Abstract
Phospholipid transfer protein activity (PLTPa) is associated with insulin levels and has been implicated in atherosclerotic disease in both mice and humans. Variation at the PLTP structural locus on chromosome 20 explains some, but not all, heritable variation in PLTPa. In order to detect quantitative trait loci (QTLs) elsewhere in the genome that affect PLTPa, we performed both oligogenic and single QTL linkage analysis on four large families (n = 227 with phenotype, n = 330 with genotype, n = 462 total), ascertained for familial combined hyperlipidemia. We detected evidence of linkage between PLTPa and chromosome 19p (lod = 3.2) for a single family and chromosome 2q (lod = 2.8) for all families. Inclusion of additional marker and exome sequence data in the analysis refined the linkage signal on chromosome 19 and implicated coding variation in LASS4, a gene regulated by leptin that is involved in ceramide synthesis. Association between PLTPa and LASS4 variation was replicated in the other three families (P = 0.02), adjusting for pedigree structure. To our knowledge, this is the first example for which exome data was used in families to identify a complex QTL that is not the structural locus.
Highlights
Phospholipid transfer protein activity (PLTPa) is associated with insulin levels and has been implicated in atherosclerotic disease in both mice and humans
We evaluated all exomic sites within the region, we emphasized those sites within genes expressed in the tissues most relevant to plasma PLTPa
PLTP structural locus single nucleotide polymorphism (SNP) rs6065904, which has been shown to be associated with PLTPa and mRNA level [23, 26], explained 5% of the genetic var(adj-PLTPa) in the families; adjustment for this SNP did not impact linkage results, as noted below
Summary
Phospholipid transfer protein activity (PLTPa) is associated with insulin levels and has been implicated in atherosclerotic disease in both mice and humans. Association between PLTPa and LASS4 variation was replicated in the other three families (P = 0.02), adjusting for pedigree structure To our knowledge, this is the first example for which exome data was used in families to identify a complex QTL that is not the structural locus.— Rosenthal, E. Linkage and association of phospholipid transfer protein activity to LASS4. Studies in mice provide evidence of a role of PLTP in lipoprotein levels and atherosclerosis. PLTPa is highly positively correlated with HDL size and concentration among inbred mouse strains [21] In human studies, both PLTP mass and PLTPa, which are weakly correlated [22], have been shown to be associated.
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