TY - JOUR
T1 - APOL1 renal-risk variants associate with reduced cerebral white matter lesion volume and increased gray matter volume
AU - African American–Diabetes Heart Study MIND (AA-DHS MIND) and Systolic Blood Pressure Intervention Trial (SPRINT) Research Groups
AU - Freedman, Barry I.
AU - Gadegbeku, Crystal A.
AU - Bryan, R. Nick
AU - Palmer, Nicholette D.
AU - Hicks, Pamela J.
AU - Ma, Lijun
AU - Rocco, Michael V.
AU - Smith, S. Carrie
AU - Xu, Jianzhao
AU - Whitlow, Christopher T.
AU - Wagner, Benjamin C.
AU - Langefeld, Carl D.
AU - Hawfield, Amret T.
AU - Bates, Jeffrey T.
AU - Lerner, Alan J.
AU - Raj, Dominic S.
AU - Sadaghiani, Mohammad S.
AU - Toto, Robert D
AU - Wright, Jackson T.
AU - Bowden, Donald W.
AU - Williamson, Jeff D.
AU - Sink, Kaycee M.
AU - Maldjian, Joseph A
AU - Pajewski, Nicholas M.
AU - Divers, Jasmin
N1 - Funding Information:
AA-DHS MIND is supported by National Institutes of Health (NIH) grants R01 NS075107 (JD, JAM, BIF), R01 NS058700 (DWB), and R01 DK071891 (BIF). The Systolic Blood Pressure Intervention Trial is funded with federal funds from the NIH, including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke, under contract numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and interagency agreement number A-HL-13-002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the coauthors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of Veterans Affairs, or the US government. For a full list of contributors to SPRINT, please see the supplementary acknowledgements list at ClinicalTrials.gov ( NCT01206062 ). We also acknowledge the support from the following Clinical and Translational Science Award Programs (CTSAs) funded by National Center for Advancing Translational Sciences (NCATS): Case Western Reserve University: UL1TR000439; Ohio State University (OSU): UL1RR025755; University of Pennsylvania: UL1RR024134 and UL1TR000003; Boston University: UL1RR025771; Stanford: UL1TR000093; Tufts: UL1RR025752, UL1TR000073, and UL1TR001064; University of Illinois: UL1TR000050; University of Pittsburgh: UL1TR000005; University of Texas Southwestern: 9U54TR000017-06; University of Utah: UL1TR000105-05; Vanderbilt University: UL1 TR000445; George Washington University: UL1TR000075; University of California, Davis: UL1 TR000002; University of Florida: UL1 TR000064; University of Michigan: UL1TR000433; Tulane University: P30GM103337 Centers of Biomedical Research Excellence (COBRE) Award National Institute of General Medical Sciences (NIGMS). The authors wish to thank study participants and study coordinators in AA-DHS MIND and SPRINT.
Publisher Copyright:
© 2016 International Society of Nephrology
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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 m2, 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.
AB - 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 m2, 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.
KW - APOL1
KW - African Americans
KW - brain
KW - cognition
KW - hypertension
KW - magnetic resonance imaging
KW - type 2 diabetes mellitus
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U2 - 10.1016/j.kint.2016.04.027
DO - 10.1016/j.kint.2016.04.027
M3 - Article
C2 - 27342958
AN - SCOPUS:84992520139
VL - 90
SP - 440
EP - 449
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 2
ER -