title: Detection of a major gene effect for LDL peak particle diameter and association with apolipoprotein H gene haplotype.
abstract: Low-density lipoprotein (LDL) size, a coronary heart disease risk factor, is influenced by both genetic and environmental factors. Results from the Quebec Family Study (QFS) revealed that the LDL peak particle diameter (LDL-PPD) aggregates in families with a heritability coefficient above 50% and is affected by a major quantitative trait locus on chromosome 17q (LOD=6.8). Complex segregation analyses have consistently demonstrated a major gene effect influencing LDL size. In the present study, we report a similar analysis in the QFS cohort, which suggests that a major gene explains 23% of the variance in age-body mass index and triglyceride-adjusted LDL-PPD. The most intuitive positional candidate gene on chromosome 17q is the apolipoprotein H gene. Direct sequencing of the promoter, coding regions, and exon-intron splicing boundaries of this gene revealed the presence of three missense mutations and two polymorphisms in the untranslated regions. Using family-based association tests, none of these variants was individually associated with LDL-PPD. However, analysis of the haplotypes constructed from the three missense mutations, suggested that one particular haplotype (frequency=20.9%) was associated with a significant increase in LDL-PPD trait values (p=0.046). Taken together, these results suggest the presence of a major gene effect influencing LDL-PPD and a positive association with a positional candidate gene located on chromosome 17q. Replication of the association between apolipoprotein H gene haplotype and LDL-PPD is required before reaching firm conclusion.
authors.affiliation: Lipid Research Center, CHUL Research Center, TR-93, 2705 Laurier Blvd Sainte-Foy, Que., Canada G1V 4G2.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.forename: Mary F
authors.initials: MF
authors.lastname: Feitosa
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Després
authors.forename: Benoît
authors.initials: B
authors.lastname: Lamarche
authors.forename: Treva
authors.initials: T
authors.lastname: Rice
authors.forename: D C
authors.initials: DC
authors.lastname: Rao
authors.forename: Claude
authors.initials: C
authors.lastname: Bouchard
authors.forename: Louis
authors.initials: L
authors.lastname: Pérusse
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Vohl
mesh_terms: D000328:Adult; D000368:Aged; D020090:Chromosome Segregation; D002886:Chromosomes, Human, Pair 17; D003327:Coronary Disease / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006023:Glycoproteins / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010316:Particle Size; D040641:Quantitative Trait Loci; D011792:Quebec; D053482:beta 2-Glycoprotein I
chemical_list: D006023:Glycoproteins; D008077:Lipoproteins, LDL; D053482:beta 2-Glycoprotein I