gene takes up free cholesterol in cells.

Identify the study purpose

The study aimed to determine whether LDL-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (i.e., HMGCR, PCSK9, ABCG5 / G8, LDLR) were associated with the risk of type 2 diabetes.

Identify the study hypothesis

The researchers studied associations of LDL-lowering genetic variants with type 2 diabetes and coronary artery disease through meta-analyses of genetic association studies. Meta-analyzes included 50,775 individuals with type 2 diabetes and 270,269 controls, including three studies and 60,801 individuals with coronary artery disease and 123,504 controls from a published meta-analysis. Data collection took place in Europe and the United States between 1991 and 2016. The inclusion and exclusion criteria were the presence of type 2 diabetes or coronary artery disease in individuals. The control groups did not have related health issues. The final study sample size was 50,775 individuals with type 2 diabetes and 60,801 individuals with coronary artery disease.

What study design was used?

Identify primary or secondary study design.

The research was based on the meta-analyses of the existing data generated or gathered from available sources at the MRC Epidemiology Unit, University of Cambridge.

Statistical techniques used?

An inverse variance-weighted meta-analysis using a fixed-effect model was used to obtain pooled estimates for each genetic variant and outcome. The I² statistic was used to quantify heterogeneity. Mendelian randomization statistical methods were used to estimate associations of LDL-C-lowering genetic variants and outcomes for each gene. Statistical analyzes for the Results section were conducted using Stata version 14.1 (StataCorp), R version 3.2.2 (R Foundation for Statistical Computing), and METAL version 2011-03-25.

Describe the main findings.

The authors found that LDL-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease and directly associated with type 2 diabetes. For a given reduction in LDL cholesterol, genetic variants were associated with a similar reduction in coronary artery disease risk. Associations with type 2 diabetes were heterogeneous, indicating gene-specific associations with metabolic risk for LDL-lowering alleles. The odds ratio (OR) of type 2 diabetes and coronary artery disease was used as a measure for the study. The odds ratio seems plausible since various statistical verification techniques were used to approve the OR’s verity.

Any bias or error in the study?

The researchers ensured the readers that the likelihood of bias for studies participating in their meta-analysis was deemed low. This was achieved through “(a) the low proportion of participants with missing data on exposure or outcome, (b) the high-quality genotyping or imputation of genetic variants included in the study” (Lotta et al., 1385).

What are the strengths and weaknesses of paper (s)?

The limitation of the study was that Mendelian randomization “generally assumes that genetic variants are associated with the endpoint exclusively via the risk factor of interest, while the authors strived for a more integral approach” (Lotta et al., 1389). Therefore, to make the results more integral, authors could use another statistical technique than Mendelian randomization to estimate associations of LDL-C-lowering genetic variants and outcomes for each gene. However, the strong side was that “the strong and specific association with LDL cholesterol, the well-known role of target genes in LDL cholesterol metabolism and the use of conditionally-distinct genetic variants at given loci strengthened the validity of the genetic models” used by the researchers (Lotta et al., 1389).

What is the conclusion/summary of the paper?

The authors concluded that “exposure to LDL-cholesterol lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes” (Lotta et al., 1390).

van den Berg, M. J., van der Graaf, Y., de Borst, G. J., Kappelle, L. J., Nathoe, H. M., Visseren, F. L., & Leiner, T. (2016). Low-density lipoprotein cholesterol, non–high-density lipoprotein cholesterol, triglycerides, and Apolipoprotein B and cardiovascular risk in patients with manifest arterial disease. The American Journal of Cardiology, 118(6), 804-810.

General epidemiology of the issue

Non-HDL cholesterol is counted by subtracting HDL cholesterol number from total cholesterol number, and therefore, indicates all the “bad” types of cholesterol. Therefore, LDL-C is included in the estimated numbers of non-HDL-C. An optimal level of non-HDL cholesterol is less than 130 milligrams per deciliter, or 3.37 millimoles per liter, whereas higher numbers imply a higher risk of heart disease. Triglyceride-rich lipoproteins are a prerequisite for increased cardiovascular risk. Apolipoprotein B is considered by some experts a better measure of circulating LDL particle number concentration. It is also thought to be a more reliable indicator of risk than LDL-C. Therefore, experts suggest adding apolipoprotein B measurement to the routine lipid panel for assessing and monitoring patients at risk for cardiovascular disease.

Identify the study purpose

The scientists say that LDL-C only partly represents the lipid burden. They also admit that non-HDL-C, triglycerides, and apolipoprotein B estimate lipid-related cardiovascular disease risk more accurately. Therefore, van den Berg et al. (2016) had the purpose to “compare the relation among LDL-C, non-HDL-C, triglycerides, and apoB and the occurrence of future vascular events and mortality in patients with manifest arterial disease” (van den Berg et al., 2016, p. 804).

