Rs5848

rs5848(T;T) found a 3.2-fold increased risk vs C-allele carriers (95% CI: 1.50-6.73, p=0.003) for ubiquitin- and TAR DNA-binding protein 43 (TDP-43)-positive frontotemporal dementia (FTLD-U also knows as FTLD-TDP43), a progressive neurodegenerative disease affecting approximately 10% of early-onset dementia patients. Detailed haplotype analysis was conducted, indicating rs5848 as most likely causal variant. FTLD-TDP43 is divided into four subtypes, some sources suggest association with type 3 only. Association between rs5848(T;T) and frontotemporal dementia is now generally assumed in literature, despite some studies failing to reproduce it.

First meta-analysis of rs5848 association with Alzheimer's disease combining previous five studies for a total of 2502 Alzheimer's disease cases and 2162 controls found association in homozygous model (TT vs. CC: OR, 1.36; 95% CI, 1.11-1.66; P=0.003) as well as recessive model. This association existed also in the Caucasian-only subset of 2227 cases and 1902 controls. Although the p-value is above usually applied guidelines, the researchers concluded the data indicates association exists. According to "First symptoms--frontotemporal dementia versus Alzheimer's disease" as well as other sources frontotemporal dementia is often misdiagnosed as Alzheimer's disease so it is possible some studies have misdiagnosed cases. FTLD is characterized by behavioral and/or language dysfunction, but usually without the amnesic syndrome involved in Alzheimer's disease at early stage.

In contrast "Reduced serum progranulin level might be associated with Parkinson's disease risk" found that only Parkinson's disease was associated with reduces progranulin levels, but found no association between progranulin levels, rs5848 or Alzheimer's disease. "Association between GRN rs5848 polymorphism and Parkinson's disease in Taiwanese population" found association between rs5848 and Parkinson's disease, but only for female Taiwanese (OR&#8202;=&#8202;1.43, 95% CI: 1.11-1.87, P&#8202;=&#8202;0.007 for single T allele among females). Most studies have found association with neurodegenerative disorders only for recessive or homozygous model, but this is one study where odds ratio follows number of alleles (OR=2.16, 95% CI: 1.24-3.78, P&#8202;=&#8202;0.006 for two alleles among females).

A functional effect is suggested in many studies such as "GRN variant rs5848 reduces plasma and brain levels of granulin in Alzheimer's disease patients" and "Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer's disease". In addition "rs5848 polymorphism and serum progranulin level" showed that progranulin level is affected by number of (T) alleles equally both in 100 patients with different forms of dementia and 36 controls: TT (164 ng/mL, 95% C.I. 138-189), CT (191 ng/mL, 95% C.I. 177-206) and CC (222 ng/mL, 95% C.I. 205-238) serum progranulin with p < 0.005. Progranulin is a growth-factor involved in regulating tumorigenesis, wound repair, development, and inflammation among other things. Rs5848 is located in the 3'-untranslated region (UTR) RNA tail of GRN in a binding-site for miR-659 which inhibits GRN translation. University of California, San Francisco is currently conducting clinical trial "|Dose Finding Study of Nimodipine for the Treatment of Progranulin Insufficiency From GRN Gene Mutations".

Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia.