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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

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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.

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Acknowledgments

Cost of this work was covered from the European Social Foundation Project No 2013/0043/1DP/1.1.1.2.0/13/APIA/VIAA/002. We thank Dr. L. Nikitina-Zake (Latvian Biomedical Research Centre) for help and advices in T1DM sample selection from the Genome database of the Latvian population.

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Authors and Affiliations

  1. Genomics and Bioinformatics, Institute of Biology of the University of Latvia, Salaspils, Latvia

    Tatjana Sjakste, Natalia Paramonova, Kristine Osina & Kristine Dokane

  2. Latvian Institute of Organic Synthesis, Riga, Latvia

    Jelizaveta Sokolovska & Nikolajs Sjakste

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  1. Tatjana Sjakste
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  2. Natalia Paramonova
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  6. Nikolajs Sjakste
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Correspondence to Tatjana Sjakste.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Central Medical Ethics Committee of Latvia (Protocol Nr. 01-29.1/17) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Communicated by Q. Wang.

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Sjakste, T., Paramonova, N., Osina, K. et al. 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. Mol Genet Genomics 291, 891–903 (2016). https://doi.org/10.1007/s00438-015-1153-0

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