Lack of an association of miR-938 SNP in IDDM10 with human type 1 diabetes
© Mi et al; licensee BioMed Central Ltd. 2011
Received: 5 August 2011
Accepted: 20 October 2011
Published: 20 October 2011
MicroRNAs (miRNAs) are a newly discovered type of small non-protein coding RNA that function in the inhibition of effective mRNA translation, and may serve as susceptibility genes for various disease developments. The SNP rs12416605, located in human type 1 diabetes IDDM10 locus, changes the seeding sequence (UGU[G/A]CCC) of miRNA miR-938 and potentially alters miR-938 targets, including IL-16 and IL-17A. In an attempt to test whether miR-938 may be a susceptibility gene for IDDM10, we assessed the possible association of the miR-938 SNP with T1D in an American Caucasian cohort of 622 patients and 723 healthy controls by TaqMan assay. Our current data do not support the association between the SNP in miR-938 and type 1 diabetes.
KeywordsType 1 diabetes polymorphism microRNAs
To the Editor
In recent years, it has become evident that the traditional central dogma of DNA transcription into messenger RNA (mRNA) and mRNA translation into proteins describes only a part of the genetic information machinery that determines which proteins might possibly be synthesized. Additional genetic information is required to control the timing and rates of protein manufacturing processes. Although only a minority of the human genome (2-3%) codes for proteins, a large fraction of the non-protein coding genome is transcribed. MicroRNAs (miRNAs) are a newly discovered type of small non-protein coding RNAs (21-25nt) that function in the inhibition of effective mRNA translation through imperfectly base pairing with the 3' untranslated region (3'-UTR) of target mRNAs. miRNA targets are largely unknown but they are thought to target about 30%-80% of total human proteins at a frequency of about one to hundreds of target genes for a given miRNA. Previous studies indicate that miRNAs play a very important role in determining cellular development, apoptosis, differentiation, and proliferation. Recent studies from our group and others have reported that miRNAs are involved in immune cell development, including CD4+CD25+FoxP3+ regulatory T cells and natural killer T cells. Furthermore, mice without expression of miRNAs in the bone marrow and the thymus develop autoimmune diseases [1, 2]. Most importantly, miRNAs as susceptibility genes contribute to various disease developments, including cancer . Human type 1 diabetes (T1D), or insulin-dependent diabetes mellitus (IDDM), is clearly a chronic autoimmune disorder caused by the interaction of environmental factors with an inherited predisposition. To date, about 50 IDDM susceptibility loci have been mapped to specific chromosome regions in the human. A long search for the gene(s) responsible for diabetes susceptibility has identified only very few candidate genes in past decades. This raises the possibility that the candidate search is a much more complex process than initially assumed, or that some non-coding regulatory genes were missed in previous studies. Given miRNA's suppressive nature and critical role in regulation, the possibility that miRNAs are T1D-risk genes may underlie the diverse findings of genetic studies, including evidence that protein altering gene polymorphisms are not generally found in T1D. Mutations located in critical areas of the mature miRNA potentially affect its structure or expression level, which may lead to abnormal protein-coded gene expression that is phenotypically similar to the disruption of the protein-coded gene itself. Thus, inadequate or miss-timed expression of a functional protein may occur either due to disruption of the DNA coding sequence, leading to a dysfunctional protein, or due to abnormal miRNA regulation of a normal gene. To date there is no direct evidence linking miRNAs and human T1D susceptibility. We previously mapped 27 miRNAs located in 9 T1D susceptibility regions , which places miRNAs as candidates for T1D susceptibility genes. Here, using available single nucleotide polymorphism (SNP) data bases, we found the SNP rs12416605 in IDDM10 is located in the seeding sequence (UGU[G/A]CCC) of miR-938, which changes miR-938 targets. Most interestingly, inflammatory cytokines IL-16 and IL-17A are potential targets of miR-938 based on miRNA targetscan analysis (http://www.targetscan.org), and IL-16 and IL-17A may be involved in T1D development [5, 6]. Thus, the mutation in the miR-938 seed sequence makes miR-938 unable to suppress IL-16 and IL-17 expression and may enhance IL-16 and IL-17 production in T1D patients.
Frequency of miR-938 SNP in American Caucasian population
Diabetic subjects (%)
Control subjects (%)
Conflict of interests
The authors declare that they have no competing interests.
Type 1 diabetes
single nucleotide polymorphism.
This work was partly supported by the Juvenile Diabetes Research Foundation (1-2005-1039, 5-2006-403, and 5-2006-918) and Henry Ford Stubnitz Grant (J80005).
- Zhou L, Seo KH, He HZ, Pacholczyk R, Meng DM, Li CG, et al: Tie2cre-induced inactivation of the miRNA-processing enzyme Dicer disrupts invariant NKT cell development. Proc Natl Acad Sci USA. 2009, 106 (25): 10266-10271. 10.1073/pnas.0811119106.PubMed CentralView ArticlePubMedGoogle Scholar
- Zhou L, Seo KH, Wong HK, Mi QS: MicroRNAs and immune regulatory T cells. Int Immunopharmacol. 2009, 9 (5): 524-527. 10.1016/j.intimp.2009.01.017.View ArticlePubMedGoogle Scholar
- Sevignani C, Calin GA, Nnadi SC, Shimizu M, Davuluri RV, Hyslop T, et al: MicroRNA genes are frequently located near mouse cancer susceptibility loci. Proc Natl Acad Sci USA. 2007, 104 (19): 8017-8022. 10.1073/pnas.0702177104.PubMed CentralView ArticlePubMedGoogle Scholar
- Zhou L, He H, Mi JX, Li C, Lee B, Mi QS: MicroRNA genes: Are they susceptibility candidates for human type 1 diabetes?. Ann N Y Acad Sci. 2008, 1150: 72-75. 10.1196/annals.1447.026.View ArticlePubMedGoogle Scholar
- Bradshaw EM, Raddassi K, Elyaman W, Orban T, Gottlieb PA, Kent SC, et al: Monocytes from patients with type 1 diabetes spontaneously secrete proinflammatory cytokines inducing Th17 cells. J Immunol. 2009, 183 (7): 4432-4439. 10.4049/jimmunol.0900576.PubMed CentralView ArticlePubMedGoogle Scholar
- Mi QS, Meagher C, Delovitch TL: CD1d-restricted NKT regulatory cells: functional genomic analyses provide new insights into the mechanisms of protection against Type 1 diabetes. Novartis Found Symp. 2003, 252: 146-60.View ArticlePubMedGoogle Scholar
- Nejentsev S, Smink LJ, Smyth D, Bailey R, Lowe CE, Payne F, et al: Sequencing and association analysis of the type 1 diabetes-linked region on chromosome 10p12-q11. BMC Genet. 2007, 8: 24-PubMed CentralView ArticlePubMedGoogle Scholar
- Liu S, Wang H, Jin Y, Podolsky R, Reddy MV, Pedersen J, et al: IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells. Hum Mol Genet. 2009, 18 (2): 358-365.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.