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. 2017 Feb;6(2):146-158.
doi: 10.3892/br.2016.833. Epub 2016 Dec 29.

Association of two synonymous splicing-associated CpG single nucleotide polymorphisms in calpain 10 and solute carrier family 2 member 2 with type 2 diabetes

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Association of two synonymous splicing-associated CpG single nucleotide polymorphisms in calpain 10 and solute carrier family 2 member 2 with type 2 diabetes

Maria Karambataki et al. Biomed Rep. 2017 Feb.

Abstract

Coding synonymous single nucleotide polymorphisms (SNPs) have attracted little attention until recently. However, such SNPs located in epigenetic, CpG sites modifying exonic splicing enhancers (ESEs) can be informative with regards to the recently verified association of intragenic methylation and splicing. The present study describes the association of type 2 diabetes (T2D) with the exonic, synonymous, epigenetic SNPs, rs3749166 in calpain 10 (CAPN10) glucose transporter (GLUT4) translocator and rs5404 in solute carrier family 2, member 2 (SLC2A2), also termed GLUT2, which, according to prior bioinformatic analysis, strongly modify the splicing potential of glucose transport-associated genes. Previous association studies reveal that only rs5404 exhibits a strong negative T2D association, while data on the CAPN10 polymorphism are contradictory. In the present study DNA from blood samples of 99 Greek non-diabetic control subjects and 71 T2D patients was analyzed. In addition, relevant publicly available cases (40) resulting from examination of 110 Personal Genome Project data files were analyzed. The frequency of the rs3749166 A allele, was similar in the patients and non-diabetic control subjects. However, AG heterozygotes were more frequent among patients (73.24% for Greek patients and 54.55% for corresponding non-diabetic control subjects; P=0.0262; total cases, 52.99 and 75.00%, respectively; P=0.0039). The rs5404 T allele was only observed in CT heterozygotes (Greek non-diabetic control subjects, 39.39% and Greek patients, 22.54%; P=0.0205; total cases, 34.69 and 21.28%, respectively; P=0.0258). Notably, only one genotype, heterozygous AG/CC, was T2D-associated (Greek non-diabetic control subjects, 29.29% and Greek patients, 56.33%; P=0.004; total cases, 32.84 and 56.58%, respectively; P=0.0008). Furthermore, AG/CC was strongly associated with very high (≥8.5%) glycosylated plasma hemoglobin levels among patients (P=0.0002 for all cases). These results reveal the complex heterozygotic SNP association with T2D, and indicate possible synergies of these epigenetic, splicing-regulatory, synonymous SNPs, which modify the splicing potential of two alternative glucose transport-associated genes.

Keywords: CAPN10; HbA1c; SLC2A2; bioinformatics analysis; family history; heterozygosity; synonymous CpG polymorphisms.

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Figures

Figure 1.
Figure 1.
(A) Nucleotide sequence of the amplified fragments containing the rs3749166 (A>G) calpain 10 polymorphism for samples 34, 40, 187, 200, 46 and 117 (rows 1–6, respectively). (B) Nucleotide sequences of the amplified fragments of rs5404 (C>T) solute carrier family 2 member 2 for the samples 3, 68, 74, 19, 47 and 77 (rows 1–6, respectively). rs3749166 and rs5404 polymorphic sites are indicated using arrows.
Figure 2.
Figure 2.
Frequencies of combined observed and expected genotypes resulting from rs3749166 and rs5404 single nucleotide polymorphism in all analyzed cases. The T2D patient frequencies are presented in parenthesis. The genotypes are presented in order of decreasing epigenetic character. Missing combined genotypes are also included. T2D, type 2 diabetes.

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References

    1. Romero PR, Zaidi S, Fang YY, Uversky VN, Radivojac P, Oldfield CJ, Cortese MS, Sickmeier M, LeGall T, Obradovic Z, et al. Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc Natl Acad Sci USA. 2006;103:8390–8395. doi: 10.1073/pnas.0507916103. - DOI - PMC - PubMed
    1. Stamm S, BenAri S, Rafalska I, Tang Y, Zhang Z, Toiber D, Thanaraj TA, Soreq H. Function of alternative splicing. Gene. 2005;344:1–20. doi: 10.1016/j.gene.2004.10.022. - DOI - PubMed
    1. Soukarieh O, Gaildrat P, Hamieh M, Drouet A, BaertDesurmont S, Frébourg T, Tosi M, Martins A. Exonic splicing mutations are more prevalent than currently estimated and can be predicted by using in silico tools. PLoS Genet. 2016;12:e1005756. doi: 10.1371/journal.pgen.1005756. - DOI - PMC - PubMed
    1. Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR. ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res. 2003;31:3568–3571. doi: 10.1093/nar/gkg616. - DOI - PMC - PubMed
    1. Anastasiadou C, Malousi A, Maglaveras N, Kouidou S. Human epigenome data reveal increased CpG methylation in alternatively spliced sites and putative exonic splicing enhancers. DNA Cell Biol. 2011;30:267–275. doi: 10.1089/dna.2010.1094. - DOI - PubMed