TY - JOUR
T1 - Detection of a major gene effect for LDL peak particle diameter and association with apolipoprotein H gene haplotype
AU - Bossé, Yohan
AU - Feitosa, Mary F.
AU - Després, Jean Pierre
AU - Lamarche, Benoît
AU - Rice, Treva
AU - Rao, D. C.
AU - Bouchard, Claude
AU - Pérusse, Louis
AU - Vohl, Marie Claude
N1 - Funding Information:
This study was supported by the Canadian Institutes of Health Research (MOP-13960 and MOP-44074). The authors would like to express their gratitude to the subjects for their excellent collaboration and to the staff of the Physical Activity Sciences Laboratory for their contribution to the study. Y. Bossé is the recipient of a Canada Graduate Scholarship Doctoral Awards. M.C. Vohl is a research scholar of the “Fonds de la recherche en santé du Québec”. J.P. Després is chair professor of human nutrition, lipidology and prevention of cardiovascular disease supported by Provigo and Pfizer Canada. B. Lamarche is a recipient of the Canada Research Chair in Nutrition, Functional Foods and Cardiovascular Health. C. Bouchard is partially funded by the George A. Bray Chair in Nutrition.
PY - 2005/10
Y1 - 2005/10
N2 - 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.
AB - 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.
KW - Apolipoprotein H
KW - Family-based association test
KW - Haplotypes
KW - LDL peak particle diameter
KW - Segregation analysis
UR - http://www.scopus.com/inward/record.url?scp=24644469238&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2005.02.008
DO - 10.1016/j.atherosclerosis.2005.02.008
M3 - Article
C2 - 16159595
AN - SCOPUS:24644469238
SN - 0021-9150
VL - 182
SP - 231
EP - 239
JO - Atherosclerosis
JF - Atherosclerosis
IS - 2
ER -