Association Of Genetic Variation And Lipid-related Concentrations In African American Men With And Without Type 2 Diabetes

Abstract

Abnormal levels of lipids and cholesterol in the blood lead to atherosclerosis, which can then cause cardiovascular disease (CVD). Specifically, decreased high-density lipoprotein (HDL) and increased low-density lipoproteins (LDL) increase the risk of CVD such as myocardial infarction and ischemic stroke. These lipid abnormalities occur more frequently in individuals with Type 2 diabetes mellitus (T2DM). In addition, uncontrolled diabetes causes damage to the blood vessels, in turn making them more prone to damage from atherosclerosis, putting these individuals at especially high risk for the development of CVD. African Americans with T2DM are at an even greater risk of CVD as a result of a combination of risk factors, among which dyslipidemia plays a prominent role. However, their lipid profile is often different from Caucasians with T2DM.

Genetic variations in ADIPOQ, APOE, CETP, NOX3, PCSK9, and PON1 are thought to lead to altered levels of circulating LDL and HDL and may potentially explain the variability seen in lipid levels. Given the increased risk of CVD in African Americans with T2DM, it is important to gain an understanding of the underlying physiology and genetics. The goal of this study is to understand the genetic association with lipid levels in AA males with and without T2DM. Our long-term goal is to identify polymorphisms that can serve as biomarkers in the prediction, development and management of CV events in patients with both T2DM and dyslipidemia. To address each aim and analyze any potential relationships and/or interactions, we employed a candidate gene case-control approach where we compared genotype frequencies of lipid related candidate genes in unrelated African American males, 30 years of age of older, not currently treated with lipid lowering agents, with T2DM and healthy nondiabetic controls.

Our data suggest that alterations in HDL and LDL particle levels are potentially due to genetic variation as well as the presence of T2DM. The CETP Taq1B B2-allele was associated with higher levels of HDL 2b and HDL L, but a lower level of HDL 3a and HDL 3b. In addition, the CETP Taq1B B2-allele was associated with decreases in small subclasses of LDL: LDL IVb, LDL IVa & LDL IIIb, where small LDL subclasses are considered more atherogenic compared to larger LDL. PON1 L55M variant allele was associated with decreases in HDL S as well as significant interactions between genotype and diabetic status on HDL 3a. The APOE E4 allele was associated with higher levels of LDL subclass: LDL 3a, LDL 2b, LDL 2a, LDL M and LDL L. With respect to PCSK9, the presence of diabetes abrogates the effects of the A443, potentiating a more atherosclerotic profile. In the absence of T2DM, levels of HDL 3a and 3b were reduced and HDL 2b elevated with the variant allele compared to the wildtype. However, we observed that, alternatively, diabetic variant allele carriers had elevated levels HDL 3a, and 3b and reduced levels of HDL 2b. The ADIPOQ variant allele was associated with lower levels of IDL 2, where lower levels of IDL potentially indicate a decrease in CVD risk.

African Americans suffer disproportionately from CVD but only an estimated 50% of CVD incidence can be explained by traditional risk factors. Inclusion of genetics as well as lipoprotein subclass information may be beneficial. We observed ADIPOQ variant allele carriers had significantly lower levels of LDL 1 and IDL 2 and APOE variant allele carriers had significantly lower levels of LDL 1, subclasses considered less atherogenic than other LDL subclasses. CETP Taq1B and PON1 L55M variant allele carriers were significantly associated with HDL subclasses, where we observed increases in larger, more efficient HDL and decreases in smaller HDL. In addition, a significant interaction between genotype and diabetic status was observed, only for CETP Taq1B, PON1 L55M and PCSK9 A443T genotype. Targeting these particular genes, as well as many others known and unknown, may serve as promising interventions for all dyslipidemic individuals. Understanding the influence that co-morbidities may have in the presence of genetic variations will facilitate the design of innovative strategies for the prevention of morbid cardiovascular events via early detection of CVD risk.