Rare Variant APOC3 R19X Is Associated With Cardio-Protective Profiles in a Diverse Population-Based Survey as Part of the Epidemiologic Architecture for Genes Linked to Environment Study

Circ Cardiovasc Genet. 2014 Dec;7(6):848-53. doi: 10.1161/CIRCGENETICS.113.000369. Epub 2014 Nov 1.


Background: A founder mutation was recently discovered and described as conferring favorable lipid profiles and reduced subclinical atherosclerotic disease in a Pennsylvania Amish population. Preliminary data have suggested that this null mutation APOC3 R19X (rs76353203) is rare in the general population.

Methods and results: To better describe the frequency and lipid profile in the general population, we as part of the Population Architecture using Genomics and Epidemiology I Study and the Epidemiological Architecture for Genes Linked to Environment Study genotyped rs76353203 in 1113 Amish participants from Ohio and Indiana and 19 613 participants from the National Health and Nutrition Examination Surveys (NHANES III, 1999 to 2002, and 2007 to 2008). We found no carriers among the Ohio and Indiana Amish. Of the 19 613 NHANES participants, we identified 31 participants carrying the 19X allele, for an overall allele frequency of 0.08%. Among fasting adults, the 19X allele was associated with lower triglycerides (n=7603; β=-71.20; P=0.007) and higher high-density lipoprotein cholesterol (n=8891; β=15.65; P=0.0002) and, although not significant, lower low-density lipoprotein cholesterol (n=6502; β= -4.85; P=0.68) after adjustment for age, sex, and race/ethnicity. On average, 19X allele participants had approximately half the triglyceride levels (geometric means, 51.3 to 69.7 versus 134.6 to 141.3 mg/dL), >20% higher high-density lipoprotein cholesterol levels (geometric means, 56.8 to 74.4 versus 50.38 to 53.36 mg/dL), and lower low-density lipoprotein cholesterol levels (geometric means, 104.5 to 128.6 versus 116.1 to 125.7 mg/dL) compared with noncarrier participants.

Conclusions: These data demonstrate that APOC3 19X exists in the general US population in multiple racial/ethnic groups and is associated with cardio-protective lipid profiles.

Keywords: genetic association studies; genetics; high-density lipoprotein cholesterol; molecular epidemiology; triglycerides.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Amish / genetics
  • Apolipoprotein C-III / genetics*
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Female
  • Gene Frequency
  • Genotype
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Nutrition Surveys
  • Polymorphism, Single Nucleotide
  • Triglycerides / blood


  • Apolipoprotein C-III
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Triglycerides