Association and linkage of LDLR gene variation with variation in plasma low density lipoprotein cholesterol.
The role of common variation in the low density lipoprotein (LDL) receptor gene (LDLR) as a determinant of variation in plasma LDL cholesterol in normolipidemic populations is not well established. To address this question, we used both association and linkage analysis to evaluate the relationship between plasma LDL cholesterol and genetic variation in LDLR and in three other candidate genes for lipoprotein metabolism, namely, APOE, PONI, and LPL. We studied a sample of 719 normolipidemic Alberta Hutterites, who comprised 1217 sib pairs. Variation in each of the four candidate genes was significantly associated with variation in plasma LDL cholesterol, but the average effects of the alleles were small. In contrast, sib pair analysis showed that only the LDLR gene variation was linked with variation in plasma LDL cholesterol (P = 0.026). Thus, the common LDLR gene variation was both associated with and linked to variation in plasma LDL cholesterol, suggesting that there is a functional impact of structural variation in LDLR on plasma LDL cholesterol in this study sample. However, the absence of linkage of variation in LDL cholesterol with the other three candidate genes, in particular APOE, is consistent with a lower sensitivity of linkage analysis compared with association analysis for detecting modest effects on quantitative traits. Attributes such as the genetic structure of the study sample, the amount of variance attributable to the locus, and the information content of the marker appear to affect the ability to detect genotype-phenotype relationships using linkage analysis.
Boright
A P
AP
Department of Medicine, St. Michael's Hospital, Ontario, Canada.
Connelly
P W
PW
Brunt
J H
JH
Morgan
K
K
Hegele
R A
RA
D000328:Adult; D000416:Alberta; D001057:Apolipoproteins E / Q000235:genetics; D043303:Aryldialkylphosphatase; D008078:Cholesterol, LDL / Q000097:blood*; D004950:Esterases / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011973:Receptors, LDL / Q000235:genetics*
D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D011973:Receptors, LDL; D004950:Esterases; D008071:Lipoprotein Lipase; D043303:Aryldialkylphosphatase