Identify the study hypothesis.

The authors hypothesized that they would find the relation among LDL-C, non-HDL-C, triglycerides, and apoB and an increased risk of cardiovascular events.

Describe the population assessed – location, study groups/arms.

The study analyzed the cohort of 7,216 patients enrolled from September 1996 to March 2014 with clinically manifest arterial disease. The scientists used data from patients enrolled in the Second Manifestations of Arterial Disease cohort. This prospective, ongoing cohort study was held at the University Medical Center Utrecht, The Netherlands. Patients aged 18 to 80 years, newly referred to the University Medical Center Utrecht with clinically manifest arterial disease or with a vascular risk factor, hyperlipidemia, hypertension, or diabetes mellitus (types 1 and 2), were asked to participate. From 2005 onward, apoB was measured, and since 2006, apoB became part of the standard screening protocol; ApoB levels were available in 3,503 patients.

What were the inclusion and exclusion criteria of the study?

Patients with either a history or a recent diagnosis of manifest arterial disease were invited to the study.

What was the Final study sample size?

The final study sample size was 7,216 patients.

What study design was used?

Identify primary and / or secondary study design (cross-sectional studies).

This study uses a primary study design and is based on the data of participants newly referred to the University Medical Center Utrecht.

Statistical techniques used.

The proportional hazards assumptions were verified using Schoenfeld residuals plotted against the (age-adjusted) time scale. The open-source software program R 3.2.0 (R Development Core Team, Vienna, Austria) was used for data analysis. Cox proportional hazard models were used to quantify the risk of major cardiovascular events (MACE; i.e., stroke, myocardial infarction, and vascular mortality) and all-cause mortality.

Describe the main findings.

Summarize main findings

Scientists found that MACE occurred in 1,185 subjects during a median follow-up of 6.5 years. They also discovered that the relation among LDL-C, non-HDL-C, and cardiovascular events was comparable in patients with cerebrovascular disease, coronary artery disease, or polyvascular disease and absent in those with aneurysm of the abdominal aorta or peripheral artery disease.

What measures were used? RR, OR, prevalence rates?

The study used the adjusted hazard ratios (HRs) determined by using the likelihood ratio test.

Do they seem plausible, strong, or weak? Why?

The hazard ratios seem plausible since there was a general tendency in HRs variations of MACE for LDL-C, non-HDL-C, triglycerides, and apoB.

Any bias or error in the study?

The researchers mentioned that there could be bias in measuring the plasma lipid levels since “although a sensitivity analysis with additional adjustment of lipid-lowering therapy did not change the results, risk of bias due to preferential use of statins in high-risk subjects was still present ”(van den Berg et al., 2016, p. 809).

What are the strengths and weaknesses of the paper?

The strengths included the prospective design and a relatively large sample of participants. The primary study design could also be considered as a strong side of the study. The limitations are that since the study started in 1996, some prevention options for cardiovascular disease could have changed. These changes could influence the association between lipids and cardiovascular disease risk. Therefore, the ongoing study could be conditionally divided according to the periods when the new methods of secondary prevention were widely introduced.

What is the conclusion/summary of the paper?

The authors concluded that “in patients with a history of cerebrovascular, coronary artery, or polyvascular disease, but not aneurysm of the abdominal aorta or peripheral artery disease, higher levels of LDL-C and non-HDL-C are related to increased risk of future MACE and comparable magnitude “(van den Berg et al., 2016, p. 804). Therefore, the hypothesis was proved.

References

Lotta, L. A., Sharp, S. J., Burgess, S., Perry, J. R., Stewart, I. D., Willems, S. M., & Wareham, N. J. (2016). Association between low-density lipoprotein cholesterol–lowering genetic variants and risk of type 2 diabetes: a meta-analysis. Jama, 316(13), 1383-1391.

van den Berg, M. J., van der Graaf, Y., de Borst, G. J., Kappelle, L. J., Nathoe, H. M., Visseren, F. L., & Leiner, T. (2016). Low-density lipoprotein cholesterol, non–high-density lipoprotein cholesterol, triglycerides, and Apolipoprotein B and cardiovascular risk in patients with manifest arterial disease. The American Journal of Cardiology, 118(6), 804-810.

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ApeGrade. "Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants Influence on Health." October 5, 2022. https://apegrade.com/low-density-lipoprotein-cholesterol-lowering-genetic-variants-influence-on-health/.

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ApeGrade. 2022. "Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants Influence on Health." October 5, 2022. https://apegrade.com/low-density-lipoprotein-cholesterol-lowering-genetic-variants-influence-on-health/.

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ApeGrade. (2022) 'Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants Influence on Health'. 5 October.

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