it runs in the family: T1D-associated genes (part 1)

it runs in the family: T1D-associated genes (part 1)

By: Shruthi Kandalai

It has been noted that T1D is a multifactorial disease, meaning that it is caused by a mix of environmental and genetic factors, with the latter relating to genes that can increase one’s susceptibility to T1D. Many such genes have been identified to be associated with diabetes and as such serve as possible biomarkers or potential treatment targets.

One such gene associated with T1D was identified in a recent paper as CNOT3, a regulatory gene that often leads to the production of proteins or the suppression of genes. Here’s what they found:

  • CNOT3 expression is significantly decreased in islets of non-obese diabetic (NOD) mice compared to non-diabetic mice.
  • Blocking production of CNOT3 in non-diabetic mice led to normal metabolism during weeks 1-4, glucose intolerance by week 8 and diabetes by week 12.
  • Without CNOT3, mRNAs related to β-cell dedifferentiation (Ngn3, Aldh1a3, Myt1, Dcx, and Tnfrsf11b) were increased and an mRNA transcription factor (Mafa) related to β-cell maturation was reduced. There were also glycolytic enzymes normally repressed in mature β-cells (Slc16a1, Ldha, Hk1, Hk2, Rest, and Pdgfra) that were upregulated. 
  • mRNA of genes affected by CNOT3 was found to be more stable (less likely to be degraded) after CNOT3 was blocked. This finding suggests that one method that CNOT3 uses to regulate these genes is through destabilizing mRNA.

An oral presentation suggested that circular RNAs (circRNAs), a novel class of non-coding RNAs that can functionally change gene expression or protein translation, may be related to T1D. Here’s what they found:

  • 134 circRNAs in NOD mice were found to be significantly different compared to normal control mice or mice with insulitis.
  • 50 circRNAs from human serum samples were found to be differentially expressed between those with T1D and healthy controls.
  • Of the identified circRNAs in mice, two were found to be homologous to human circRNAs and showed differences in expression between controls, insulitis and T1D.

This data coincides with another paper discussing how circRNAs have been identified to vary between diabetic patients (both T1D and T2D) and healthy controls.

Another study set out to better understand the difference between haplotypes (inheritance patterns) between Caucasian and Asian (Japanese and Korean) populations. Specifically, the group wanted to understand how genes associated with T1D may vary by race, since many Western studies include mostly Caucasian populations, and T1D is less common and harder to study in Asian countries. Here’s what they found:

  • HLA, also known as IDDM1 (insulin-dependent diabetes mellitus gene 1), codes for a complex of proteins related to the major histocompatibility complex II and is involved in initiating immune responses. In Caucasian populations, haplotypes DR3 and DR4 have been associated with T1D, but neither is common in the Japanese population. Instead, a different DR4 haplotype and DR9 haplotype are associated with T1D in Japanese populations, and likewise, these haplotypes are also uncommon in Caucasian populations. The DR2 haplotype, present in both populations, is protective against T1D.
  • INS, also known as IDDM2 (insulin-dependent diabetes mellitus gene 2), codes for insulin. Allelic variations in the upstream region of this gene have been associated with T1D in Caucasian populations, with haplotype class I increasing susceptibility and haplotype class III increasing protection. The haplotype class I is extremely prevalent (>90%) in the Japanese population with a meta-analysis of data showing it to be significantly associated with T1D in Japanese populations.
  • CTLA4, also known as IDDM12 (insulin-dependent diabetes mellitus gene 12), codes for an immune receptor that can downregulate immune response. In Caucasian populations, this gene has been associated with susceptibility to autoimmune thyroid disorder and some data supports its implication in susceptibility to T1D. In the Japanese population, CTLA4 was associated with T1D only in patients with autoimmune thyroid disorder.
  • PTPN22 affects the response of immune B cells and T cells and has been implicated in many autoimmune conditions in Caucasian populations, including T1D. The specific variant related to T1D in Caucasians, R620W, was not found in either the 1500 Japanese or 150 Korean patients studied. However, five novel single nucleotide variations were found to be associated with T1D in the Japanese population, one of which was also associated with T1D in the Korean population.
  • SUMO4, also known as IDDM5 (insulin-dependent diabetes mellitus gene 5), codes for ubiquitin-related modifiers that modulate protein activity. The M55V mutation has been implicated in Caucasian populations by two groups. However, subsequent studies showed inconsistencies with the association in this population. The mutation, along with other single nucleotide variations downstream, was associated with susceptibility to T1D in the Japanese and Korean populations.

The takeaway: Many genes have been associated with increased susceptibility to T1D in both mouse models and human samples. Better understanding these genes may lead to disease biomarkers or novel targets for individualized treatments. 

Sources:

  • Mostafa, D., Yanagiya, A., Georgiadou, E., Wu, Y., Stylianides, T., Rutter, G. A., . . . Yamamoto, T. (2020). Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation. Communications Biology, 3(1).
  • Yin, C., & Mi, Q. (2020). 113-OR: Circular RNAs: Promising Biomarkers for Type 1 Diabetes. Diabetes, 69.
  • Zaiou, M. (2020). CircRNAs Signature as Potential Diagnostic and Prognostic Biomarker for Diabetes Mellitus and Related Cardiovascular Complications. Cells, 9(3), 659.
  • Ikegami, H., Fujisawa, T., Kawabata, Y., Noso, S., & Ogihara, T. (2006). Genetics of Type 1 Diabetes: Similarities and Differences between Asian and Caucasian Populations. Annals of the New York Academy of Sciences, 1079(1), 51-59.

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