Rs5848 Variant Influences GRN mRNA Levels in Brain and Peripheral Mononuclear Cells in Patients with Alzheimer\u2019s Disease

Mutations in the progranulin gene (GRN), causative for Frontotemporal Lobar Degeneration with ubiquitin-immunoreactive neuronal inclusions (FTLD-U), could also be associated with Alzheimer's disease (AD). The influence of GRN genetic variability on susceptibility to AD and on expression levels in a series of neuropathologically-confirmed AD patients as well as in peripheral mononuclear cells (PBMC) and in cells isolated from cerebrospinal fluid (CSF) was investigated. An association study of rs9897526 and rs5848 was carried out in an Italian population and in a replication population of European American patients and controls. None of the variants tested act as unequivocal susceptibility factor in both populations although rs9897526 anticipated the onset of the disease in the Italian population. GRN expression in the parietal lobe of AD cases showed a 0.76-fold decrease compared with controls (1.31 +/- 0.07 versus 1.73 +/- 0.12, P = 0.0025). Patients carrying the rs5848 TT genotype had the lowest GRN expression levels (0.96 +/- 0.12, P = 0.014). Despite no significant differences were found in the relative PBMC and CSF GRN expression in patients compared to controls, stratifying patients according to the presence of rs5848 T allele, a 0.57-fold decrease in GRN mRNA levels over C carriers was found in PBMC (1.22 +/- 0.23 versus 0.70 +/- 0.12, P = 0.04). Similarly to data obtained in brain samples, patients carrying the TT genotype showed the lowest GRN mRNA levels (TT = 0.46 +/- 0.14, CC = 1.22 +/- 0.23; P = 0.013). These data argue against a direct role of GRN as a susceptibility factor for sporadic AD but support a role of GRN as a disease-modifying gene, possibly contributing to the failure of neuronal survival

Cerebrospinal fluid progranulin levels in patients with different multiple sclerosis subtypes

Progranulin has recently attracted attention due to the discovery of mutations in its encoding gene (GRN) in several cases of frontotemporal lobar degeneration, but also for a possible role in inflammatory processes. In adult central nervous system, GRN mRNA is expressed in forebrain, olfactory bulbs and spinal cord. Progranulin cerebrospinal fluid (CSF) levels were evaluated in 55 patients with multiple sclerosis (MS) as well as in 35 subjects with non-inflammatory neurological diseases (NIND), 7 individuals with other inflammatory neurological disease (OIND) and 8 controls (CON), matched for ethnic background, gender and age. No statistically significant differences were found in patients compared with either NIND, OIND or CON (P > 0.05), even stratifying according to disease subtype or gender. A positive correlation between progranulin CSF levels and age was observed in patients (rho = 0.29, P = 0.03). According to these data, progranulin does not likely play a major role in the pathogenesis of MS

Decreased circulating miRNA levels in patients with primary progressive multiple sclerosis

Emerging evidence underlines the importance of micro(mi)RNAs in the pathogenesis of multiple sclerosis (MS). Free-circulating miRNAs were investigated in serum from MS patients compared to controls. Statistically significant decreased levels of miR-15b, miR-23a and miR-223 were observed in MS patients (p < 0.05). Results were validated and replicated in two further independent MS populations. A direct correlation between miRNA levels and the EDSS score was determined in PPMS (p < 0.007). The generalized trend toward miRNA down-regulation could result in over-expression of target genes involved in disease pathogenesis. Circulating miRNA profiling could thus represent a new avenue to identify easily detectable disease biomarkers. \ua9 The Author(s) 2013

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

Progranulin (GRN) gene variability has been analyzed in a sample of 354 patients with multiple sclerosis (MS) compared with 343 controls. No significant differences were observed, but by stratifying according to MS subtypes, a significant increased frequency of the rs2879096 TT genotype was found in primary progressive MS (PPMS) patients versus controls (16.0 vs 3.5%, P0.023, odds ratio (OR) 5.2, 95% confidence interval (CI) 1.2-21.4). In addition, in PPMS, an association with the C allele of rs4792938 was observed (55.3 vs 33.5%, P0.011, OR 2.4, 95% CI 1.2-4.7). An independent population was studied as replication, failing to confirm results previously obtained. Stratifying according to gender, an association with rs4792938 C allele was found in male PPMS patients compared with controls (40.7 vs 26.9%, P0.002, OR 1.87, 95% CI 1.2-2.8). An association with the rs2879096T allele was observed (29.2 in patients compared with 18.9% in controls, P0.012, OR 1.77, 95% CI 1.1-2.8). Haplotype analysis showed that TC haplotype frequency is increased in PPMS male patients compared with male controls (25.7 vs 16.6%; P0.02, OR 1.69, 95% CI 1.1-2.7), whereas the respective GC haplotype seems to exert a protective effect, as its frequency is decreased in patients compared with controls (55.8% vs 70.9%; P0.001, OR 0.52, 95% CI 0.4-0.8). Therefore, GRN haplotypes likely influence the risk of developing PPMS in males

Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses