Genetics
Two new CETP and LIPC gene mutations identified as causes of extremely high HDL cholesterol in Thai patients (Metabolism 2009)
Original title: Two novel mutations and functional analyses of the CETP and LIPC genes underlying severe hyperalphalipoproteinemia
This study investigated whether reduced CETP and hepatic lipase (HL) activities contribute to hyperalphalipoproteinemia (HALP, very high HDL-cholesterol) in the Thai population, recruiting 38 individuals with HDL-cholesterol of at least 2.59 mmol/L (100 mg/dL) and an equal number of normal controls, measuring enzyme activities and sequencing the CETP and LIPC genes in subjects with low activity. Mean CETP and HL activities were significantly lower in the HALP group than controls (34 vs 44 pmol per microliter per hour, P=.04; and 150 vs 227 nmol free fatty acid per mL per minute, P=.002). Among 19 subjects with low CETP activity, 6 were heterozygous for the known D442G mutation and 1 carried a novel deletion mutation, c.734_737delTCCC. Among 16 subjects with low HL activity, 1 carried a novel missense mutation, c.421G>A (G119S), predicted to be functionally damaging. The authors conclude these two novel CETP and LIPC mutations likely cause low enzyme activity and elevated HDL-cholesterol.
Original abstract
Previous studies have shown that CETP and LIPC mutations contribute to hyperalphalipoproteinemia (HALP) in some populations. We investigated whether activities in cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) contribute to HALP in the Thai population and performed genetic analyses of the CETP and LIPC genes. We recruited 38 individuals with high-density lipoprotein cholesterol (HDL-C) levels of at least 2.59 mmol/L (100 mg/dL) (HALP group) and an equal number of individuals with normal serum HDL-C levels (control group). The CETP and HL activities were determined in both groups. Genetic analyses covering all the coding regions and exon-intron junctions of the CETP and LIPC genes were performed in subjects who had low CETP activity and HL activity, respectively. The mean CETP and HL activities were significantly lower in the HALP group than in the control group (34 +/- 4 vs 44 +/- 3 pmol/[microL h], P = .04 and 150 +/- 17 vs 227 +/- 16 nmol free fatty acid/[mL min] P = .002, respectively). Of the 38 individuals with HALP, 19 and 16 were found to have low CETP activity and HL activity, respectively. Of the 19 subjects with low CETP activity, 6 subjects were found to be heterozygous for a known functionally relevant c.1325A>G (D442G) mutation. The other subject was found to be heterozygous for a novel deletion mutation, c.734_737delTCCC mutation. Of the 16 subjects with low HL activity, 8 and 2 subjects were found to be heterozygous for known variants, c.283 G>A (V73M) and c.1068A>C (L334F), respectively. These variants have previously been shown not to be associated with HALP. Another subject was found to be heterozygous for a novel missense mutation, c.421G>A (G119S). Its amino acid change, absence in controls, evolutionary conservation, occurrence in functionally important domain, and predicted damaging function suggested that the G119S mutation is functionally relevant. Two novel mutations in the CETP and LIPC genes found in this study are likely to be the causes of low enzyme activities and elevated HDL-C levels.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.