CRP Gene Variation Affects Early Development of Alzheimer's Disease-related Plaques

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

Disclosures

J Neuroinflammation. 2011;8(96) 

In This Article

Results

Cohort

The Tampere Autopsy Study (TASTY) (Table 1) consisted of 603 autopsy cases (35.7% females) of subjects who died mainly out-of-hospital over a three year period. Data on memory problems or possible dementia were collected from hospital records and/or next of kin. Of the series 558 cases (92.5%) were included in the brain tissue microarray (TMA) construction. Not all samples were included due to data discrepancies, technical issues and sample decay/damage.

Senile Plaques and Neurofibrillary Tangles

Senile plaque (SP) frequency was available for 553 (90.9%), and neurofibrillary tangle (NFT) counts for 484 (80.3%). Both lesions were positively associated with age.[28]

Genotyping

APOE genotyping was performed on 601 cases and CRP genotypes were acquired for 537 cases (89%). APOE and CRP genotyping indicated that there were no significant differences in the distribution of allele frequencies in each age group, and that they followed Hardy-Weinberg proportions.

Associations Between Genotypes and Neuropathological Lesions

Univariate logistic regression analysis showed that the SNP rs2794521 (p = 0.067) was associated with SP prevalence (yes/no SP presence). However, including age and APOE4 carriership as covariates weakened the association (p = 0.096).

When we took into account the phenotype of SP (Table 2), two high-CRP level-linked SNPs - rs3091244 (TA carriers; OR 6.7, p = 0.007) and rs3093075 (CA carriers; OR 3.5, p = 0.003) - appeared to convey increased risk for early non-neuritic SP compared to no SP. There was also a tendency towards increased risk for late neuritic SP (OR 4.5, p = 0.072; OR 2.1, p = 0.080, respectively).

On the contrary, carriers of the low-CRP level-linked C allele of SNP rs2794521 (OR 0.46, CI 0.22 – 0.96, p = 0.039) were less likely to have non-neuritic SP, derived from an association with the common CT genotype (OR 0.43, p = 0.037). A trend towards the same associations was seen with neuritic SP. Conversely, the high-CRP level SNPs rs1130864 (TT carriers; OR 0.26, p = 0.076) and rs1205 (CC carriers; OR 0.39, p = 0.056) showed a non-significant trend towards protection for non-neuritic compared to no SP.

In multivariate logistic regression, CRP haplotypes composed of alleles related to high-CRP levels, such as TAGCC, were associated with presence of non-neuritic SP (OR 2.99, p = 0.007), significantly increasing the risk of occurrence (Table 3). On the contrary, haplotype carriership of alleles linked with lower CRP levels, such as CCGCC, reduced (OR 0.45, p = 0.034) the likelihood of possessing non-neuritic SP. Similar, but-non significant tendencies towards these associations were also seen for both haplotypes and neuritic SP.

Haplotype pair analyses compared all haplotype pairs with prevalence above 6% against the most common pair (TTGTC/TCGCT). None of the haplotype pairs were associated with SP prevalence. Analyses with SP phenotype suggested a trend towards protection for the haplotype pair TTGTC/TTGTC (p = 0.065) and TCGCT/CCGCC (p = 0.070) with non-neuritic SP, although the association weakened with the inclusion of age and APOE4 carriership as covariates (data not shown).

NFT prevalence (yes/no presence) showed an association only with SNP rs2794521, using univariate logistic regression (p = 0.059). Inclusion of APOE genotype and age as covariates weakened the association (p = 0.107).

Semi-quantitative analyses of SP density did not reveal any significant associations with any of the CRP genotypes, and splitting the data by gender did not provide any additional results (data not shown).

Immunohistochemistry

CRP IHC staining (positive/negative) was found to be significantly correlated with Aβ (amyloid-β) staining (positive/negative) in all studied brain regions in the cohort, (Chi square p < 0.0001, Figure 1). Aβ IHC staining, however, was not found to be associated with any of the CRP SNPs or haplotypes. In univariate analyses, CRP IHC staining was significantly associated with high-CRP level TT genotypes of SNPs rs3091244 (OR 5.9, CI 1.20 – 28.87, p = 0.029) and rs1130864 (OR 5.9, CI 1.21 – 28.95, p = 0.028) (Figure 2). Individual haplotype (yes/no carriership) were not, but the haplotype pair TTGTC/TTGTC was significantly associated (OR = 5.5, CI = 1.03 – 29.48, p = 0.047) with CRP IHC staining. This relationship strengthened on inclusion of APOE4 carriership and age as covariates (OR = 14.9, CI = 1.14 – 196.37, p = 0.040), however the CI were extremely large.

Figure 1.

Co-localisation of CRP and Aβ immunohistochemical staining (a) Aβ staining (b) CRP staining (c) merge, 100 × magnification.

Figure 2.

CRP SNPs and prevalence of CRP immunohistochemical staining (positive/negative) with SNPs rs3091244 and rs1130864. Genotypes in order of population frequency, with * referring to 'no CRP staining' versus 'positive staining' with most common genotype as reference group.

Multiple Testing Correction

We performed FDR calculations on our results, assuming that 11 independent tests were performed (6 SNPs and 5 haplotypes). These showed that with an FDR < 0.05, or 5% false positives, most of our results were still applicable (see Table 4). The SNPs and haplotypes of the CRP gene which were seen most often in analyses were rs2794521 (genotype CT), rs3091244 (genotypes TA and TT), rs3093075 (genotype CA) and haplotype TAGCC.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....