Abstract
BackgroundRheumatoid arthritis (RA) and Alzheimer's disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors recently identified in genome-wide association studies (GWAS) for their association with AD in a two-stage, case-control analysis.ResultsIn our Stage 1 analysis of ~800 AD and ~1,200 non-AD individuals, three of seventeen RA-associated SNPs were nominally associated with AD (p < 0.05) with one SNP, rs2837960, retaining significance after correction for multiple testing (p = 0.03). The rs2837960_G (minor) allele, which is associated with increased RA risk, was associated with increased AD risk. Analysis of these three SNPs in a Stage 2 population, consisting of ~1,100 AD and ~2,600 non-AD individuals, did not confirm their association with AD. Analysis of Stage 1 and 2 combined suggested that rs2837960 shows a trend for association with AD. When the Stage 2 population was age-matched for the Stage 1 population, rs2837960 exhibited a non-significant trend with AD. Combined analysis of Stage 1 and the age-matched Stage 2 subset showed a significant association of rs2837960 with AD (p = 0.002, OR 1.24) that retained significance following correction for age, sex and APOE (p = 0.02, OR = 1.20). Rs2837960 is near BACE2, which encodes an aspartic protease capable of processing the AD-associated amyloid precursor protein. Testing for an association between rs2837960 and the expression of BACE2 isoforms in human brain, we observed a trend between rs2837960 and the total expression of BACE2 and the expression of a BACE2 transcript lacking exon 7 (p = 0.07 and 0.10, respectively).ConclusionsRA-associated SNPs are generally not associated with AD. Moreover, rs2837960_G is associated with increased risk of both RA and, in individuals less than 80 years of age, with AD. Overall, these results contest the hypothesis that genetic variants associated with RA confer protection against AD. Further investigation of rs2837960 is necessary to elucidate the mechanism by which rs2837960 contributes to both AD and RA risk, likely via modulation of BACE2 expression.
Highlights
Rheumatoid arthritis (RA) and Alzheimer’s disease (AD) are inversely associated
RA-associated single nucleotide polymorphisms (SNP) are generally not associated with AD To evaluate whether RA-associated SNPs are associated with AD, we began by identifying SNPs that are robustly associated with RA risk and evaluated these SNPs for their association with AD in an exploratory Stage 1 case-control population of ~800 AD and ~1200 non-AD individuals
Contrary to the hypothesis that alleles associated with increased RA risk are associated with reduced AD risk, only three of the seventeen RA-associated SNPs in our Stage 1 study were nominally significant for association with AD (p < 0.05, Table 1)
Summary
Rheumatoid arthritis (RA) and Alzheimer’s disease (AD) are inversely associated. There is a long-standing, inverse relationship between the prevalence of Alzheimer’s disease (AD) and of rheumatoid arthritis (RA). Jenkinson and colleagues first described the decreased prevalence of RA in patients suffering from senile dementia of the Alzheimer’s type as compared to cognitively intact individuals [1]. The basis of this inverse relationship is unclear but may include both genetic and environmental factors. RA and AD each have a strong genetic component, i.e., 50% of RA risk and 60% of AD risk is attributable to genetic factors, supporting the original hypothesis of Jenkinson and colleagues that genetics might explain the relationship between AD and RA [4,5]. Antiinflammatory medications used therapeutically for the treatment of RA could decrease AD risk by reducing AD-associated inflammation or via other mechanisms,
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