RESEARCH
ARTICLE
Lower Plasma Apolipoprotein A1 Levels Are Found in Parkinson’s Disease and Associate With Apolipoprotein A1 Genotype Christine R. Swanson, PhD,1 Katherine Li, BA,1 Travis L. Unger, BS,1 Michael D. Gallagher, BS,1,2 Vivianna M. Van Deerlin, MD, PhD,3 Pinky Agarwal, MD,4 James Leverenz, MD,5 John Roberts, MD,6 Ali Samii, MD,7 Rachel Goldmann Gross, MD,1 Howard Hurtig, MD,1 Jacqueline Rick, PhD,1 Daniel Weintraub, MD,8 John Q. Trojanowski, MD, PhD,3 Cyrus Zabetian, MD,7 and Alice S. Chen-Plotkin, MD1* 1
Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA Cellular and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 3 Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 4 Booth Gardner Parkinson’s Care Center, Evergreen Hospital Medical Center, Kirkland, Washington, USA 5 Cleveland Clinic Ruvo Center for Brain Health, Cleveland, Ohio, USA 6 Virginia Mason Medical Center, Seattle, Washington, USA 7 VA Puget Sound Health Care System and Department of Neurology, University of Washington Seattle, Seattle, Washington, USA 8 Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 2
ABSTRACT:
The discovery of novel plasmabased biomarkers could lead to new approaches in the treatment of Parkinson’s disease (PD). Here, we explore the role of plasma apolipoprotein A1 (ApoA1) as a risk marker for PD and evaluate the influence of APOA1 promoter variation on plasma ApoA1 levels. Plasma ApoA1 and the single-nucleotide polymorphism, rs670, were assayed in a discovery cohort (cohort 1) of 301 PD patients, 80 normal controls (NCs), and 165 subjects with other neurodegenerative diseases, as well as a cohort (cohort 2) of 158 PD patients from a second clinical site. Additionally, rs670 was genotyped in a third cohort of 1,494 PD and 925 NC subjects from both clinical sites. Compared to both normal and disease controls, PD patients have lower plasma ApoA1 (P < 0.001 for both comparisons). Moreover, in PD patients, plasma ApoA1 levels are correlated with genotype at the APOA1 promoter polymorphism, rs670. Specifically,
lower plasma ApoA1 levels were found in rs670 major allele (G) homozygotes in both cohort 1 (P 5 0.009) and in a replication cohort (cohort 2; n 5 158 PD patients; P 5 0.024). Finally, evaluating rs670 genotype frequencies in 1,930 PD cases versus 997 NCs, the rs670 GG genotype shows a trend toward association (odds ratio: 1.1; P 5 0.10) with PD. Our results are compatible with a model whereby circulating ApoA1 levels may be useful in risk-stratifying subjects for the development of PD, with higher ApoA1 levels suggesting relative protection. Future studies evaluating modulation of ApoA1 as a novel therapeutic strategy in PD are warranted. C 2014 International Parkinson and Movement Disorder V Society
K e y W o r d s : Apolipoprotein A1; Parkinson’s disease; biomarker; genotype; ApoA1
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*Correspondence to: Dr. Alice S. Chen-Plotkin, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, 3 West Gates, 3400 Spruce Street, Philadelphia, PA 19104, USA; [email protected]
Funding agencies: The clinical data in this project were collected though the support of the University of Pennsylvania and University of Washington Morris K. Udall Parkinson’s Disease Research Center of Excellence grants from the National Institute of Neurological Disorders and Stroke (P50 NS053488 and P50NS062684). A.S.C.-P. is supported by the National Institutes of Health (NIH; UO1 NS082134), the Burroughs Wellcome Fund Career Award for Medical Scientists, a Doris Duke Clinician Scientist Development Award, and the Benaroya Fund. C.Z. is supported
by the NIH (R01 NS065070) and the Department of Veterans Affairs (Merit Award 1101BX000531). Relevant conflicts of interest/financial disclosures: Nothing to disclose.
