عوامل ژنتیک چندگانه بیماری پارکینسون در یک جمعیت چینی
|کد مقاله||سال انتشار||مقاله انگلیسی||ترجمه فارسی||تعداد کلمات|
|31139||2015||7 صفحه PDF||سفارش دهید||4490 کلمه|
Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)
Journal : Neurobiology of Aging, Volume 36, Issue 4, April 2015, Pages 1765.e1–1765.e6
It has been reported that some single-nucleotide polymorphisms (SNPs) are associated with the risk of Parkinson's disease (PD), but whether a combination of these SNPs would have a stronger association with PD than any individual SNP is unknown. Sixteen SNPs located in the 8 genes and/or loci (SNCA, LRRK2, MAPT, GBA, HLA-DR, BST1, PARK16, and PARK17) were analyzed in a Chinese cohort consisting of 1061 well-characterized PD patients and 1066 control subjects from Central South of Mainland China. We found that Rep1, rs356165, and rs11931074 in SNCA gene; G2385R in LRRK2 gene; rs4698412 in BST1 gene; rs1564282 in PARK17; and L444P in GBA gene were associated with PD with adjustment of sex and age (p < 0.05) in the analysis of 16 variants. PD risk increased when Rep1 and rs11931074, G2385R, rs1564282, rs4698412; rs11931074 and G2385R, rs1564282, rs4698412; G2385R and rs1564282, rs4698412; and rs1564282 and rs4698412 were combined for the association analysis. In addition, PD risk increased cumulatively with the increasing number of variants (odds ratio for carrying 3 variants, 3.494). In summary, we confirmed that Rep1, rs356165, and rs11931074 in SNCA gene, G2385R in LRRK2 gene, rs4698412 in BST1 gene, rs1564282 in PARK17, and L444P in GBA gene have an independent and combined significant association with PD. SNPs in these 4 genes have a cumulative effect with PD.
Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, is characterized by resting tremor, rigidity, bradykinesia, and impaired postural reflexes. The majority of the patients are sporadic cases. Although the etiology of PD remains unclear, approximately 5%–10% of the patients have been found affected by the genetic factors (Dauer and Przedborski, 2003 and Samii et al., 2004). Several genes have been identified associating with familial PD. To date, >13 genes have been cloned associating with the monogenic forms of parkinsonism and related disorders (Chartier-Harlin et al., 2011, Lesage and Brice, 2009, Vilariño-Güell et al., 2011 and Zimprich et al., 2011). However, these cannot explain the etiology of the vast majority of patients with an apparently sporadic late-onset disease. There is an increasing evidence that genetic susceptibility contributes to the etiology of PD. It has been reported that some polymorphisms are associated with the risk of PD, such as Rep1, rs356165, and rs11931074 in SNCA gene ( Mueller et al., 2005, Satake et al., 2009, Simón-Sánchez et al., 2009 and Tan et al., 2010a); G2385R and R1628P in LRRK2 gene ( Ross et al., 2011, Tan et al., 2010a and Tan et al., 2010b); rs242562 and rs2435207 in MAPT gene ( Skipper et al., 2004 and Vandrovcova et al., 2009); and L444P in GBA gene ( Sidransky et al., 2009 and Sun et al., 2010). More recently, genome-wide association studies (GWASs) of complex diseases have identified sequence variants that are consistently associated with the risk of such diseases. Some well-known loci are further confirmed to be linked with the risk of PD, such as SNCA and MAPT, and some other new loci or polymorphisms were also found to be associated with the risk of PD, such as PARK16, PARK17 (GAK), PARK18 (HLA-DR), and BST1 gene ( Edwards et al., 2010; Pankratz et al., 2010, Saad et al., 2011, Satake et al., 2009, Simón-Sánchez et al., 2009 and UK Parkinson's Disease Consortium,Wellcome Trust Case Control Consortium et al., 2011). In The Lancet, the International Parkinson Disease Genomic Consortium reported the first meta-analysis of datasets from 5 PD GWASs from the United States and Europe to identify loci associated with PD (discovery phase). Totally, 11 loci surpassed the threshold for genome-wide significance that included 6 previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK, and LRRK2) ( International Parkinson Disease Genomics Consortium et al., 2011). Because monogenic forms of the disease are rare, a polygenic model has long been suggested to explain the genetic contribution to the pathogenesis of the majority of PD cases. Often, such variants have limited use in the assessment of disease risk in an individual patient because most of them confer a relatively small risk. Whether combinations of individual variants will confer larger more clinically useful associations with increased risk remain to be shown. Until now, there are only a few studies reporting about the gene-gene interaction on susceptibility to PD, such as the interaction of SNCA and MAPT gene; SNCA, MAPT, and GSK3B; and FGF20 and MAOB ( Elbaz et al., 2011 and Gao et al., 2008; Trotta et al., 2012 and Wider et al., 2011). There was no systemic evaluation of the independent effects of the 6 known genes or loci (MAPT, SNCA, HLA-DRB5, BST1, GAK, and LRRK2) on the susceptibility to Chinese PD. Whether a combination of single-nucleotide polymorphisms (SNPs) in these genes would have a stronger association with PD than any individual SNPs is unknown. In this study, we investigated whether independent and joint effects of variants in the previously mentioned 8 genes and/or loci will contribute to PD in a Chinese cohort consisting of 1061 well-characterized PD patients and 1066 control subjects from Central South of Mainland China. Because PARK16 and L444P in GBA gene were reported associating with the risk of Asian PD ( Satake et al., 2009, Sidransky et al., 2009 and Sun et al., 2010), we also analyzed the 2 loci in this study.