HMGA1 – Type 2 Diabetes Mellitus

Multiple case–control studies have evaluated the association of the HMGA1 locus with type 2 diabetes mellitus (Type 2 Diabetes Mellitus). In a Han Chinese discovery cohort (96 cases/96 controls) and two replication cohorts (2,533 cases/2,643 controls), the HMGA1 intronic insertion c.136-14dup was associated with increased diabetes risk (OR 1.34; population attributable risk 5.0%) (PMID:22411136). This finding was replicated in a Hispanic‐American cohort (320 cases/824 controls) with OR 1.44 for carriers (PMID:24148075). A transethnic meta‐analysis of 13,789 cases and 13,460 controls confirmed a modest but statistically significant effect of the rs146052672 variant on T2D risk (PMID:26296198). However, large studies in French Caucasians (16,605 cases/46,179 controls) and an ethnically diverse hypertensive cohort (3,070 subjects) found no association with c.136-14dup (PMID:22210315; PMID:23302499).

Inheritance is complex and polygenic, with no reported Mendelian segregation of HMGA1 variants. No affected relatives with segregating variants were described in family studies. The variant spectrum is largely confined to the recurrent intronic c.136-14dup insertion, observed across multiple ethnicities. No loss-of-function or missense variants have been implicated in monogenic diabetes.

Functional studies support a pathogenic mechanism whereby HMGA1 regulates insulin receptor (INSR) gene transcription. HMGA1 deficiency or the rs146052672 allele reduces HMGA1 protein levels, leading to downregulation of INSR expression, impaired insulin signaling, and hyperglycemia in cell and mouse models (PMID:40233659). This mechanism is concordant with the observed association with insulin resistance and T2DM.

Conflicting evidence arises from large European and diverse cohorts showing lack of association of the c.136-14dup variant with diabetes risk, underscoring heterogeneity between populations and study designs. Functional analyses suggest the variant is not inherently functional in some contexts, and linkage disequilibrium may differ across ancestries.

On balance, the genetic and experimental data place HMGA1 as a moderate evidence susceptibility locus for T2DM. Additional large, multiethnic cohorts and deep‐phenotyping, as well as mechanistic studies, are needed to resolve population-specific effects and to move toward clinical risk stratification.

Key take-home: HMGA1 c.136-14dup is a moderate‐risk variant for type 2 diabetes, acting through reduced HMGA1‐dependent INSR transcription and insulin resistance.

References

• Diabetologia • 2012 • Polymorphism of HMGA1 is associated with increased risk of type 2 diabetes among Chinese individuals. PMID:22411136
• Metabolic syndrome and related disorders • 2014 • Evidence that an HMGA1 gene variant associates with type 2 diabetes, body mass index, and high-density lipoprotein cholesterol in a Hispanic-American population. PMID:24148075
• PloS One • 2015 • The Association between HMGA1 rs146052672 Variant and Type 2 Diabetes: A Transethnic Meta-Analysis. PMID:26296198
• Diabetes • 2012 • Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk. PMID:22210315
• Journal of Translational Medicine • 2013 • Lack of association of the HMGA1 IVS5-13insC variant with type 2 diabetes in an ethnically diverse hypertensive case control cohort. PMID:23302499
• EBioMedicine • 2025 • HMGA1 deficiency: a pathogenic link between tau pathology and insulin resistance. PMID:40233659

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