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A3 FUT2 location

The FUT2 gene is located on chromosome 19. More information can be found here: http://ghr.nlm.nih.gov/gene/FUT2

One of the interesting traits one can determine from their 23andMe results is their resistance to the norovirus . The norovirus is a single stranded RNA, non-enveloped virus that causes viral gastroenteritis. This very unpleasant illness, often called the “stomach flu”, causes vomiting, diarrhea and abdominal discomfort, to name a few of the most common symptoms. The infection is self-limiting and usually only lasts 24-48 hours. However, the CDC estimates that 19-21 million Americans are infected with the norovirus each year, causing 56,000-71,000 hospitalizations and 570-800 deaths (3). Because of this high incidence of infection and lack of vaccines or treatment, it is important to engage in proper hygiene and disinfecting of surfaces where food is prepared, unless of course you are resistant to the virus. Even so, it still is important to minimize the spread of this dread disease, as most of the population is susceptible to the virus.

GeneticsEdit

What does it mean, genetically, to be resistant to the norovirus? Norovirus resistance is a highly heritable trait in which one possesses both versions of the single nucleotide polymorphism (SNP) for the FUT2 gene . The FUT2 gene is located on chromosome 19q13.33 (4). The homozygous genotype for this SNP, in which a guanine (G) is replaced with an adenine (A) base on both homologous chromosomes, introduces a stop codon and causes a lack of function in the FUT2 gene. The FUT2 encodes an enzyme, fucosyltransferase, which synthesizes H type 1 antigen in the intestinal mucosa and saliva (1,3). The H type 1 antigen is the precursor for AB histo-blood group antigens (HBGAs) (4). Therefore, FUT2 determines “secretor status”. If one is deficient in this gene, then they are a “non-secretor”, and will not have the H type 1 antigen or AB antigens in their mucosa or saliva. This “non-secretor status” is also associated with norovirus resistance. The newest research (2011) suggests that a specific norovirus genogroup I genotype I (GI/1) depends on H type 1 oligosaccharide binding to infect the host (1). Therefore, people who do not express H type 1 are not infected by this strain of the virus. Those who are resistant to the norovrius genogroup I are also resistant to genogroup II, the clinically most common virus. 

John Burke's Genetic Profile

John Burke has the genotype AA, as shown in his 23andMe profile. "A" refers to the adenine SNP in the FUT2 gene. Because Dr. Burke has both copies of the A SNP, or rather he inherited the SNP form both his mother and his father, he is homozygous recessive for the SNP. Therefore, Dr. Burke is a non-secretor and the norovirus will not be able to infect his cells. He is resistant to the norovirus, should not become infected by the virus, and, accordingly, never feel the unpleasant symptoms of infection. However, this resistance may not last forever. If the virus evolves and a new strain develops, he may be susceptible to infection. See more information under the New Research section below. 

Ethnic Origin & Family PlanningEdit

Studies have shown that specific polymorphisms have ethnic specificity. A nonsense mutation in the 428th position of the gene is most prominent in populations of European descent whereas a nonsense mutation in the 571st position of the gene is most often seen in people with Pacific Island descent (1). It is estimated that about 20% of Europeans are homozygous recessive for the SNP and are therefore resistant to norovirus infection (3). In addition, capsid protein specificity to different HBGAs suggests a host-pathogen co-evolution (3).

It is important to remember that although you may be resistant to the norovirus, your children may not be. It depends if your partner possesses the trait as well. For this reason, among others, it is important to continue to

A3 JB

Example of 23andMe results for a norovirus resistant patient.

 take precautions. However, one can calculate the chance that a future child is resistant using the principles of Hardy-Weinburg equilibrium . Let's assume that 1 in 5 are resistant to norovirus (q2=20%) and one parent is norovirus resistant and transmitts the A allele (say the mother). The frequency of the A allele is q=0.45 (square root of 1/5) and, therefore, the frequency of the G allele is p=0.55 (p+q=1). The carrier frequency of the population is 2pq=2(0.55)(0.45)=0.50, meaning that the chance the father is carrying the A allele is 50%. The chance that the child will inherit the A allele from both parents is the product of the chance that the mother has the A allele (1) times the chance she transmits it (1) times the chance that the father has the A allele (0.50)  times the chance he transmits it (0.50). Therefore, the chance that the child is norovirus resistant is (1)(1)(0.5)(0.5)=0.25 or 25%.

