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Genetic Association Study in Latin American Populations Uncovers Novel Risk Variant for Type 2 Diabetes

NEW YORK (GenomeWeb News) – A genetic association study of Mexicans and Latin Americans uncovered a novel variant linked to type 2 diabetes risk, a consortium of researchers reported yesterday in Nature. The variant, in SLC16A11, is expressed in hepatic cells and appears to affect lipid metabolism. Additionally, the researchers traced the variant back to admixture with Neandertals.

The SIGMA Type 2 Diabetes Consortium genotyped some 3,800 Mexicans and Latin Americans with type 2 diabetes and 4,400 controls to search for additional disease risk alleles and examine the population genetics of the disease.

Type 2 diabetes is prevalent among Latin Americans, with a frequency nearly twice that of US non-Hispanic whites, the researchers noted, but many genetic studies had previously focused on people of European or Asian ancestry.

"By expanding our search to include samples from Mexico and Latin America, we've found one of the strongest genetic risk factors discovered to date, which could illuminate new pathways to target with drugs and a deeper understanding of the disease," said co-corresponding author José Florez, a Broad Institute associate member, in a statement.

Florez and his SIGMA colleagues analyzed some 9.2 million SNPs in 3,848 Mexicans and Latin Americans with diabetes and in 4,366 non-diabetic controls from the same populations. From this, they replicated previous findings at TCF7L2 and KCNQ1.

They also uncovered a novel association that encompassed SLC16A11 and SLC16A13. The strongest signal, they reported, included a silent mutation and four missense mutations.

These five variants, the researchers noted, are in strong linkage disequilibrium and co-segregate as part of the same haplotype. They are also common in samples from people of Latin American ancestry and appear to show the same levels of association with type 2 diabetes. The prediction tool SIFT determined one of the missense SNPs to be damaging and the other three to be tolerated changes.

By combining data from the current study with 1000 Genomes Project data, the SIGMA researchers determined that the risk allele was rare or absent in samples from people of European and African descent and present at intermediate levels in samples from people of Asian descent. Its frequency in people of American descent, though, reached 50 percent. They replicated this association in about 22,000 samples from people from diverse ancestral backgrounds.

This sequence, the investigators added, is highly divergent, and has an estimated time to common ancestor that dates back some 799,000 years — a timeframe that precedes human migration out of Africa. However, this variant is not found in any African populations and is uncommon in Europeans, leading the researchers to hypothesize that it is a Neandertal-derived allele that arose due to admixture between the hominin lines.

While neither the published Neandertal nor Denisovan genomes contain the diabetes risk variant, the researchers found that an unpublished genome from a Neandertal is homologous for the haplotype, including all four missense mutations. Additionally, the Neandertal sequence forms a clade with the risk haplotype with a coalescence time that comes after the split between humans and Neandertals, and the haplotype has not undergone the degradations that would be expected if 9,000 generations had passed, underscoring the possibility that it was introduced through admixture.

"[The] haplotype is not only similar to the Neandertal sequence, but was probably introduced into modern humans relatively recently through archaic admixture," the researchers said.

According to the researchers' calculations, people with the risk variant are about 26 percent more likely to develop diabetes, and the risk variant explains about 20 percent of the increased prevalence of type 2 diabetes in Mexicans and Latin Americans.

SLC16A11, the researchers reported, is expressed in the liver, thyroid, and salivary glands and belongs to the solute-carrying SLC16 family. By expressing SLC16A11 in HeLa cells, which typically do not express that protein, the researchers found that its expression leads to substantial increases in triacylglycerol levels as well as smaller increases in diacylglycerol levels and decreases in lysophosphatidylcholine, cholesterol ester, and sphingomyelin lipids levels, indicating that SLC16A11may have a role in hepatic lipid metabolism. Triacylglycerol levels, the researchers noted, have previously been associated with type 2 diabetes risk, and the increases in intracellular lipids has been linked to insulin resistance in people.

"[W]e've uncovered a new clue about the biology of diabetes," said co-senior author David Altshuler, deputy director and chief academic officer at the Broad. "We are now hard at work trying to figure out what is being transported, how this influences triglyceride metabolism, and what steps lead to the development of type 2 diabetes."