title: Association of PGC-1alpha polymorphisms with age of onset and risk of Parkinson's disease.
abstract: BACKGROUND
  Peroxisome proliferator-activated receptor-γ co-activator (PGC)-1α is a transcriptional co-activator of antioxidant genes and a master regulator of mitochondrial biogenesis. Parkinson's disease (PD) is associated with oxidative stress and mitochondrial dysfunction and recent work suggests a role for PGC-1α. We hypothesized that the rs8192678 PGC-1α single nucleotide polymorphism (SNP) may influence risk or age of onset of PD. The A10398G mitochondrial SNP has been inversely associated with risk of PD in some studies. In the current study we analyzed whether rs8192678 or other PGC-1α SNPs affect PD risk or age of onset, singularly or in association with the A10398G SNP.
  
  
  METHODS
  Genomic DNA samples from 378 PD patients and 173 age-matched controls were analyzed by multiplexed probe sequencing, followed by statistical analyses of the association of each SNP, alone or in combination, with risk or age of onset of PD. Adjustments were made for age of onset being less than the age of sampling, and for the observed dependence between these two ages. The PD samples were obtained as two separate cohorts, therefore statistical methods accounted for different sampling methods between the two cohorts, and data were analyzed using Cox regression adjusted for sampling in the risk set definition and in the model.
  
  
  RESULTS
  The rs8192678 PGC-1α SNP was not associated with the risk of PD. However, an association of the PGC-1α rs8192678 GG variant with longevity was seen in control subjects (p=0.019). Exploratory studies indicated that the CC variant of rs6821591 was associated with risk of early onset PD (p=0.029), with PD age of onset (p=0.047), and with longevity (p=0.022). The rs2970848 GG allele was associated with risk of late onset PD (p=0.027).
  
  
  CONCLUSIONS
  These data reveal possible associations of the PGC-1α SNPs rs6821591 and rs2970848 with risk or age of onset of PD, and of the PGC-1α rs8192678 GG and the rs6821591 CC variants with longevity. If replicated in other datasets, these findings may have important implications regarding the role of PGC-1α in PD and longevity.
authors: Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Room CLS-638, Boston, MA 02215, USA.
authors: Joanne
authors: J
authors: Clark
authors: Sonika
authors: S
authors: Reddy
authors: Kangni
authors: K
authors: Zheng
authors: Rebecca A
authors: RA
authors: Betensky
authors: David K
authors: DK
authors: Simon
references: Ann Neurol. 2003 Sep;54(3):281-2
references: 12953259
references: Ann Neurol. 2006 Oct;60(4):389-98
references: 17068789
references: Sci Transl Med. 2010 Oct 6;2(52):52ra73
references: 20926834
references: Diabetes. 2006 Jul;55(7):2148-52
references: 16804087
references: Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94
references: 17911161
references: Cardiovasc Res. 2005 Jun 1;66(3):562-73
references: 15914121
references: Dis Markers. 2005;21(4):175-80
references: 16403952
references: J Neurol. 2008 May;255(5):668-73
references: 18438697
references: Am J Hum Genet. 2003 Apr;72(4):804-11
references: 12618962
references: BMC Med Genet. 2010 Apr 01;11:53
references: 20356410
references: Diabetologia. 2006 Mar;49(3):501-5
references: 16435105
references: J Neurol Sci. 2005 Sep 15;236(1-2):49-54
references: 15975594
references: Endocr J. 2008 Dec;55(6):991-7
references: 18614852
references: Methods Mol Biol. 2000;132:365-86
references: 10547847
references: J Biol Chem. 1983 May 10;258(9):5834-9
references: 6343397
references: Diabetes. 2008 Apr;57(4):809-16
references: 18162502
references: Lancet Neurol. 2008 Jan;7(1):97-109
references: 18093566
references: Endocr Rev. 2006 Dec;27(7):728-35
references: 17018837
references: Diabetologia. 2004 Dec;47(12):2176-84
references: 15592662
references: Diabetologia. 2002 May;45(5):740-3
references: 12107756
references: Neurosci Lett. 2007 Feb 21;413(3):202-5
references: 17174475
references: Am J Pathol. 2000 Aug;157(2):401-10
references: 10934145
references: Clin Exp Pharmacol Physiol. 2008 Oct;35(10):1172-7
references: 18565194
references: Mol Neurodegener. 2009 Jan 08;4:3
references: 19133136
references: Hum Genet. 2007 Dec;122(5):535-40
references: 17701054
references: Clin Chim Acta. 2008 Dec;398(1-2):70-4
references: 18786524
references: J Hum Genet. 2008;53(4):349-356
references: 18286226
references: Neuroepidemiology. 1993;12(6):336-44
references: 8309509
references: Diabetologia. 2005 Jul;48(7):1323-30
references: 15937669
references: Neurology. 2000 Feb 8;54(3):703-9
references: 10680807
references: Cell Metab. 2006 Nov;4(5):349-62
references: 17055784
references: Eur J Neurol. 2004 Apr;11(4):231-5
references: 15061824
references: J Appl Physiol (1985). 2008 Oct;105(4):1352-8
references: 18467552
references: Neuroscientist. 2002 Jun;8(3):192-7
references: 12061498
references: Int J Neurosci. 1993 Mar-Apr;69(1-4):125-30
references: 8082998
references: Cell Tissue Res. 2004 Oct;318(1):175-84
references: 15503153
references: Biochem Biophys Res Commun. 2006 Jun 9;344(3):708-12
references: 16631115
references: Endocr Rev. 2003 Feb;24(1):78-90
references: 12588810
references: Eur J Hum Genet. 2005 Jun;13(6):748-52
references: 15827561
references: Science. 2004 May 21;304(5674):1158-60
references: 15087508
references: Aging Cell. 2008 Jan;7(1):101-11
references: 18031569
references: Cell. 2006 Oct 20;127(2):397-408
references: 17055439
references: Diabetologia. 2008 Apr;51(4):615-22
references: 18270681
references: BMC Cardiovasc Disord. 2008 Dec 11;8:37
references: 19077249
references: Mol Neurodegener. 2009 Feb 06;4:10
references: 19200361
references: Hypertension. 2005 Apr;45(4):565-70
references: 15738346
references: Diabetes Care. 2007 Apr;30(4):842-7
references: 17251276
references: Hypertension. 2003 Feb;41(2):368-72
references: 12574109
references: Pharmacol Biochem Behav. 2001 Mar;68(3):461-8
references: 11325400