Type 2 Diabetes Mellitus and Variants of the HMGA1 Gene

Type 2 diabetes mellitus (DM) is one of the most common metabolic disorders, affecting nearly 250 million people worldwide. It is associated with major diabetes-related complications, including retinopathy, nephropathy, neuropathy, and cardiovascular disease.

Individuals with type 2 DM are resistant to endogenous and exogenous insulin; both genetic and environmental factors contribute to the onset of hyperglycemia. Heredity is closely connected to insulin resistance, but the actual genetic connections to type 2 DM have not yet been determined. The interaction of insulin with target cells is mediated by the insulin receptor (INSR), a glycoprotein that is located on the plasma membrane and serves a crucial role both in directing insulin to target tissues and initiating the responses of these tissues to the hormone. The high-mobility group A1 (HMGA1) protein is a key regulator of INSR gene expression.

This group of investigators had previously identified a functional HMGA1 gene variant in 2 insulin-resistant patients with decreased INSR expression and type 2 DM. These individuals had normal INSR genes, but had a novel genetic variant (c.*369del) in the 3' noncoding region of the HMGA1 messenger RNA that contributed to the reduction of messenger RNA half-life and subsequent decline in HMGA1 expression. For this study [JAMA. 2011;305(9):903-912], the authors examined DNA from a large number of patients with type 2 DM to determine the prevalence of functional HMGA1 gene variants associated with the disease.

The investigators also conducted case-control studies in 3 populations with the major variant to determine the association of HMGA1 gene variants with type 2 DM. The investigators studied 3 distinct populations (Calabria, Italy; Northern California; and France) of white Northern European ancestry. The Italian group, followed from 2003 to 2009, consisted of 3278 type 2 DM patients and 3328 controls split into 2 groups; the American patients (n=970, recruited between 1994 and 2005) and controls (n=958, recruited in 2004 and 2009); and the French group, recruited in 1992 (354 patients, 50 controls). Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus–transformed lymphoblasts from patients with type 2 DM and controls.

The main outcome measure was the frequency of HMGA1 gene variants among cases and controls. Odds ratios (ORs) for type 2 DM were estimated by logistic regression analysis. The most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of type 2 DM patients in all 3 populations. The prevalence of the IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group; OR, 15.77 [95% confidence interval (CI), 8.57-29.03]; P<.001 and 7.23% vs 3.32% in the other control group; OR, 2.03 [95% CI, 1.51-3.43]; P<.001). In the American population, the prevalence of IVS5-13insC variant was 7.7% among patients with type 2 DM versus 4.7% among controls (OR, 1.64 [95% CI, 1.05-2.57]; P=.03). In the French population, the prevalence of IVS5-13insC variant was 7.6% among patients with type 2 DM and 0% among controls (P=.046).

In all, the investigators found 3 new functional variants of the HMGA1 gene that were associated with decreased INSR gene and INSR protein expression and type 2 DM in a significant proportion of affected individuals of white European descent. The authors noted that they had found a novel and relatively common variant showing a heterozygous single-nucleotide insertion at position −13 of exon 6 (IVS5-13insC). This variant was associated with reduced levels of HMGA1 messenger RNA and HMGA1 protein, possibly by skipping exon 6 and affecting RNA splicing. The investigators said that all of the above new variants were shown to be associated with type 2 DM in white European subjects.