Monday, September 18, 2017

All for one (population) and one for all

Type 2 diabetes (T2D) is a world-wide health problem, but it hits especially hard in Latin America, where incidence is higher than in many other parts of the world. To investigate the genetic basis for this difference, researchers from the U.S., Mexico, and Spain teamed up to look for genetic coding variants associated with T2D risk that are more common in people of Hispanic descent. In their recent paper (Mercader et al. 2017, Diabetes), the researchers discovered such variants and uncovered the molecular details of how one in particular affects T2D risk. Their results suggest a new avenue for drug development that could benefit diabetics of all ancestries. And surprisingly, although Hispanics have higher T2D risk, this variant actually protects against T2D.

In designing the study, Mercader and colleagues decided to focus on variants located within protein-coding sequences, whose effects can be more direct and more straightforward to test than those of variants outside genes. They used exome chip analysis, which considers only variants in protein-coding regions of the genome, to genotype both diabetics and non-diabetics of Hispanic descent from Mexico and the U.S. Their dataset, SIGMA exome chip analysis, is accessible in the T2D Knowledge Portal and described on our Data page.

To find variants that might differentially affect the Hispanic population, the researchers looked for T2D-associated variants that were common in Hispanics, but rare or low-frequency in people of European ancestry. The most significant variant in this category, rs149483638, is present at a minor allele frequency (MAF) of 17% in people of Hispanic ancestry, but has MAF of only 1%, 0.1%, and 0.02% in East Asian, African, or European ancestries, respectively.

Surprisingly, although enriched in this population that is more vulnerable to T2D, the rs149483638 effect allele is protective against T2D. People who are heterozygous for the effect allele (a T at position 2161530 of chromosome 11 rather than a C) have 22% decreased risk of T2D, while homozygous carriers have 40% decreased risk.

After the initial discovery, the investigators performed more analyses to verify whether rs149483638 was the causal variant in the region, and replicated the T2D association in independent datasets. All the results supported the hypothesis that this particular variant directly reduces T2D risk.

The variant is located in the IGF2 gene, which encodes a peptide similar to insulin that has previously been linked to growth disorders, obesity, and T2D. Alternative splicing generates two different isoforms of IGF2, and the protective allele disrupts a predicted acceptor site for the splicing event that would generate isoform 2. Could the absence of IGF2 isoform 2 be protective against T2D?

Mercader and colleagues performed further experiments to address the questions of whether the rs149483638 effect allele blocks the production of isoform 2 and whether this has an impact on T2D risk. In human cell culture, the protective allele did indeed block splicing at that site.

To see whether this happens in humans, the researchers tested tissue samples for the presence of isoform 2, and found that its expression was lower in people carrying the protective allele. Furthermore, among people who lacked the protective allele, those with T2D showed higher expression of isoform 2 in their visceral fat tissue than did those without T2D. Levels of isoform 2 in non-diabetics were also positively correlated with levels of HbA1c, which is an indicator of elevated blood glucose levels. No such correlations were seen for levels of IGF2 isoform 1.

Taken together, these results support the involvement of isoform 2 in the elevation of T2D risk, suggesting an intriguing possibility: could lowering levels of isoform 2 be an effective way to lower T2D risk?

If lowering isoform 2 levels were to be used as a T2D therapeutic, it would be important to know that this reduction had no adverse effects. Genetic data can shed light on this question as well. The authors looked in the Exome Aggregation Consortium (ExAC) database and in the clinical records of their study subjects, and saw no health effects other than lowered T2D risk in carriers of the protective variant. They also performed a phenome-wide association study (PheWAS) in the in Genetic Epidemiology Research on Aging (GERA) cohort, and saw no association of the T2D-protective allele with any of 18 medical conditions.

Thus it seems likely that loss of IGF2 isoform 2 would not be harmful, setting the stage for research into drugs that could specifically inhibit isoform 2 or block its production as a way to delay or treat the development of T2D.

These fascinating results have opened multiple avenues for future research. What is the specific biological role of IGF2 isoform 2 in T2D? It differs from isoform 1 only in that it carries an extra 56 N-terminal amino acids. Isoform 1 predominates, while isoform 2 is expressed at very low levels—although its highest expression is seen in pancreatic islets, liver, and fat, all tissues that are relevant for T2D. Elucidating the molecular details of this role will increase our understanding of the biological mechanisms in T2D. And from an evolutionary perspective, the question of how this protective variant came to be enriched in this population is an interesting one.

The motto of the Three Musketeers was "All for one and one for all," meaning that the group supports each member and each member supports the group. As this paper illustrates, this theme is also emerging in human genetics. By investigating distinct populations, we can not only learn about those specific populations but also gain knowledge to benefit all humankind.