Genetic marker may predict heart disease risk in people with HIV

A genetic marker associated with atherosclerosis and oxidative stress in mice and humans is strongly associated with the incidence of cardiovascular disease, metabolic syndrome and poorer immune recovery in people with HIV, Spanish researchers report in the February 15th edition of the Journal of Infectious Diseases.

If proven in larger studies and different populations the finding could lead to the use of genetic screening to differentiate patients with HIV at higher risk of cardiovascular disease, or to identify patients who may benefit from antioxidant therapy and lipid-lowering drugs to modify their risk, even when their cholesterol levels are near-normal.

The research centres on a set of genetic polymorphisms, or gene variants, that regulate the production of paraoxonase-1 (PON1), an enzyme that preserves HDL and LDL cholesterol from peroxidation. (Lipid peroxidation is one mechanism through which cardiovascular disease is thought to develop.)

Studies have produced conflicting results regarding the relationship between variations in the gene that expresses paraoxonase and the risk of cardiovascular disease (Wheeler 2004), despite evidence from mouse models that the presence or absence of the gene in mice is associated with the risk of atherosclerosis.

Cardiovascular disease is an increasingly frequent cause of death in people with HIV, but there is a lack of clarity about the relative contributions of antiretroviral drugs, inflammatory processes due to HIV infection and the well-recognised risk factors such as smoking, weight, lack of exercise, diet and age on cardiovascular risk in people with HIV.

The same research group, at the Hospital Universitari de Sant Joan in Catalunya, Spain, previously reported that people with HIV who showed rapid progression of atherosclerosis (as measured by intima media thickness) had lower CD4 counts.

The group also found that two polymorphisms – SDF1-3`A and CX3CR-1 249I – associated with inflammatory chemokines implicated in the development of atherosclerosis, protected against progression of atherosclerosis (Coll 2007).

Although the new Spanish study, conducted by Jordi Camps and colleagues, does not set out to clarify the contributions of risk factors, it does seek to determine whether a genomic marker predicts a higher risk of cardiovascular disease. This in turn could shed light on potential pathways by which cardiovascular disease develops in people with HIV, the extent to which these pathways are specific to people with HIV infection, and potential interventions to reduce the risk.

Camps and colleagues at the Hospital Universitari de Sant Joan in Catalunya, Spain, first looked at the distribution of PON1 haplotypes in a cohort of 234 HIV-positive patients and 633 uninfected adults, all Caucasian.

Two haplotypes (H10 and H5) showed significant differences in distribution between the two populations. H10 was significantly more common in people with HIV, while H5 was significantly less common.

They then performed a case control study in HIV-infected patients in which those receiving antiretroviral therapy who manifested lipodystrophy, metabolic disorders, a positive cardiovascular risk or atherosclerosis (determined by carotid artery intima media thickness), were matched with HIV-positive patients who did not manifest any of these conditions.

The case control study was designed to analyse the relationship between PON1 haplotype and the abovementioned conditions, as well as its relationship to viral suppression and CD4 cell restoration.

The researchers found that the H7 haplotype was associated with greater increases in CD4 cell count, higher levels of HDL cholesterol and apolipoprotein A1, lower triglyceride levels and lower rates of subclinical arteriosclerosis.

However the absence of the H7 haplotype was only modestly predictive of atherosclerosis in a linear regression model, but multivariate analysis showed that after controlling for classic cardiovascular risk factors, absence of the H7 haplotype predicted the presence of atherosclerosis.

The authors speculate about the mechanism by which PON1 influences the risk of cardiovascular disease in people with HIV.

“It is possible that the PON1 genotypic background modulates the lipid profile and also confers a better oxidative status, which in turn, lowers CD4+ cell apoptosis, and consequently, lowers the predisposition to atherosclerosis related to the proinflammatory and prooxidative status of this patient population,” they write.