Full financial disclosures and author roles may be found in the online version of this article. Received: 13 May 2014; Revised: 25 June 2014; Accepted: 16 July 2014 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26022
Movement Disorders, Vol. 00, No. 00, 2014
1
S W A N S O N
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TABLE 1. Demographic information for clinical cohorts of PD and NCs Cohort 1 Clinical/Demographic Features
No. female/male (n) Age at DNA, median years (IQR) Age at plasma, median years (IQR) Age at PD onset, median years (IQR) Disease duration, median years (IQR) UPDRS motor score, median score (IQR) Modified H & Y stage (IQR) MoCA (IQR)
PD
NC
Cohort 2 P Value a
Cohort 3
PD
NC
PD
NC
P Value
301 116/185 67.0 (60.0-74.0) 67.0 (60.0-75.0) 59.0 (52.9-67.0) 7.0 (4.0-11.0) 23.0 (14.0-33.0)
80 45/35 66.0 (61.0-77.0) 65.50 (59.3-75.0) N/A N/A N/A
0.04 NSb NSb — — —
158 49/109 65.0 (59.0-71.3) 67.43 (62.5-75.5) 58.0 (50.5-65.0) 6.0 (3.0-11.0) 27.0 (19.0-35.0)
N/A N/A N/A N/A N/A N/A
1,494 444/1050 68.0 (60.0-75.0) N/A 60.0 (51.0-67.0) 7.0 (4.0-11.0) N/A
925 581/344 66.0 (57.0-74.0) N/A N/A N/A N/A
ARTICLE
Lower Plasma Apolipoprotein A1 Levels Are Found in Parkinson’s Disease and Associate With Apolipoprotein A1 Genotype Christine R. Swanson, PhD,1 Katherine Li, BA,1 Travis L. Unger, BS,1 Michael D. Gallagher, BS,1,2 Vivianna M. Van Deerlin, MD, PhD,3 Pinky Agarwal, MD,4 James Leverenz, MD,5 John Roberts, MD,6 Ali Samii, MD,7 Rachel Goldmann Gross, MD,1 Howard Hurtig, MD,1 Jacqueline Rick, PhD,1 Daniel Weintraub, MD,8 John Q. Trojanowski, MD, PhD,3 Cyrus Zabetian, MD,7 and Alice S. Chen-Plotkin, MD1* 1
Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA Cellular and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 3 Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 4 Booth Gardner Parkinson’s Care Center, Evergreen Hospital Medical Center, Kirkland, Washington, USA 5 Cleveland Clinic Ruvo Center for Brain Health, Cleveland, Ohio, USA 6 Virginia Mason Medical Center, Seattle, Washington, USA 7 VA Puget Sound Health Care System and Department of Neurology, University of Washington Seattle, Seattle, Washington, USA 8 Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 2
ABSTRACT:
The discovery of novel plasmabased biomarkers could lead to new approaches in the treatment of Parkinson’s disease (PD). Here, we explore the role of plasma apolipoprotein A1 (ApoA1) as a risk marker for PD and evaluate the influence of APOA1 promoter variation on plasma ApoA1 levels. Plasma ApoA1 and the single-nucleotide polymorphism, rs670, were assayed in a discovery cohort (cohort 1) of 301 PD patients, 80 normal controls (NCs), and 165 subjects with other neurodegenerative diseases, as well as a cohort (cohort 2) of 158 PD patients from a second clinical site. Additionally, rs670 was genotyped in a third cohort of 1,494 PD and 925 NC subjects from both clinical sites. Compared to both normal and disease controls, PD patients have lower plasma ApoA1 (P < 0.001 for both comparisons). Moreover, in PD patients, plasma ApoA1 levels are correlated with genotype at the APOA1 promoter polymorphism, rs670. Specifically,
lower plasma ApoA1 levels were found in rs670 major allele (G) homozygotes in both cohort 1 (P 5 0.009) and in a replication cohort (cohort 2; n 5 158 PD patients; P 5 0.024). Finally, evaluating rs670 genotype frequencies in 1,930 PD cases versus 997 NCs, the rs670 GG genotype shows a trend toward association (odds ratio: 1.1; P 5 0.10) with PD. Our results are compatible with a model whereby circulating ApoA1 levels may be useful in risk-stratifying subjects for the development of PD, with higher ApoA1 levels suggesting relative protection. Future studies evaluating modulation of ApoA1 as a novel therapeutic strategy in PD are warranted. C 2014 International Parkinson and Movement Disorder V Society
K e y W o r d s : Apolipoprotein A1; Parkinson’s disease; biomarker; genotype; ApoA1
------------------------------------------------------------------------------------------------------------------------------
*Correspondence to: Dr. Alice S. Chen-Plotkin, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, 3 West Gates, 3400 Spruce Street, Philadelphia, PA 19104, USA; [email protected]
Funding agencies: The clinical data in this project were collected though the support of the University of Pennsylvania and University of Washington Morris K. Udall Parkinson’s Disease Research Center of Excellence grants from the National Institute of Neurological Disorders and Stroke (P50 NS053488 and P50NS062684). A.S.C.-P. is supported by the National Institutes of Health (NIH; UO1 NS082134), the Burroughs Wellcome Fund Career Award for Medical Scientists, a Doris Duke Clinician Scientist Development Award, and the Benaroya Fund. C.Z. is supported
by the NIH (R01 NS065070) and the Department of Veterans Affairs (Merit Award 1101BX000531). Relevant conflicts of interest/financial disclosures: Nothing to disclose.
Full financial disclosures and author roles may be found in the online version of this article. Received: 13 May 2014; Revised: 25 June 2014; Accepted: 16 July 2014 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26022
Movement Disorders, Vol. 00, No. 00, 2014
1
S W A N S O N
E T
A L
TABLE 1. Demographic information for clinical cohorts of PD and NCs Cohort 1 Clinical/Demographic Features
No. female/male (n) Age at DNA, median years (IQR) Age at plasma, median years (IQR) Age at PD onset, median years (IQR) Disease duration, median years (IQR) UPDRS motor score, median score (IQR) Modified H & Y stage (IQR) MoCA (IQR)
PD
NC
Cohort 2 P Value a
Cohort 3
PD
NC
PD
NC
P Value
301 116/185 67.0 (60.0-74.0) 67.0 (60.0-75.0) 59.0 (52.9-67.0) 7.0 (4.0-11.0) 23.0 (14.0-33.0)
80 45/35 66.0 (61.0-77.0) 65.50 (59.3-75.0) N/A N/A N/A
0.04 NSb NSb — — —
158 49/109 65.0 (59.0-71.3) 67.43 (62.5-75.5) 58.0 (50.5-65.0) 6.0 (3.0-11.0) 27.0 (19.0-35.0)
N/A N/A N/A N/A N/A N/A
1,494 444/1050 68.0 (60.0-75.0) N/A 60.0 (51.0-67.0) 7.0 (4.0-11.0) N/A
925 581/344 66.0 (57.0-74.0) N/A N/A N/A N/A
