title: A nonsynonymous SNP within PCDH15 is associated with lipid traits in familial combined hyperlipidemia.
abstract: Familial combined hyperlipidemia (FCHL) is a common lipid disorder characterized by the presence of multiple lipoprotein phenotypes that increase the risk of premature coronary heart disease. In a previous study, we identified an intragenic microsatellite marker within the protocadherin 15 (PCDH15) gene to be associated with high triglycerides (TGs) in Finnish dyslipidemic families. In this study we analyzed all four known nonsynonymous SNPs within PCDH15 in 1,268 individuals from Finnish and Dutch multigenerational families with FCHL. Association analyses of quantitative traits for SNPs were performed using the QTDT test. The nonsynonymous SNP rs10825269 resulted in a P = 0.0006 for the quantitative TG trait. Additional evidence for association was observed with the same SNP for apolipoprotein B levels (apo-B) (P = 0.0001) and total cholesterol (TC) levels (P = 0.001). None of the other three SNPs tested showed a significant association with any lipid-related trait. We investigated the expression of PCDH15 in different human tissues and observed that PCDH15 is expressed in several tissues including liver and pancreas. In addition, we measured the plasma lipid levels in mice with loss-of-function mutations in Pcdh15 (Pcdh15(av-Tg) and Pcdh15(av-3J)) to investigate possible abnormalities in their lipid profile. We observed a significant difference in plasma TG and TC concentrations for the Pcdh15(av-3J) carriers when compared with the wild type (P = 0.013 and P = 0.044, respectively). Our study suggests that PCDH15 is associated with lipid abnormalities.
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. huertasa@cshs.org
authors.forename: Adriana
authors.initials: A
authors.lastname: Huertas-Vazquez
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Plaisier
authors.forename: Ruishuang
authors.initials: R
authors.lastname: Geng
authors.forename: Blake E
authors.initials: BE
authors.lastname: Haas
authors.forename: Jenny
authors.initials: J
authors.lastname: Lee
authors.forename: Marleen M
authors.initials: MM
authors.lastname: Greevenbroek
authors.forename: Carla
authors.initials: C
authors.lastname: van der Kallen
authors.forename: Tjerk W A
authors.initials: TW
authors.lastname: de Bruin
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: Kumar N
authors.initials: KN
authors.lastname: Alagramam
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
mesh_terms: D000483:Alleles; D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D005192:Family Health; D005260:Female; D005387:Finland; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000097:blood / Q000235:genetics*; D015810:Linkage Disequilibrium; D008055:Lipids / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood
chemical_list: C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D008055:Lipids; D014280:Triglycerides; D002784:Cholesterol