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Genetic Variants Linked to Type 2 Diabetes

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Findings Offer Promise for New Therapies

Association of rare variants in HMGA1 with type 2 diabetes as seen in this study supports the role of insulin resistance in the pathogenesis of the disease, Dr. Abhimanyu Garg wrote in an accompanying editorial (JAMA 2011;305:938-9).

There are some concerns regarding the conclusions of the study, such as the large variation in the frequency of the most common variants among control populations, which make it difficult to ascertain true effect size. However, the study also offers important promise for future therapies.

"With the discovery of novel loci for type 2 [diabetes] and development of better understanding of the molecular mechanisms by which these variants affect the susceptibility of diabetes, combined with the sophisticated metabolic phenotyping related to beta-cell dysfunction, insulin resistance, incretin hormones, hepatic glucose, and lipid metabolism, distinct subtypes of type 2 [diabetes] will be recognized more clearly," he wrote.

This could lead to targeted therapies for various disease subtypes, as has been the case recently with common variants near the ataxia-telangiectasia mutated gene, which were recently associated with treatment success with metformin, he explained.

"It is anticipated that the discoveries of novel loci such as HMGA1 will soon be translated into therapeutic decision making and thereby improve the health of patients with type 2 [diabetes]," he concluded.

Dr. Garg is with the University of Texas Southwestern Medical Center, Dallas. He reported receiving grants from the National Institutes of Health, the U.S. Food and Drug Administration, and Amylin.


 

FROM JAMA

Patients with type 2 diabetes were more likely to have genetic variations for a key protein regulating cells’ insulin receptors, according to a multinational case-control study.

The variants’ presence could serve as an early predictive marker of insulin resistance and type 2 diabetes, particularly in patients with a family history of the disease, the study’s authors noted.

The investigators examined variations in the high-mobility group A1 protein, or HMGA1, a key regulator of insulin receptor gene expression. The protein’s most frequent functional variant was found in 7.2% of the study’s 3,278 Italian patients with type 2 diabetes, compared with 0.4% and 3.3% of two Italian control groups (2,544 and 784 patients) without diabetes, significant differences resulting in adjusted odds ratios of 15.8 and 2.0, respectively.

In addition, the variant was found in 7.7% of 970 U.S. case patients, compared with 4.7% of 958 U.S. control patients (adjusted odds ratio, 1.6), a significant difference, and in 7.6% of 354 French case patients vs. 0% of 50 French controls, also a significant difference, reported Dr. Eusebio Chiefari of the University of Catanzaro (Italy) and colleagues (JAMA 2011;305:903-12).

Three other functional variants also were observed in the Italian population, although those variants were not studied in the U.S. and French populations because of the relatively small sample sizes.

Overall, when all four variants were analyzed, nearly 10% of Italian patients with type 2 diabetes were found to have HMGA1 defects, compared with less than 1% of controls.

The four functional variants of the HMGA1 gene were also shown to be associated with decreased insulin receptor (INSR) gene and insulin receptor protein expression.

"Because insulin downregulates its own receptor, we performed two different studies to rule out the possibility that the hyperinsulinemia we observed in our patients with HMGA1 gene variants was downregulating the INSR," the researchers said. Both tests ruled out a hyperinsulinemia effect, they added.

"We believe our observation that nearly 10% of individuals with type 2 diabetes have deleterious variations in the gene encoding HMGA1 has important clinical implications," the researchers wrote. In addition to potentially predicting insulin resistance, the variants might predict response to therapy. In addition, patients with HMGA1 variants and type 2 diabetes might have a different clinical course than do other patients with type 2 diabetes, the investigators said. The search for new type 2 diabetes therapies could include agents that upregulate the expression of HMGA1, they added.

More studies of the HMGA1 gene and its variants are needed, the investigators concluded, including studies in other racial types, to improve understanding of the role HMGA1 plays in insulin resistance and type 2 diabetes.

Dr. Chiefari and his colleagues reported no disclosures. Telethon-Italy, MIUR Italy, and the National Institutes of Health providing funding for the study.

Video: Gene Variations Associated With Risk of Type 2 Diabetes, from The JAMA Report

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