U.S. Department of Health and Human Services

Rare Genetic Mutations that Protect Against Type 2 Diabetes Suggest Possible Approach for Treating the Disease

Researchers examining multiple different ethnic populations have identified rare mutations in the gene SLC30A8 that appear to significantly reduce risk for type 2 diabetes.  Most mutations have little or no impact on health, and some have detrimental health effects, particularly if they interfere with the proper function of an important gene; but occasionally mutations may be found that reduce the function of a gene (referred to as loss-of-function mutations), yet provide a detectable health benefit.  Such mutations offer a particularly alluring possibility: the potential to design medicines that specifically reduce the activity of the gene, or of the protein it encodes, in a way that may be similarly beneficial for people who do not have the protective mutation.  To identify possible loss-of-function mutations that might protect against type 2 diabetes, the research team focused on genes already thought to be involved in diabetes because common variations in or near the genes are known to be associated with modest differences in risk for the disease.  Among nearly 14,000 people, almost half of whom had type 2 diabetes, they found a mutation that truncates the protein encoded by the SLC30A8 gene in 21 people without diabetes, but in only 7 people who had the disease.  Expanding their analysis to include about 150,000 people of multiple racial/ethnic backgrounds (African American, European, South Asian, and East Asian), the researchers found more protein-truncating mutations in SLC30A8.  Overall, they found that these rare mutations were about three times as likely to occur in people who did not have type 2 diabetes as in those who did, strongly suggesting that SLC30A8 loss-of-function mutations protect against type 2 diabetes.
Surprisingly, this was just the opposite of the previous scientific consensus about the gene and its function.  SLC30A8 encodes a protein called ZnT8 that helps bring zinc into cells.  ZnT8 is produced at high levels in the insulin-producing β (beta) cells of the pancreas, where zinc is known to play an important role: it stabilizes insulin stored within the cells prior to secretion.  In humans, there are two common SLC30A8 variants that both encode full-length ZnT8 proteins, although the ZnT8 proteins produced by the two variants are slightly different from one another.  One of these two common variants was previously associated with a modest increase in risk for type 2 diabetes, and was also thought to reduce zinc transport.  Taken together, the results of the newer and older studies represent something of a puzzle: rare mutations that completely inactivate one of a person’s two copies of SLC30A8 lower risk of type 2 diabetes, while a much more common version of SLC30A8 that encodes a lower activity form of ZnT8 raises disease risk.  Further research is needed to explain this paradox, and to determine whether type 2 diabetes can be better treated or prevented through therapeutic modulation of ZnT8 function.
Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R, Blangero J, Bowden DW, Brandslund I, Brosnan J, Burslem F, Chambers J, Cho YS, Christensen C, Douglas DA, Duggirala R, Dymek Z, Farjoun Y, Fennell T, Fontanillas P, Forsén T, Gabriel S, Glaser B, Gudbjartsson DF, Hanis C, Hansen T, Hreidarsson AB, Hveem K, Ingelsson E, Isomaa B, Johansson S, Jørgensen T, Jørgensen ME, Kathiresan S, Kong A, Kooner J, Kravic J, Laakso M, Lee JY, Lind L, Lindgren CM, Linneberg A, Masson G, Meitinger T, Mohlke KL, Molven A, Morris AP, Potluri S, Rauramaa R, Ribel-Madsen R, Richard AM, Rolph T, Salomaa V, Segrè AV, Skärstrand H, Steinthorsdottir V, Stringham HM, Sulem P, Tai ES, Teo YY, Teslovich T, Thorsteinsdottir U, Trimmer JK, Tuomi T, Tuomilehto J, Vaziri-Sani F, Voight BF, Wilson JG, Boehnke M, McCarthy MI, Njølstad PR, Pedersen O; Go-T2D Consortium; T2D-GENES Consortium, Groop L, Cox DR, Stefansson K, Altshuler D. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet 46:357–363, 2014.