CRP gene variation affects early development of Alzheimer's disease-related plaques

Kok, Eloise; Alanne-Kinnunen, Mervi; Isotalo, Karita; Luoto, Teemu M.; Haikonen, Satu; Goebeler, Sirkka; Perola, Markus; Hurme, Mikko; Haapasalo, Hannu; Karhunen, Pekka J.

doi:10.1186/1742-2094-8-96

Cited by 15 publications

(7 citation statements)

References 37 publications

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“…All previous MR studies were substantially limited to a single or a few outcomes, used only SNPs in the CRP gene, or had sample sizes much smaller than that of the present study ( S1 Table ). In addition to these studies, the current GWAS data do not corroborate epidemiological observations suggesting that elevated CRP levels are associated with amyotrophic lateral sclerosis [ 101 ], Alzheimer disease [ 102 ], Parkinson disease [ 103 ], and major depressive disorder [ 104 ]. Furthermore, patients with immunity-related disorders frequently have a very high CRP level (as high as 100 mg/l) due to their disease status.…”

Section: Discussioncontrasting

confidence: 87%

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

et al. 2016

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BackgroundC-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.Methods and FindingsWe performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed.The strengths (F-statistics) of the IVs were 31.92–3,761.29 and 82.32–9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79–0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94–0.98]; p < 1.72 × 10−6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10−4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10−4) showed a statistically significant (p < 2.45 × 10−4) protective effect with an OR of 0.97 (95% CI 0.95–0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84–0.94]; p < 2.4 × 10−5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74–0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70–0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00–1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01–1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05–1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11–1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06–0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003–0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004–0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008–0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes...

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Section: Discussioncontrasting

confidence: 87%

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

et al. 2016

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“…These results are well in accordance with studies of CRP function in AD. CRP gene variants have been associated with plaque development in AD [ 27 ]. The protein has been linked to amyloid pathology in APP/PS1 (amyloid precursor protein/presenilin 1) mice, and Strang et al .…”

Section: Discussionmentioning

confidence: 99%

Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer’s disease

et al. 2018

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BackgroundNeuroinflammation has gained increasing attention as a potential contributing factor in Alzheimer’s disease (AD) pathology. A clinical cerebrospinal fluid biomarker capable of monitoring this process during the course of the disease has yet to emerge, chiefly owing to contradictory research findings. In this study, we sought to clarify the utility of inflammatory biomarkers in diagnostic procedures of AD in three steps: (1) to screen for proteins that are robustly detectable in cerebrospinal fluid; (2) based on this analysis, to explore any associations between the analytically robust markers and salient pathological features of AD; and (3) to determine the discriminative power of these markers in the clinical diagnosis of AD.MethodsFrom a total of 46 proteins, 15 that were robustly detectable in cerebrospinal fluid were identified. A subsequent analysis of these markers in a cohort of 399 patients (nondemented subjects, patients with mild cognitive impairment [MCI], and patients with AD, supplemented by smaller cohorts of other diseases) was conducted. Fluid biomarker data were related to AD pathology and neuropsychological markers and adjusted for confounders such as age, sex, apolipoprotein E genotype, and biobank storage time.ResultsCerebrospinal fluid levels of C-reactive protein and soluble TREM2 differed between nondemented subjects, patients with MCI, or patients with AD and were associated with amyloid and tau pathology. Several markers were associated with tau pathology only or with other neurodegenerative diseases. Correlations between neuropsychological performance and inflammatory markers were weak, but they were most prominent in AD and for the most challenging cognitive tests. All investigated covariates had significant influence, with varying effects across the markers. Still, none of the markers achieved discriminative power of more than 70% to distinguish between patient groups defined by clinical or neuropathological categories.ConclusionsBasic analytical considerations proved indispensable for this type of study because only one-third of the tested markers were robustly detectable in cerebrospinal fluid. Detectable inflammatory protein markers were associated in multiple ways with AD pathology. Yet, even significantly associated markers were not powerful enough in terms of effect strength, sensitivity, and specificity, and hence they were not suited for direct use in clinical diagnostic practice. Targets other than those most commonly considered in this field of research might provide results with better clinical applicability.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0353-3) contains supplementary material, which is available to authorized users.

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“…For these reasons, this protein has been proposed as an early biomarker for AD. Moreover, SNPs on CRP gene like rs1130864 and rs1800947 have been involved with altered CRP levels (Kok et al, 2011 ) and with a possible association with AD in Caucasians (Flex et al, 2004 ; van Oijen et al, 2007 ). Additionally, the cyclooxygenase-2 (COX-2) is encoded by the prostaglandin-endoperoxide synthase 2 gene (PTGS2); this enzyme involved in neuroinflammation, is responsible for prostaglandins (PG’s) synthesis.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of inflammation-related genes polymorphisms in Mexican with Alzheimerâ€™s disease: a pilot study

Toral-Ríos¹,

Franco-Bocanegra

Rosas-Carrasco

et al. 2015

Front. Cell. Neurosci.

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Amyloid peptide is able to promote the activation of microglia and astrocytes in Alzheimer’s disease (AD), and this stimulates the production of pro-inflammatory cytokines. Inflammation contributes to the process of neurodegeneration and therefore is a key factor in the development of AD. Some of the most important proteins involved in AD inflammation are: clusterin (CLU), complement receptor 1 (CR1), C reactive protein (CRP), tumor necrosis factor α (TNF-α), the interleukins 1α (IL-1α), 6 (IL-6), 10 (IL-10) and cyclooxygenase 2 (COX-2). In particular, COX-2 is encoded by the prostaglandin-endoperoxide synthase 2 gene (PTGS2). Since variations in the genes that encode these proteins may modify gene expression or function, it is important to investigate whether these variations may change the developing AD. The aim of this study was to determine whether the presence of polymorphisms in the genes encoding the aforementioned proteins is associated in Mexican patients with AD. Fourteen polymorphisms were genotyped in 96 subjects with AD and 100 controls; the differences in allele, genotype and haplotype frequencies were analyzed. Additionally, an ancestry analysis was conducted to exclude differences in genetic ancestry among groups as a confounding factor in the study. Significant differences in frequencies between AD and controls were found for the single-nucleotide polymorphism (SNP) rs20417 within the PTGS2 gene. Ancestry analysis revealed no significant differences in the ancestry of the compared groups, and the association was significant even after adjustment for ancestry and correction for multiple testing, which strengthens the validity of the results. We conclude that this polymorphism plays an important role in the development of the AD pathology and further studies are required, including their proteins.

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CRP gene variation affects early development of Alzheimer's disease-related plaques

Cited by 15 publications

References 37 publications

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer’s disease

Evaluation of inflammation-related genes polymorphisms in Mexican with Alzheimerâ€™s disease: a pilot study

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