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.

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Aim:The ryanodine receptor 1 (RYR1) is a calcium ion channel in the sarcoplasmic reticulum of skeletal muscle. Multiple polymorphic loci have been identified in the RYR1 gene in human and animals and some of them are associated with certain phenotypes. However, there are still few data on the RYR1 genetic variability in pig and only the missense mutation Arg615Cys, associated with the malignant hyperthermia, porcine stress syndrome and meat quality, has been studied in several commercial and local breeds. The aim of the current study was to genotype the rs344435545 (C1972T, Arg615Cys), rs196953058 (T8434C, Phe2769Leu) and rs323041392 (G12484A, Asp4119Asn) in the Latvian local pig breed Latvian White and to evaluate the eventual functionality of amino acid substitutions. Methods: Loci were genotyped by the restriction fragment length polymorphism technology in the collection of 8 samples of original Latvian White collected in 2006 and 103 samples of Latvian White collected in three Latvian geographically distant private farms in 2015. SIFT online tool was applied to evaluate a potential effect of the amino acid substitutions on protein functions. Results: The loci rs344435545 and rs196953058 were found to be monomorphic in both collections. On the contrary, the rs323041392 showed a high level of polymorphism in the original Latvian White with GG/GA/ AA genotype correlation equal to 3/4/1 and the absence of polymorphism in 2015 collection. From the studied loci only the rs344435545 was identified as possessing potential to change functions of the protein. Conclusions:The unfavourable rs344435545 T allele having functional effect on the protein function, appears not to have been introduced in Latvian White pig breed. Full loss of the rs323041392 variability in Latvian White happened in nine years of private farming, could be a message to Latvian and other European livestock industry that the breeding intensification may decrease the genetic diversity, specific features performance and adaptability to the environmental challenges in local breeds of small populations. K e y w o r d s: RYR1, polymorphism, genetic diversity, pig