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 identiWed 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 signiWcant association with any lipid-related trait. We investigated the expression of PCDH15 in diVerent 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 proWle. We observed a signiWcant diVerence 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.

Plasticity in Membrane Cholesterol Contributes toward Electrical Maturation of Hearing

“…Thus, our findings are consistent with the growing evidence that specialized lipid microdomains may play a critical role in hair cell functions. On a pragmatic level, recent reports have associated hyperlipidemia and dyslipidemia with hearing loss (47,48). The findings that outer hair cell function is tuned to membrane cholesterol content (49,17) further strengthens the growing evidence suggesting that membrane lipid microdomains may be important for hair cell physiology and pathophysiology.…”

Prediction of Breast Cancer Survival Using Clinical and Genetic Markers by Tumor Subtypes

“…Rs10825036 is close to the PCDH15 gene which encodes integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Previously, the SNPs of the PCDH15 gene are known for associations with adverse events caused by chemotherapy in breast cancer[ 49 ] as well as with lipid abnormalities[ 50 ]. The lipid profiles have been associated with the risk, stage, and recurrence of breast cancer[ 51 – 53 ].…”

Common variants at 10p12.31, 10q21.1 and 13q12.13 are associated with sporadic pituitary adenoma

“…Mutations in PCDH15 result in hearing loss and Usher syndrome type 1F (USH1F) 19,20 . SNPs in this gene have also been found to be associated with lipid abnormalities 21 and immune response to smallpox vaccine 22 . During the embryonic stage in mice, Pcdh15 is highly expressed in Rathke's pouch, which ultimately develops into the pituitary 23 .…”