Genetic variation in phospholipid transfer protein modulates lipoprotein profiles in hyperalphalipoproteinemia

Abstract

We previously demonstrated the role of a Phospholipid Transfer Protein (PLTP) gene variation (rs2294213) in determining levels of HDL-C in hypoalphalipoproteinemia (HypoA). We have now explored the role of PLTP in hyperalphalipoproteinemia (HyperA). The human PLTP gene was screened for sequence anomalies by DNA melting in 107 subjects with HyperA. The association with plasma lipoprotein levels was evaluated. We detected 7 sequence variations:, 1 previously reported variation (rs2294213), and 5 novel mutations including 1 missense mutation (L106F). PLTP activity was unchanged in the p.L106F mutation. The frequency of the rs2294213 minor allele was markedly increased in the HyperA group (7.0%) in comparison with a control group (4.3%) and the HypoA group (2.2%). Moreover, rs2294213 was strongly associated with HDL-C levels. Linear regression models predict that possession of the rs2294213 minor allele increases HDL-C independent of triglycerides. These findings extend the association of rs2294213 with HDL-C levels into the extremes of the HDL distribution.

Genetic causes of high and low serum HDL-cholesterol

“…Aouizerat et al ( 122 ) ( 127 ) identifi ed an intronic SNP (rs2294213) more prevalent in the controls (4%) than in the low HDL-C subjects (2%) and associated with higher HDL-C levels ( P -value < 0.001). Given these fi ndings, the authors also sequenced PLTP in 107 subjects with high HDL-C levels (>80 th percentile for age and sex) in a subsequent study ( 128 ). In agreement with their previous fi ndings, the MAF of rs2294213 was markedly increased in the high HDL-C group (7%) ( 128 ), suggesting that SNPs in PLTP may contribute to the entire range of variation in plasma HDL-C.…”

“…Given these fi ndings, the authors also sequenced PLTP in 107 subjects with high HDL-C levels (>80 th percentile for age and sex) in a subsequent study ( 128 ). In agreement with their previous fi ndings, the MAF of rs2294213 was markedly increased in the high HDL-C group (7%) ( 128 ), suggesting that SNPs in PLTP may contribute to the entire range of variation in plasma HDL-C. This fi nding is the fi rst evidence for a direct link between variation in PLTP and HDL-C levels in humans.…”

Genetic and nongenetic sources of variation in phospholipid transfer protein activity

“…Using imputed data, we fi nd that SNP rs2294213 predicts PLTP activity. We do not confi rm effects of this SNP on HDLC ( 26 ) or other lipids; however, power for these tests is limited by the poor imputational accuracy.…”

“…While all other SNPs in the results were genotyped, we investigated the imputed SNP rs22494213 in the discovery cohort based on prior reports associated with HDL level ( 26 ). This SNP was not in strong LD with genotyped SNPs.…”

“…In that report, the rs7679 T allele was associated with increased PLTP expression, increased HDL level, and decreased triglyceride level. SNP rs2294213 has been reported to be associated with raised HDL, lowered triglycerides, and higher PLTP activity ( 26 ). The lipid profi les would suggest that increased expression might be cardioprotective.…”