title: APOL1 renal-risk variants associate with reduced cerebral white matter lesion volume and increased gray matter volume.
abstract: To assess apolipoprotein L1 gene (APOL1) renal-risk-variant effects on the brain, magnetic resonance imaging (MRI)-based cerebral volumes and cognitive function were assessed in 517 African American-Diabetes Heart Study (AA-DHS) Memory IN Diabetes (MIND) and 2568 hypertensive African American Systolic Blood Pressure Intervention Trial (SPRINT) participants without diabetes. Within these cohorts, 483 and 197 had cerebral MRI, respectively. AA-DHS participants were characterized as follows: 60.9% female, mean age of 58.6 years, diabetes duration 13.1 years, estimated glomerular filtration rate of 88.2 ml/min/1.73 m(2), and a median spot urine albumin to creatinine ratio of 10.0 mg/g. In additive genetic models adjusting for age, sex, ancestry, scanner, intracranial volume, body mass index, hemoglobin A1c, statins, nephropathy, smoking, hypertension, and cardiovascular disease, APOL1 renal-risk-variants were positively associated with gray matter volume (β = 3.4 × 10(-3)) and negatively associated with white matter lesion volume (β = -0.303) (an indicator of cerebral small vessel disease) and cerebrospinal fluid volume (β= -30707) (all significant), but not with white matter volume or cognitive function. Significant associations corresponding to adjusted effect sizes (β/SE) were observed with gray matter volume (0.16) and white matter lesion volume (-0.208), but not with cerebrospinal fluid volume (-0.251). Meta-analysis results with SPRINT Memory and Cognition in Decreased Hypertension (MIND) participants who had cerebral MRI were confirmatory. Thus, APOL1 renal-risk-variants are associated with larger gray matter volume and lower white matter lesion volume suggesting lower intracranial small vessel disease.
authors.affiliation: Department of Internal Medicine, Section on Nephrology; Wake Forest School of Medicine, Winston-Salem, NC.|Centers for Diabetes Research and Genomics and Personalized Medicine Research; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Department of Medicine, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Crystal A
authors.initials: CA
authors.lastname: Gadegbeku
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, PA.
authors.forename: R Nick
authors.initials: RN
authors.lastname: Bryan
authors.affiliation: Centers for Diabetes Research and Genomics and Personalized Medicine Research; Wake Forest School of Medicine, Winston-Salem, NC.|Department of Biochemistry; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: Department of Biochemistry; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.affiliation: Department of Internal Medicine, Section on Nephrology; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Lijun
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Internal Medicine, Section on Nephrology; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Rocco
authors.affiliation: Department of Biochemistry; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: S Carrie
authors.initials: SC
authors.lastname: Smith
authors.affiliation: Department of Biochemistry; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Jianzhao
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Radiologic Sciences, Advanced Neuroscience Imaging Research (ANSIR) Laboratory; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Whitlow
authors.affiliation: Department of Radiologic Sciences, Advanced Neuroscience Imaging Research (ANSIR) Laboratory; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Wagner
authors.affiliation: Division of Public Health Sciences, Department of Biostatistical Sciences; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Department of Internal Medicine, Section on Nephrology; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Amret T
authors.initials: AT
authors.lastname: Hawfield
authors.affiliation: Michael E. DeBakey Veterans Administration Medical Center and Baylor College of Medicine, Houston, TX.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Bates
authors.affiliation: Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Lerner
authors.affiliation: Department of Medicine, George Washington University, Washington, DC.
authors.forename: Dominic S
authors.initials: DS
authors.lastname: Raj
authors.affiliation: Department of Medicine, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Sadaghiani
authors.affiliation: Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, TX.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Toto
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Jackson T
authors.initials: JT
authors.lastname: Wright
authors.affiliation: Centers for Diabetes Research and Genomics and Personalized Medicine Research; Wake Forest School of Medicine, Winston-Salem, NC.|Department of Radiology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Williamson
authors.affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Kaycee M
authors.initials: KM
authors.lastname: Sink
authors.affiliation: Department of Radiologic Sciences, Advanced Neuroscience Imaging Research (ANSIR) Laboratory; Wake Forest School of Medicine, Winston-Salem, NC.|Department of Radiology, Advanced Neuroscience Imaging Research (ANSIR) Laboratory; University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Maldjian
authors.affiliation: Division of Public Health Sciences, Department of Biostatistical Sciences; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Pajewski
authors.affiliation: Division of Public Health Sciences, Department of Biostatistical Sciences; Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Divers
mesh_terms: D001741:Black or African American / Q000235:genetics; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D001794:Blood Pressure; D001921:Brain / Q000098:blood supply; D002318:Cardiovascular Diseases / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D059345:Cerebral Small Vessel Diseases / Q000453:epidemiology* / Q000235:genetics; D003071:Cognition; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D005919:Glomerular Filtration Rate; D066128:Gray Matter / Q000033:anatomy & histology* / Q000000981:diagnostic imaging; D006801:Humans; D006973:Hypertension / Q000453:epidemiology; D007674:Kidney Diseases / Q000150:complications / Q000235:genetics*; D007677:Kidney Function Tests; D008075:Lipoproteins, HDL / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D016032:Randomized Controlled Trials as Topic; D012306:Risk; D066127:White Matter / Q000033:anatomy & histology* / Q000000981:diagnostic imaging
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL
keywords: APOL1; African Americans; brain; cognition; hypertension; magnetic resonance imaging; type 2 diabetes mellitus