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

Jonathan C Cohen, Alexander Pertsemlidis, Saleemah Fahmi, Sophie Esmail, Gloria L Vega, Scott M Grundy, Helen H Hobbs

Research output: Contribution to journalArticlepeer-review

328 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1810-1815
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
StatePublished - Feb 15 2006


  • Cholesterol absorption
  • Complex trait
  • Genetic architecture
  • Mutation
  • Plant sterol

ASJC Scopus subject areas

  • General


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