Evidence for a major gene accounting for mild elevation in LDL cholesterol: the NHLBI Family Heart Study.
Studies of rare Mendelian disorders of low density lipoprotein cholesterol (LDL-C) metabolism have identified specific genetic mutations in the LDL receptor and apolipoprotein B. Although these rare mutations account for a small proportion of LDL-C variation, twin and adoption studies indicate that at least 50% of the overall LDL-C observed variation is genetically determined. In a heterogeneous sample of 3227 subjects from the NHLBI Family Heart Study collected from four US centres, we find evidence for a common major gene accounting for mild elevations (1.25 standard deviations) in LDL-C. The analysis favored a recessive model with a frequency of 0.52 for the gene influencing elevated LDL-C, phenotypic means of 113 mg/dl for the normal genotypes and 146 mg/dl for the abnormal genotype, and a significant polygenic heritability. This statistically-inferred major gene accounted for 24% of the variation in LDL-C, with polygenes accounting for another 28% of the variation. Using parameters for major gene transmission estimated in the segregation analysis, LDL-C showed no linkage to the LDL receptor gene (LDLR), nor to the apolipoprotein E gene (APOE), nor to the cholesterol 7alpha-hydroxylase gene (CYP7A1), indicating the major gene effect influencing mild elevation in LDL-C is not explained by any of these candidate loci.
Coon
H
H
Department of Psychiatry, University of Utah, Salt Lake City 84108, USA. hilary@wilbur.med.utah.edu
Leppert
M F
MF
Kronenberg
F
F
Province
M A
MA
Myers
R H
RH
Arnett
D K
DK
Eckfeldt
J H
JH
Heiss
G
G
Williams
R R
RR
Hunt
S C
SC
D000328:Adult; D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D008078:Cholesterol, LDL / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009316:National Institutes of Health (U.S.); D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics; D012737:Sex Factors; D014481:United States
D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D005819:Genetic Markers; D011973:Receptors, LDL; D002790:Cholesterol 7-alpha-Hydroxylase