title: 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.
abstract: 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.
  
  
  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.
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.). dana.crawford@case.edu.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Logan
authors.initials: L
authors.lastname: Dumitrescu
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Robert
authors.initials: R
authors.lastname: Goodloe
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Kristin
authors.initials: K
authors.lastname: Brown-Gentry
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Boston
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Bob
authors.initials: B
authors.lastname: McClellan
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Cara
authors.initials: C
authors.lastname: Sutcliffe
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Rachel
authors.initials: R
authors.lastname: Wiseman
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Paxton
authors.initials: P
authors.lastname: Baker
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Melissa
authors.initials: M
authors.lastname: Allen
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Ping
authors.initials: P
authors.lastname: Mayo
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schnetz-Boutaud
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Holli H
authors.initials: HH
authors.lastname: Dilks
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: From the Institute for Computational Biology (D.C.C., P.M., J.L.H.), Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH (D.C.C., J.L.H.); Center for Human Genetics Research (L.D., R.G., K.B.-G., J.B., B.M., M.A., N.S.-B.), Department of Molecular Physiology and Biophysics (L.D.), Vanderbilt Technologies for Advanced Genomics Core Facility, Vanderbilt University, Nashville, TN (C.S., R.W., P.B., H.H.D.); Hussman Institute for Human Genomics, University of Miami, FL (M.A.P.-V., W.K.S.); and Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (T.I.P.).
authors.forename: Toni I
authors.initials: TI
authors.lastname: Pollin
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D061365:Amish / Q000235:genetics; D053305:Apolipoprotein C-III / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009749:Nutrition Surveys; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood
chemical_list: D053305:Apolipoprotein C-III; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides
keywords: genetic association studies; genetics; high-density lipoprotein cholesterol; molecular epidemiology; triglycerides