SNPs in CAST are associated with Parkinson disease: A confirmation study

Allen, Andrew S.; Satten, Glen A.

doi:10.1002/ajmg.b.31061

Cited by 6 publications

(6 citation statements)

References 19 publications

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“…This raises the question of whether single nucleotide polymorphisms (SNPs) in the CAST gene or regions that regulate mRNA expression for CAST may increase susceptibility for onset or severity of human IBD. In fact, 48 CAST SNPs have been identified, 20 within the CAST gene itself (39). None of these SNPs have to date been associated with either Crohn's disease or ulcerative colitis through genome-wide association studies.…”

Section: Discussionmentioning

confidence: 99%

“…The lack of data associating CAST SNPs with IBD is not surprising, given the complex genetic architecture of these diseases in humans (4). One disease that has been linked to CAST SNPs is Parkinson's Disease, which is a very different inflammatory disease (39, 40). In fact, the study of the calpain/CAST system in disease pathogenesis has to a large extent focused on its role in apoptosis related to ischemia/reperfusion injury, cancer, muscular dystrophy, or neurological disease (41).…”

Section: Discussionmentioning

confidence: 99%

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Calpastatin Prevents NF-κB–Mediated Hyperactivation of Macrophages and Attenuates Colitis

Huang

Rose

Hoffmann

et al. 2013

The Journal of Immunology

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Calpain enzymes proteolytically modulate cellular function and have been implicated in inflammatory diseases. In this study, we found that calpain levels did not differ between intestinal tissues from inflammatory bowel disease (IBD) patients and healthy controls, but IBD tissues showed increased levels of the endogenous calpain inhibitor, calpastatin (CAST). To investigate the role of CAST in the immune system during IBD, mice were x-ray irradiated and reconstituted with either CAST knockout (KO) or wild-type (WT) bone marrow and subjected to dextran sulfate sodium (DSS)-induced colitis. CAST KO recipients with induced colitis exhibited more severe weight loss, bloody diarrhea, and anemia compared to WT controls. Histological evaluation of colons from KO recipients with colitis revealed increased inflammatory pathology. Macrophages purified from the colons of KO recipients had higher IL-6, TNFα, and IFNγ mRNA levels compared to WT controls. Mechanistic investigations using siRNA and KO bone marrow to generate CAST deficient macrophages showed that CAST deficiency during activation with bacterial PAMPs including heat-killed E. faecalis or CpG DNA led to increased IκB cleavage, NF-κB nuclear localization, and IL-6 and TNFα secretion. Thus, CAST plays a central role in regulating macrophage activation and limiting pathology during inflammatory disorders like IBD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Calpastatin Prevents NF-κB–Mediated Hyperactivation of Macrophages and Attenuates Colitis

Huang

Rose

Hoffmann

et al. 2013

The Journal of Immunology

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“…PD prevalence was set at 0.02. Genotype relative risk was set according to the study of Allen et al [14]. Accordingly, the minimal sample size for cases or control was 464 (rs1065407) or less.…”

Section: Methodsmentioning

confidence: 99%

“…Approximately 5–10% of patients are now known to have monogenic forms of the disease [8] and recent genome-wide association studies (GWAS) identified several susceptibility loci albeit none of the results reached genome-wide significance [9]–[12]. Most recent studies pointed to a strong association between late-onset sporadic PD and two genetic variants (rs1559085 and rs27852) in calcium-dependent protease calpain inhibitor calpastatin (CAST) gene [13], [14]. These findings are of interest, because SN dopaminergic neurons have significant calcium-dependent pacemaker activity, and altered calcium homeostasis has been implicated PD pathogenesis [15].…”

Section: Introductionmentioning

confidence: 99%

Calpastatin Gene (CAST) Is Not Associated with Late Onset Sporadic Parkinson’s Disease in the Han Chinese Population

Zhang

Ding²,

Wang³

et al. 2013

PLoS ONE

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Recent studies point to an association between the late-onset sporadic Parkinson’s disease (PD) and single nucleotide polymorphisms (SNPs) rs1559085 and rs27852 in Ca2+-dependent protease calpain inhibitor calpastatin (CAST) gene. This finding is of interest since loss of CAST activity could result in over activated calpain, potentially leading to Ca2+ dysregulation and loss of substantia nigra neurons in PD. We explored the association between CAST SNPs and late-onset sporadic PD in the Han Chinese population. The study included 615 evaluable patients (363 male, 252 female) with PD and 636 neurologically healthy controls (380 male, 256 female) matched for age, gender, ethnicity, and area of residence. PD cases were identified from the PD cohort of the Chinese National Consortium on Neurodegenerative Diseases (www.chinapd.cn). A total of 24 tag-SNPs were genotyped capturing 95% of the genetic variation across the CAST gene. There was no association found between any of the polymorphisms and PD in all models tested (co-dominant, dominant-effect and recessive-effect). Similarly, none of the common haplotypes was associated with a risk for PD. Our data do not support a significant association between the CAST gene polymorphisms and late onset sporadic PD in the Han Chinese population.

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“…Such strata are uninformative for association testing and lead to a decrease in power to detect SNP‐disease association. For this reason, in this article and in other publications, where we have used the stratification score to analyze GWAS data [Allen et al, ; Allen and Satten, , , ; Sarasua et al, ], we use principal components or spectral‐graph analysis (which produces ancestry components that are constructed without using information on disease) to construct

C_{j}

.…”

Section: Methodsmentioning

confidence: 99%

Stratification‐Score Matching Improves Correction for Confounding by Population Stratification in Case‐Control Association Studies

Epstein

Duncan

Broadaway

et al. 2012

Genetic Epidemiology

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SUMMARY Proper control of confounding due to population stratification is crucial for valid analysis of case-control association studies. Fine matching of cases and controls based on genetic ancestry is an increasingly popular strategy to correct for such confounding, both in genome-wide association studies (GWAS) as well as studies that employ next-generation sequencing, where matching can be used when selecting a subset of participants from a GWAS for rare-variant analysis. Existing matching methods match on measures of genetic ancestry that combine multiple components of ancestry into a scalar quantity. However, we show that including non-confounding ancestry components in a matching criterion can lead to inaccurate matches, and hence to an improper control of confounding. To resolve this issue, we propose a novel method that assigns cases and controls to matched strata based on the stratification score (Epstein et al., 2007, AJHG: 80: 921–930), which is the probability of disease given genomic variables. Matching on the stratification score leads to more accurate matches because case participants are matched to control participants who have a similar risk of disease given ancestry information. We illustrate our matching method using the African-American arm of the GAIN GWAS of schizophrenia. In this study, we observe that confounding due to stratification that can be resolved by our matching approach but not by other existing matching procedures. We also use simulated data to show our novel matching approach can provide a more appropriate correction for population stratification than existing matching approaches.

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SNPs in CAST are associated with Parkinson disease: A confirmation study

Cited by 6 publications

References 19 publications

Calpastatin Prevents NF-κB–Mediated Hyperactivation of Macrophages and Attenuates Colitis

Calpastatin Prevents NF-κB–Mediated Hyperactivation of Macrophages and Attenuates Colitis

Calpastatin Gene (CAST) Is Not Associated with Late Onset Sporadic Parkinson’s Disease in the Han Chinese Population

Stratification‐Score Matching Improves Correction for Confounding by Population Stratification in Case‐Control Association Studies

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