Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
Mol Neurodegener. 2011 May 19;6:33. doi: 10.1186/1750-1326-6-33.
Rheumatoid 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.
In 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).
RA-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.
类风湿关节炎（RA）和阿尔茨海默病（AD）呈负相关。为了验证与 RA 风险增加相关的遗传因素与 AD 风险降低相关的假设，我们在两阶段病例对照分析中评估了最近在全基因组关联研究（GWAS）中确定的 RA 遗传风险因素与 AD 的相关性。
在我们对800 名 AD 和1200 名非 AD 个体的第一阶段分析中，17 个 RA 相关 SNP 中有三个与 AD 呈名义关联（p<0.05），其中一个 SNP rs2837960 在进行多次测试校正后仍具有统计学意义（p=0.03）。与 RA 风险增加相关的 rs2837960_G（次要）等位基因与 AD 风险增加相关。在由1100 名 AD 和2600 名非 AD 个体组成的第二阶段人群中对这三个 SNP 进行分析，并未证实其与 AD 的相关性。第一阶段和第二阶段合并分析表明，rs2837960 与 AD 呈关联趋势。当第二阶段人群与第一阶段人群年龄匹配时，rs2837960 与 AD 呈非显著趋势。第一阶段和年龄匹配的第二阶段亚组的综合分析显示，rs2837960 与 AD 显著相关（p=0.002，OR 1.24），在校正年龄、性别和 APOE 后仍具有统计学意义（p=0.02，OR=1.20）。rs2837960 位于 BACE2 附近，BACE2 编码一种能够加工 AD 相关淀粉样前体蛋白的天冬氨酸蛋白酶。在检测 rs2837960 与人类大脑中 BACE2 异构体表达之间的关联时，我们观察到 rs2837960 与 BACE2 的总表达以及缺乏外显子 7 的 BACE2 转录本的表达之间存在趋势（p=0.07 和 0.10）。
与 RA 相关的 SNP 通常与 AD 无关。此外，rs2837960_G 与 RA 和 80 岁以下个体的 AD 风险增加相关。总体而言，这些结果与与 RA 相关的遗传变异可预防 AD 的假设相矛盾。需要进一步研究 rs2837960，以阐明 rs2837960 如何通过调节 BACE2 表达，导致 AD 和 RA 风险增加的机制。