New Research

Additional research suggests that distinct strains of the norovirus show unique specificity to different HBGAs and, moreover, the norovirus persists in the human population by evolving to bind to different HBGAs. Although this
A3 Receptor

This shows the receptor for the GII.4 norovirus strain. RBD (receptor binding domains) show where interactions occur with HBGA carbohydrates in the host. Purple, pink and yellow sites have changed over the last 20 years of viral evolution. More information can be found here: http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0050031#pmed-0050031-g004

trait appears to be inherited in a Mendelian, highly penetrant fashion in some studies, such as those that 23andMe references, it goes to show that perhaps these SNPs in the FUT2 gene may not confer resistance to all infections of the norovirus (1,3). Phylogenetic analysis of the norovirus have revealed that capsid genes, expressed as viral-like particles (VLPs) on the virus's surface, have changed over time causing the VLP-carbohydrate binding patterns to change as well (5). Therefore, strain specific norovirus susceptibility depends on which alleles a person possesses. In the future, it may be possible that this genotype for norovirus resistance changes, as new viral strains evolve.

23andMe is a great place to start the investigation into one's genetics. However, the most recent publication they reference was published in 2007. There is new (2011) research suggesting that norovirus resistance may also be associated with type 1 diabetes, Crohn's disease, slower progression of HIV and increased susceptibility to Helicobacter pylori infection (4). It may be important to keep this in mind if one already has a predisposition to one of these diseases.

References


1. Kindbal, Elin, Britt Akerlind, et al. "Host genetic resistance to symptomatic norovirus (GGII.4) infections in Denmark." Journal of Clinical Microbiology 45.8 (2007): 2720-22. PubMed. Web. 15 Sep 2013. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1951234/>. 

2. "Noroirus." Center for Disease Control and Prevention. Center for Disease Control and Prevention.. Web. 15 Sep 2013. <http://www.cdc.gov/norovirus/>.

3. "Norovirus Resistance." 23andMe. 23andMe. Web. 15 Sep 2013. <www.23andme.com>.

4. Smith, Deborah, Jason Cooper, et al. "FUT2 nonsecretor status links type 1 diabetes to susceptibility and resistance to infection." Diabetes. 60.11 (2011): 3081-84. Web. 16 Sep. 2013. <http://diabetes.diabetesjournals.org/content/60/11/3081.full.pdf html>.

5. Zheng, Du-Ping, Lisa Lindesmith, et al. "Mechanisms of GII.4 norovirus persistence in human populations."PLOS Medicine. 5.2 (2008): n. page. Web. <http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050031 >.

23andMe References

Le Pendu et al. (2006) . “Mendelian resistance to human norovirus infections.” Semin Immunol 18(6):375-86.

Lindesmith et al. (2003) . “Human susceptibility and resistance to Norwalk virus infection.”Nat Med 9(5):548-53.

Hutson et al. (2005) . “Norwalk virus infection associates with secretor status genotyped from sera.” J Med Virol 77(1):116-20.

Kindberg et al. (2007) . “Host genetic resistance to symptomatic norovirus (GGII.4) infections in Denmark.” J Clin Microbiol 45(8):2720-2.

Thorven et al. (2005) . “A homozygous nonsense mutation (428G-->A) in the human secretor (FUT2) gene provides resistance to symptomatic norovirus (GGII) infections.” J Virol 79(24):15351-5.