Cholesterol and serotonin transporter polymorphism interactions in late-life depression

Abstract

Background

It has been suggested that the functional polymorphism in the serotonin transporter gene linked promoter region (5-HTTLPR) modifies associations between vascular diseases (coronary artery syndrome or stroke) and depression. This study investigated whether the 5-HTTLPR polymorphism has modifying effects on previously identified associations between cholesterol levels and prevalence/incidence of late-life depression.

Methods

In 732 community residents aged 65+, depression was ascertained (Geriatric Mental State Schedule) at baseline and after 2 years. 5-HTTLPR genotype and lipid levels (total, HDL and LDL cholesterol and triglycerides) were assayed. Covariates were age, sex, education, disability, and cognitive function.

Results

Significant associations between lower baseline HDL cholesterol levels with prevalent and incident depression were also modified by 5-HTTLPR polymorphism, and were only significant in the presence of one or more copies of the s allele.

Conclusion

A more atherogenic lipid profile, as indicated by lower HDL cholesterol is a risk factor for late-life depression and this risk is modified by a gene implicated in serotonin transport.

Introduction

Vascular disease has been suggested to be an important risk factor for depression in late-life (Alexopoulos et al., 1997) and dylipidemia is an important risk factor for vascular outcomes. Low high density lipoprotein (HDL) cholesterol has been found to be a risk factor for incident depression (Kim et al., 2006) as well as a correlate of prevalent depression (Kim et al., 2004, Dimopoulos et al., 2007, Lehto et al., 2008), consistent with this hypothesis. However, for total cholesterol, lower rather than higher levels have more often been found to be associated with depression in older people (Aijänseppä et al., 2002, Morgan et al., 1993). One plausible underlying mechanism is that a reduction in serum cholesterol might decrease brain cell membrane cholesterol, and decrease the exposure of protein serotonin receptors on the membrane surface, resulting in a poorer uptake of serotonin from the blood and less serotonin entry into brain cells (Engelberg, 1992). Indeed, serum cholesterol levels have been found to be positively associated with serotonergic activity measured by cortisol responses to meta-chlorophenylpiperazine (Buydens-Branchey et al., 2000, Terao et al., 2000), although this finding has not always been replicated (Papakostas et al., 2003, Sarchiapone et al., 2001).

The serotonin transporter (5-HTT) of the brain provides the primary target for the action of selective antidepressant drugs, and is a plausible candidate gene for mediating susceptibility to depression (Ogilvie et al., 1996). There is a biallelic polymorphism in the 5-HTT gene linked promoter region (5-HTTLPR) with short (s) and long (l) alleles. In relation to cholesterol levels, total cholesterol levels have been found to be significantly higher in s/l heterozygotes than either s/s or l/l homozygotes (Comings et al., 1999), and low density lipoprotein (LDL) cholesterol levels have been found to be significantly higher in those with l allele than those with s allele (Fischer et al., 2006). Despite the potential for interactive effects between 5-HTTLPR polymorphism and cholesterol levels on depression, this has not been investigated to date in a community population.

In a previous analysis of data from a prospective community study of an older Korean population, we found that cholesterol levels were associated with prevalence and incidence of depression (Kim et al., 2004, Kim et al., 2006); specifically, lower baseline high density lipoprotein (HDL) cholesterol levels was associated with both prevalent and incident depression, and a U-shaped association was found between baseline total cholesterol and incident depression. In the present analyses, we aimed to investigate whether cholesterol levels (total and sub-fractions) were associated with 5-HTTLPR polymorphism, and whether the 5-HTTLPR polymorphism modified previously identified associations between baseline levels and incidence of depression.