CETP is the least frequently mutated of three genes (LIPG, CETP, GALNT2) found in Caucasian families with extremely high HDL cholesterol (PLoS One 2012)

Original title: Segregation of LIPG, CETP, and GALNT2 mutations in Caucasian families with extremely high HDL cholesterol

PLoS One · 1 January 2012 · 5

Tietjen I, Hovingh GK, Singaraja RR, Radomski C, Barhdadi A, McEwen J, Chan E, Mattice M, Legendre A, Franchini PL, Dubé MP, Kastelein JJ et al.

Sequencing the coding regions of LIPG, CETP, and GALNT2 in 171 unrelated Dutch Caucasian probands with HDL cholesterol at or above the 90th percentile, mutations were most frequent in LIPG (12.9%), followed by GALNT2 (2.3%) and CETP (0.6%), with 6 of 10 mutations being novel (60.0%), and mutations segregated with elevated HDL cholesterol in family members. The LIPG mutations N396S and R476W, which usually raise HDL cholesterol, were unexpectedly found in 6 probands with low HDL cholesterol (at or below the 10th percentile), 5 of whom also carried mutations in ABCA1, LCAT, or LPL. No CETP or GALNT2 mutations were found among 136 unrelated probands with low HDL cholesterol, and rare coding and splicing mutations in LIPG, CETP, and GALNT2 are enriched in hyperalphalipoproteinemia.

Original abstract

To date, few mutations are described to underlie highly-elevated HDLc levels in families. Here we sequenced the coding regions and adjacent sequence of the LIPG, CETP, and GALNT2 genes in 171 unrelated Dutch Caucasian probands with HDLc≥90th percentile and analyzed segregation of mutations with lipid phenotypes in family members. In these probands, mutations were most frequent in LIPG (12.9%) followed by GALNT2 (2.3%) and CETP (0.6%). A total of 6 of 10 mutations in these three genes were novel (60.0%), and mutations segregated with elevated HDLc in families. Interestingly, the LIPG mutations N396S and R476W, which usually result in elevated HDLc, were unexpectedly found in 6 probands with low HDLc (i.e., ≤10th percentile). However, 5 of these probands also carried mutations in ABCA1, LCAT, or LPL. Finally, no CETP and GALNT2 mutations were found in 136 unrelated probands with low HDLc. Taken together, we show that rare coding and splicing mutations in LIPG, CETP, and GALNT2 are enriched in persons with hyperalphalipoproteinemia and segregate with elevated HDLc in families. Moreover, LIPG mutations do not overcome low HDLc in individuals with ABCA1 and possibly LCAT and LPL mutations, indicating that LIPG affects HDLc levels downstream of these proteins.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.