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12-05-2011 | Cardiometabolic | Article

SORT1 gene SNP has age-dependent effect on LDL cholesterol

Abstract

Free abstract

MedWire News: A single nucleotide polymorphism (SNP) in the sortilin 1 (SORT1) gene exerts an age-dependent effect on levels of low-density lipoprotein (LDL) cholesterol, report researchers.

The team found that the genotype-specific differences in LDL cholesterol levels were significantly greater for younger individuals than for older individuals.

"These findings may help elucidate the mode of action of the SORT1 gene and impact potential therapeutic interventions targeting this pathway," say Brian Shirts and colleagues, from the University of Utah in Salt Lake City, USA.

The team genotyped 14 previously identified SNPs associated with high-density lipoprotein cholesterol, LDL cholesterol, or triglyceride levels in 2302 individuals from the Utah Pedigree Study.

Overall, only the effect of rs646776 at the SORT1 locus on LDL cholesterol levels was statistically significant.

Therefore, the team analyzed the mean rs646776 genotype-associated change in LDL cholesterol levels in 1099 individuals over an average 22.5-year follow-up period.

LDL cholesterol levels significantly increased over time for all genotypes, with GG carriers showing the greatest change, at 26.3 mg/dl (0.68 mmol/l), followed by AG carriers (19.4 mg/dl [0.50 mmol/l]), and then AA carriers (15.1 mg/dl [0.39 mmol/l]).

Linear regression revealed that the effect of rs646776 on LDL cholesterol levels was age dependent, with genotype-associated differences in LDL cholesterol levels significantly decreasing with increasing age.

"Primarily for the younger ages, each copy of the G allele was associated with lower LDL cholesterol levels, whereas this effect diminishes with age," say the researchers.

This explains why GG carriers had the greatest change over time, and therefore, the effect of the SORT1 locus may be greater than previously reported in young individuals and lesser than previously thought in older individuals, they add.

Of note, LDL cholesterol heritability was estimated at 43%, with 4.3% due to rs646776 and 0.2% due to the age-rs646776 interaction, which, the researchers say, indicates that at least a small portion of 'missing' heritability is due to gene-age interactions.

"Future confirmatory studies and risk prediction algorithms should take this effect into account," concludes the team in the journal Atherosclerosis.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2011

By Nikki Withers