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Genetic determinants of human serum sterol levels
Author(s) -
Stiles Ashlee Renee,
Russell David W
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.990.1
Subject(s) - single nucleotide polymorphism , oxysterol , biology , snp , phenotype , sterol , genetics , gene , cholesterol , genome wide association study , endocrinology , genotype
24‐hydroxycholesterol (24‐OHC) is a metabolite of brain cholesterol metabolism and a substrate for bile acid synthesis. Mutation of the cholesterol 24‐hydroxlase gene in mice ( Cyp46A1 ) causes severe learning defects. Targeted and untargeted approaches were taken to identify genetic determinants controlling serum 24‐OHC levels. First, we measured 24‐OHC levels in 3230 individuals from the Dallas Heart Study, a multi‐ethnic patient cohort. Genome‐wide analysis of non‐synonymous variations and dense single nucleotide polymorphism (SNP) scans of lipid metabolism genes revealed one highly significant (P=2.1× 10 −27 ) genetic association between elevated 24‐OHC and SNPs in an oxysterol 7□‐hydroxylase gene ( CYP39A1 ). Expression analysis in transfected cells revealed that the identified SNPs decreased CYP39A1 enzymatic activity when compared to wild‐type, revealing a loss of enzymatic function. Currently, we are correlating these findings with clinical phenotype data to reveal the role of this oxysterol in disease which allows others to understand the roles of oxysterols in‐vivo . Similar association studies were done for other sterols measured in the cohort and results from these experiments will be reported.