No abstract

Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Since common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in three independent replication cohorts, consisting of 2,279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer’s disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (PDISC=5.6×10−9; PJOINT=3.7×10−27). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (PDISC=6.7×10−5; PREP=9.4×10−3; PJOINT=2.3×10−5). This variant influences the expression of two adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type II diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system associated with demyelination and axonal loss. A whole genome association scan suggested that allelic variants in the CD58 gene region, encoding the costimulatory molecule LFA-3, are associated with risk of developing MS. We now report additional genetic evidence, as well as resequencing and fine mapping of the CD58 locus in patients with MS and control subjects. These efforts identify a CD58 variant that provides further evidence of association with MS (P ‫؍‬ 1.1 ؋ 10 ؊6 , OR 0.82) and the single protective effect within the CD58 locus is captured by the rs2300747 G allele. This protective rs2300747 G allele is associated with a dose-dependent increase in CD58 mRNA expression in lymphoblastic cell lines (P ‫؍‬ 1.1 ؋ 10 ؊10 ) and in peripheral blood mononuclear cells from MS subjects (P ‫؍‬ 0.0037). This protective effect of enhanced CD58 expression on circulating mononuclear cells in patients with MS is supported by finding that CD58 mRNA expression is higher in MS subjects during clinical remission. Functional investigations suggest a potential mechanism whereby increases in CD58 expression, mediated by the protective allele, up-regulate the expression of transcription factor FoxP3 through engagement of the CD58 receptor, CD2, leading to the enhanced function of CD4 ؉ CD25 high regulatory T cells that are defective in subjects with MS.M ultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system associated with demyelination, axonal loss, and brain atrophy; susceptibility to this disease is affected by both genetic variation and environmental risk factors (1, 2). The initial episode of neurologic dysfunction results in a clinical diagnosis of a clinically isolated demyelinating syndrome (CIS), and a second episode leads to a diagnosis of MS (1). Increasing evidence suggests that activated, autoreactive T cells play a central role in MS pathophysiology, as evidenced by the efficacy of treatments such as Natalizumab (anti-VLA-4 monoclonal antibody) that block lymphocyte egress from the vascular compartment into the CNS (3). Furthermore, the control of activated T cells by natural regulatory CD4 ϩ T cells is impaired in subjects with MS (4). This population of regulatory CD4 ϩ T cells expresses high levels of the IL-2 receptor (CD25) and FoxP3, an important transcription factor for regulatory T cells (4). We have now begun to integrate these immunologic observations with results of our genetic studies in patients with MS.Two novel MS susceptibility loci have recently been identified using a genome-wide association scan approach, and these 2 loci, IL2RA and IL7R, have now been validated in independent subject collections (5-9). In the genome scan, several other loci, including the CD58 locus, displayed suggestive evidence of association with MS susceptibility. Since CD58 (LFA-3) costimulates and enhances T cell receptor signaling by engaging CD2 (10), the CD58 locus is an attractive target for understanding ...