The screening of the 3'UTR sequence of LRRK2 identified an association between the rs66737902 polymorphism and Parkinson's disease.
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic determinants of familial and sporadic Parkinson's disease (PD). Most of the mutational screenings analyzed the exon-coding sequence. Our aim was to determine whether LRRK2 3' untranslated region (UTR) variants were associated with the risk of developing PD in a large cohort of patients (n=743) and controls (n=523) from Spain. We identified a total of 12 3'UTR variants (two new). Single-nucleotide polymorphism (SNP) rs66737902 C allele was overrepresented in patients (P=0.005; odds ratio=1.47). This SNP was in linkage disequilibrium with the p.R1441G mutation, but the association remained significant among mutation-negative cases. We found a significant lower level of the LRRK2 transcript in the Substantia nigra (SN) of PD postmortem donors (n=9) who were rs66737902 C carriers (P=0.01). This SNP was predicted to affect a binding site for miR-138-2-3p. We showed that this microRNA was expressed in all the SN samples. In conclusion, we found a significant association between SNP rs66737902 and the risk of developing PD. This effect on PD risk could be explained by differences in LRRK2 transcript levels between the two alleles.
Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, Spain.
Lucía F
LF
Cardo
1] Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, Spain [2] Department of Medicine, University of Oviedo, Oviedo, Spain.
Eliecer
E
Coto
Neurología, Hospitales Universitario Central Asturias and Álvarez Buylla-Mieres, Asturias, Spain.
René
R
Ribacoba
1] Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA [2] Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
Ignacio F
IF
Mata
Neurología, Hospitales Universitario Central Asturias and Álvarez Buylla-Mieres, Asturias, Spain.
Germán
G
Moris
Neurología, Hospitales Universitario Central Asturias and Álvarez Buylla-Mieres, Asturias, Spain.
Manuel
0000000252180774
M
Menéndez
Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, Spain.
Victoria
V
Alvarez
D020413:3' Untranslated Regions; D016022:Case-Control Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism
D020413:3' Untranslated Regions; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases