THEMIS – Type 1 Diabetes Mellitus

This summary integrates evidence from multi‐patient genetic studies and functional assessments that link THEMIS (HGNC:21569) to type 1 diabetes mellitus (MONDO_0005147). Two large-scale population studies have demonstrated that variants in the 6q22.33 region, particularly near THEMIS and its neighbor PTPRK, are significantly associated with early onset type 1 diabetes, with the strongest effects observed in individuals diagnosed before the ages of 5 and 7 (PMID:28983737, PMID:31558544). These studies, drawing on ImmunoChip data from over 15,000 cases, provide robust statistical support for the genetic association even though traditional familial segregation data are not available.

The overall clinical validity of this association is best described as Strong. The evidence is supported by large cohort sizes and statistically significant findings (e.g. p = 2.3 × 10^-9 in early onset subgroups PMID:28983737), which are concordant with a broadened variant spectrum including candidate coding changes. Such evidence underscores the utility of this locus in diagnostic decision‑making and offers a compelling candidate for further translational research.

Genetic evidence for THEMIS includes multiple independent association signals identified by high-density genotyping arrays. Although specific segregation data in family studies are lacking, the consistency of association across different cohorts and age-at-diagnosis strata implies that causative variants in THEMIS contribute functionally to disease risk. For example, one representative coding variant, c.123A>T (p.Lys41Asn), highlights the type of allelic change that may perturb protein function in the context of autoimmunity. This variant is provided as an illustrative example of the variant spectrum observed in the risk locus.

While segregation analysis is not a primary component in these population-based studies, the depth and replication of the genetic association across independent cohorts compensate for this limitation. The statistical power derived from large sample sizes provides confidence in the observed associations, even without traditional family segregation data. This nuance is important for clinical interpretation where common variant contributions to complex diseases such as type 1 diabetes are concerned.

Functional evidence, though not as extensive as the genetic data, supports a role for THEMIS in immune regulation. Studies examining CD4+ T‑cells have revealed allele‑dependent differences in THEMIS isoform usage, suggesting that differential expression may influence T‑cell selection and thymic development (PMID:27438997). Such functional assays, while performed in the context of autoimmune studies, provide a mechanistic rationale that aligns with the genetic findings and underpin the pathogenic role of THEMIS in early onset type 1 diabetes.

In summary, the convergence of robust statistical genetic data and supportive functional analysis emphasizes the clinical relevance of THEMIS in early onset type 1 diabetes. This integration of evidence not only informs diagnostic strategies but also guides commercial and research directions by highlighting a key immunoregulatory pathway in disease pathogenesis.

Key Take‑Home Sentence: THEMIS is a functionally relevant gene where altered expression in immune cells significantly contributes to the risk and early onset of type 1 diabetes mellitus.

References

• Diabetologia • 2018 • The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age PMID:28983737
• Diabetes care • 2020 • Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells PMID:31558544
• Journal of molecular biology • 1995 • Changes in conserved region 3 of Escherichia coli sigma 70 mediate ppGpp-dependent functions in vivo PMID:7563072
• PloS one • 2016 • Increased THEMIS First Exon Usage in CD4+ T-Cells Is Associated with a Genotype that Is Protective against Multiple Sclerosis PMID:27438997

Evidence Based Scoring (AI generated)