Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease

Abstract

The only recognized genetic determinant of the common forms of Alzheimer's disease (AD) is the e4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2741 genes in chromosomal regions of interest using brain tissue of AD cases and controls. From 82 differentially expressed genes, 1156 polymorphisms were genotyped in two independent discovery subsamples (n = 945). Seventeen genes exhibited at least one polymorphism associated with AD risk, and following correction for multiple testing, we retained the interleukin (IL)-33 gene. We first confirmed that the IL-33 expression was decreased in the brain of AD cases compared with that of controls. Further genetic analysis led us to select three polymorphisms within this gene, which we analyzed in three independent case-control studies. These polymorphisms and a resulting protective haplotype were systematically associated with AD risk in non-APOE e4 carriers. Using a large prospective study, these associations were also detected when analyzing the prevalent and incident AD cases together or the incident AD cases alone. These polymorphisms were also associated with less cerebral amyloid angiopathy (CAA) in the brain of non-APOE e4 AD cases. Immunohistochemistry experiments finally indicated that the IL-33 expression was consistently restricted to vascular capillaries in the brain. Moreover, IL-33 overexpression in cellular models led to a specific decrease in secretion of the Ab 40 peptides, the main CAA component. In conclusion, our data suggest that genetic variants in IL-33 gene may be associated with a decrease in AD risk potentially in modulating CAA formation.

Inflammatory Cytokines and Alzheimer’s Disease: A Review from the Perspective of Genetic Polymorphisms

“…They found protective effects of rare alleles of three intronic SNPs (rs7044343, rs1157505, and rs11792633) and the associated haplotypes [36]. In addition, functional analyses have revealed interactions between these protective allele and decreased cerebral amyloid angiopathy in the brains of non-APOE e4 individuals with AD [36]. Subsequently, consistent results for rs11792633 were obtained in a Han Chinese population; however, rs7044343 failed to affect AD risk, and the rs1157505 polymorphism was not observed [102].…”

“…A study by Chapuis et al initially identified the association between IL-33 polymorphisms and AD risk in Caucasian populations. They found protective effects of rare alleles of three intronic SNPs (rs7044343, rs1157505, and rs11792633) and the associated haplotypes [36]. In addition, functional analyses have revealed interactions between these protective allele and decreased cerebral amyloid angiopathy in the brains of non-APOE e4 individuals with AD [36].…”

“…Decreased expression of IL-33 has been reported in the brains of AD patients [36]. In a cellular model, overexpressed IL-33 was reported to promote the production of Ab [36]. A study by Chapuis et al initially identified the association between IL-33 polymorphisms and AD risk in Caucasian populations.…”

“…Decreased expression of IL-33 has been reported in the brains of AD patients [36]. In a cellular model, overexpressed IL-33 was reported to promote the production of Ab [36].…”

Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia

“…Angiopoietins have important roles in vascular development and angiogenesis, and disturbances in this process can result in a range of diseases, such as agerelated blindness, cancer and stroke. 71,72 Chapuis et al 73 have shown, by performing a transcriptomal analysis of brains followed by SNP genotyping in the differentially expressed genes, that six SNPs in ANGPT4 were associated with AD. A 65% difference in gene expression was found between the brains of AD and controls.…”