Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels

doi:10.1073/pnas.0508483103

Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels

*Donald W. Reynolds Cardiovascular Clinical Research Center,
^†Center for Human Nutrition,
^‡McDermott Center for Human Growth and Development,
^∥Department of Molecular Genetics,
^¶Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9052

Edited by Joseph L. Goldstein, University of Texas Southwestern Medical Center, Dallas, TX, and approved December 15, 2005 (received for review September 28, 2005)

Abstract

An approach to understand quantitative traits was recently proposed based on the finding that nonsynonymous (NS) sequence variants in certain genes are preferentially enriched at one extreme of the population distribution. The NS variants, although individually rare, are cumulatively frequent and influence quantitative traits, such as plasma lipoprotein levels. Here, we use the NS variant technique to demonstrate that genetic variation in NPC1L1 contributes to variability in cholesterol absorption and plasma levels of low-density lipoproteins (LDLs). The ratio of plasma campesterol (a plant sterol) to lathosterol (a cholesterol precursor) was used to estimate relative cholesterol absorption in a population-based study. Nonsynonymous sequence variations in NPC1L1 were five times more common in low absorbers (n = 26 of 256) than in high absorbers (n = 5 of 256) (P < 0.001). The rare variants identified in low absorbers were found in 6% of 1,832 African-Americans and were associated with lower plasma levels of LDL cholesterol (LDL-C) (96 ± 36 mg/dl vs. 105 ± 36 mg/dl; P = 0.005). These data, together with prior findings, reveal a genetic architecture for LDL-C levels that does not conform to current models for quantitative traits and indicate that a significant fraction of genetic variance in LDL-C is due to multiple alleles with modest effects that are present at low frequencies in the population.

Footnotes

^§To whom correspondence should be addressed at:
Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9052.
E-mail: jonathan.cohen{at}utsouthwestern.edu
Author contributions: J.C.C., S.M.G., and H.H.H. designed research; A.P., S.F., S.E., G.L.V., and S.M.G. performed research; G.L.V. contributed new reagents/analytic tools; J.C.C., A.P., S.F., S.E., G.L.V., S.M.G., and H.H.H. analyzed data; and J.C.C. and H.H.H. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Freely available online through the PNAS open access option.
Abbreviations:

Ca:L,

campesterol-to-lathosterol ratio;

LDL,

low-density lipoprotein;

LDL-C,

LDL cholesterol;

NS,

nonsynonymous;

NPC1L1,

Niemann–Pick Type C1 Like 1;

PCSK9,

proprotein convertase subtilisin/kexin type 9 precursor.
Freely available online through the PNAS open access option.