title: Genetic variations in the PSMA3, PSMA6 and PSMC6 genes are associated with type 1 diabetes in Latvians and with expression level of number of UPS-related and T1DM-susceptible genes in HapMap individuals.
abstract: The ubiquitin-proteasome system (UPS), a key player of proteostasis network in the body, was implicated in type 1 diabetes mellitus (T1DM) pathogenesis. Polymorphisms in genes encoding proteasome subunits may potentially affect system efficiency. However, data in this field are still limited. To fulfil this gap, single nucleotide polymorphisms in the PSMB5 (rs11543947), PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827) and PSMA3 (rs2348071) genes were genotyped on susceptibility to T1DM in Latvians. The rs11543947 was found to be neutral and other loci manifested disease susceptibility, with rs1048990 and rs2348071 being the most significantly associated (P < 0.001; OR 2.042 [1.376-3.032] and OR 2.096 [1.415-3.107], respectively). Risk effect was associated with female phenotype for rs2277460 and family history for rs2277460, rs2295826 and rs2295827. Five-locus genotypes being at risk simultaneously at any two or more loci showed strong (P < 0.0001) T1DM association. The T1DM protective effects (P < 0.001) were shown for five-locus genotype and haplotype homozygous on common alleles and composed of common alleles, respectively. Using SNPexp data set, correlations have been revealed between the rs1048990, rs2295826, rs2295827 and rs2348071 T1DM risk genotypes and expression levels of 14 genes related to the UPS and 42 T1DM-susceptible genes encoding proteins involved in innate and adaptive immunity, antiviral response, insulin signalling, glucose-energy metabolism and other pathways implicated in T1DM pathogenesis. Genotype-phenotype and genotype-genotype clusterings support genotyping results. Our results provide evidence on new T1DM-susceptible loci in the PSMA3, PSMA6 and PSMC6 proteasome genes and give a new insight into the T1DM pathogenesis.
authors.affiliation: Genomics and Bioinformatics, Institute of Biology of the University of Latvia, Salaspils, Latvia. tanja@email.lubi.edu.lv.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Sjakste
authors.affiliation: Genomics and Bioinformatics, Institute of Biology of the University of Latvia, Salaspils, Latvia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Paramonova
authors.affiliation: Genomics and Bioinformatics, Institute of Biology of the University of Latvia, Salaspils, Latvia.
authors.forename: Kristine
authors.initials: K
authors.lastname: Osina
authors.affiliation: Genomics and Bioinformatics, Institute of Biology of the University of Latvia, Salaspils, Latvia.
authors.forename: Kristine
authors.initials: K
authors.lastname: Dokane
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Jelizaveta
authors.initials: J
authors.lastname: Sokolovska
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Nikolajs
authors.initials: N
authors.lastname: Sjakste
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000328:Adult; D000483:Alleles; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D060148:HapMap Project; D006239:Haplotypes; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007844:Latvia; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D025801:Ubiquitin / Q000235:genetics
chemical_list: D007328:Insulin; D025801:Ubiquitin; C488165:PSMA3 protein, human; C465641:PSMA6 protein, human; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities; C000609606:PSMC6 protein, human
keywords: Gene expression; PSMA3; PSMA6; PSMC6; SNP; T1DM