title: Increased burden of cardiovascular disease in carriers of APOL1 genetic variants.
abstract: BACKGROUND
  Two distinct alleles in the gene encoding apolipoprotein L1 (APOL1), a major component of high-density lipoprotein, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease. Approximately 14% of Americans with African ancestry carry 2 APOL1 risk alleles, accounting for the high chronic kidney disease burden in this population.
  
  
  OBJECTIVE
  We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African Americans.
  
  
  RESULTS
  We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and chronic kidney disease was confirmed (P=2.4×10(-6)). Among JHS participants with 2 APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without versus 37/280 events among participants with 2 risk alleles; odds ratio, 2.17; P=9.4×10(-4)). We replicated this novel association of APOL1 genotype with CVD in Women's Health Initiative (WHI) participants (66/292 events among participants without versus 37/101 events among participants with 2 risk alleles; odds ratio, 1.98; P=8.37×10(-3); JHS and WHI combined, P=8.5×10(-5); odds ratio, 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and chronic kidney disease.
  
  
  CONCLUSIONS
  APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with 2 APOL1 risk alleles may benefit from intensive interventions to reduce CVD.
authors.affiliation: From the Department of Genetics, Harvard Medical School, Boston, MA (K.I., A.G.B., M.G.P., S.R.D., J.N.H., J.G.S., C.S.); Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (K.I., A.G.B., J.F., G.G., N.G., S.B.G., C.N.-C., S.K., J.N.H., D.M.A., M.R.P., J.G.S., C.S.); Center for Human Genetic Research, Massachusetts General Hospital, Boston (J.F., C.N.-C., S.K., D.M.A.); Division of Nephrology, Department of Medicine (D.J.F., G.G., M.R.P.) and Center for Vascular Biology Research, Department of Medicine (D.J.F.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; Departments of Medicine (H.A.T., E.R.F.) and Physiology and Biophysics (J.G.W.), University of Mississippi Medical Center, Jackson; Jackson State University, MS (H.A.T.); Tougaloo College, MS (H.A.T.); Cardiology Division, Massachusetts General Hospital, Boston (C.N.-C., S.K.); Divisions of Genetics and Endocrinology and Program in Genomics, Children's Hospital, Boston, MA (J.N.H.); and Howard Hughes Medical Institute and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (C.S.).
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ito
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bick
authors.forename: Jason
authors.initials: J
authors.lastname: Flannick
authors.forename: David J
authors.initials: DJ
authors.lastname: Friedman
authors.forename: Giulio
authors.initials: G
authors.lastname: Genovese
authors.forename: Michael G
authors.initials: MG
authors.lastname: Parfenov
authors.forename: Steven R
authors.initials: SR
authors.lastname: Depalma
authors.forename: Namrata
authors.initials: N
authors.lastname: Gupta
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Herman A
authors.initials: HA
authors.lastname: Taylor
authors.forename: Ervin R
authors.initials: ER
authors.lastname: Fox
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: David M
authors.initials: DM
authors.lastname: Altshuler
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine
authors.initials: C
authors.lastname: Seidman
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics* / Q000706:statistics & numerical data*; D000368:Aged; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D050197:Atherosclerosis / Q000208:ethnology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D015994:Incidence; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000208:ethnology / Q000235:genetics; D012307:Risk Factors
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL
keywords: atherosclerosis; continental population groups; epidemiology; genetics; renal insufficiency, chronic; risk factors