Several SLC30A8 mutations may protect in type 2 diabetes

Type 2 diabetes (T2D) is a chronic condition in which the body does not produce or respond correctly to insulin, resulting in elevated blood glucose levels. Although diabetes is diagnosed primarily in adults, its onset can start as early as childhood. Did you know that certain mutations in the SLC30A8 gene may offer some protection against it?

There is no cure. However, diet and exercise can help patients manage the condition. Sometimes, insulin therapy is also needed. 

The exact cause of the disease is unknown. However, experts agree that being overweight and inactivity are risk factors. Having a family history also increases T2D risk.

Person running
Exercise can lower diabetes risk. Photo by Jenny Hill on Unsplash

Chronically high insulin levels in the bloodstream, as occurs in type 2 diabetes, can create serious complications. Specifically, it increases the risk of conditions such as heart disease, nerve damage, kidney disease, eye damage, slow healing, sleep apnea, and dementia.

The most effective way to prevent or manage type 2 diabetes is a healthy lifestyle. These recommendations include eating foods low in fat and high in fiber, avoiding inactivity for long periods, and losing weight.

While good eating and exercise habits will always have an impact, human genetics plays a role too. A study published in Nature Genetics found 12 genetic mutations that protect against type 2 diabetes. These variants are rare (<0.1% frequency) in the general population.

Did you know that some rare variants can offer protection from type 2 diabetes? The majority of the population does not have them, which is normal. However, the folks that do get some extra protection. 

You can use the Nebula Gene Analysis Tool to find this gene and see if you have these functional variants. Keep reading to learn what these mutations are and how you can check your status.

The Study

Overall, the authors of this study sequenced ~150,000 individuals across five ethnicities.

The gene SLC30A8 encodes a certain kind of protein known as a zinc transporter. This protein is involved with insulin crystallization. Furthermore, previous studies have identified a common variant in this gene related to type 2 diabetes risk. This background suggests that there may be other variants on this gene and around the SNP related to type 2 diabetes.

Specifically, the authors of the Nature Genetics paper were looking for protective variants that may also be therapeutic targets.  

Initial sequencing in 758 individuals from Finland or Sweden, followed by another analysis on 21,000 individuals, found two potentially relevant variants on the SLC30A8 gene. The one found in the second analysis was confirmed by a larger European dataset.

Beyond these initial results, the group sought to identify additional mutations that may represent more diverse populations. 

Using a curated dataset of 35 million variants, they found another protein-truncating variant in SLC30A8 also associated with a significant reduction in type 2 diabetes risk (they observed the mutation in 0.03% of type 2 diabetes cases versus 0.18% in non-diabetic controls). 

Diabetes management tools
Diabetes testing and management. Photo by Towfiqu barbhuiya on Unsplash

Finally, they performed exome sequencing on about 12,000 individuals including African American, East Asian, European, Hispanic, and South Asian subjects, which revealed nine additional protein-truncating proteins.

When they combined all sequencing data, the authors found that heterozygosity for any of the 12 protein-truncating variants was associated with 65% reduced type 2 diabetes risk. The chances of having one of these mutations in the general population are less than 1%. 
Because these mutations are loss-of-function variants (they inactivate one copy of SLC30A8) that protect against disease, they could be effective targets for future drugs designed to prevent disease. 

Explore your Genome!

Did you know you can use the Nebula Gene Analysis Tool (available with Deep and Ultra Deep WGS) to check whether you have these protective variants?

This tool empowers you to examine any gene in your genome and identify important genetic variants and mutations. 

  1. When you click on the “Get Started” button your VCF file will be loaded into the Gene Analysis tool in a new tab.
  2. Type “SLC30A8” into the search bar at the top. 
  3. The Gene Analysis tool will extract genetic variants in the SLC30A8 gene from your VCF file and display them to you using symbols that have different colors. The colors denote the potential importance of variants. The Gene Analysis tool determines this by referencing the ClinVar database and other resources.
  4. Any red and orange variants could potentially be important. Click on them to check if any of them are truncating variants like the ones described in the study described above.

12 variants discovered to truncate SLC30A8

  1. p.Arg138X
  2. p.Lys34SerfsX50
  3. c.71+2T>A
  4. p.Met50Ile
  5. c.271+G>A
  6. c.419-1G>C
  7. p.Trp152X
  8. p.Gln174X
  9. c.572+1G>A
  10. p.Tyr284X
  11. p.Ile291PhefsX2
  12. p.Ser327ThrafsX5


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. 2014 Apr;46(4):357-63. doi: 10.1038/ng.2915. Epub 2014 Mar 2. PMID: 24584071; PMCID: PMC4051628.

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