Good afternoon! Today we’re gonna talk about the role of genetics in immune disorders in general, and Allergy in particular. This topic timely one as recently a new gene was discovered[1] that is related to many functions in the immune system (and by extension messed-up versions of it are correlated to many diseases). This is the third part of a series exploring immunology and immune disorders. If you’re interested, feel free to check out parts 1 – Overview of the immune system and 2 – Allergy, Hypersensitivity and Tolerance.

Many studies have been conducted now looking at the role of genetics in autoimmune disorders, and have found that in all cases genes played a role in predisposing the individual to that disease, but environmental factors set it off. For instance in the case of Multiple Sclerosis (an autoimmune disorder where the body attacks the myelin in neurons), twin studies showed that if one identical twin has MS, the other twin has a 25-30% chance of getting MS, whereas if they are non-identical twins that chance goes down to 6%[2].

Studies where a group with and without a disease have had their genes sequenced, and scientists looked for genes that appear more frequently in the afflicted population. If one gene sticks out as overwhelmingly influential, it is considered monogenic. Most immune disorders are polygenic. Once the gene(s) most likely to appear exclusively with the afflicted population are discovered, Scientists can sequence specifically the active DNA in a particular cell type to identify if the gene is exclusive to the function of, say, a B cell (maybe it’s a protein involved in the construction of antibodies). Furthermore, individual genes are studied by taking mice and engineering them so that gene no longer functions, and seeing how things break.

Studies where the entire genome is sequenced are called Genome-Wide Association Studies (GWAS for short). While they have been a powerful tool in discovering genes, there are a few limitations. One such is the fact that many of the loci associated with disease are non-coding regions[3]. It also stands to reason given the vast number of genes being analyzed that false positives could randomly occur, especially when assessing genes that have a small positive correlation with the disease. The response to address that seems to be to increase the sample size of humans sequenced. Here[4] is a study in which 14,000 genomes were used.

Of the genes discovered, genes associated with the cell surface receptors associated with recognition of antigens and presentation within the adaptive immune system play a much larger role in autoimmune disorders[5] (also see MHC). Outside of those genes, several others have been discovered. According to X and Y in “Cellular and Molecular Immunology”:

“PTPN22. A variant of the protein tyrosine phosphatase
PTPN22, in which arginine at position 620 is replaced
with a tryptophan, is associated with rheumatoid
arthritis, T1D (Type 1 Diabetes), autoimmune thyroiditis, and other
autoimmune diseases. The disease-associated variant
causes complex signaling alterations in multiple
immune cell populations. Precisely how these changes
lead to autoimmunity is not known.”

The book goes on to list several other examples. Here’s another that stood out:

“Insulin: Polymorphisms in the insulin gene that
encode variable numbers of repeat sequences are
associated with T1D. These polymorphisms may affect
the thymic expression of insulin. It is postulated that
if the protein is expressed at low levels in the thymus
because of a genetic polymorphism, developing T cells
specific for insulin may not be negatively selected.
These cells survive in the mature immune repertoire
and are capable of attacking insulin-producing islet β
cells and causing diabetes.”

Among the autoimmune diseases, there are known genes correlated with Rheumatoid Arthritis, Type I Diabetes, SLE (Systemic Lupus Erythematosus), Multiple Sclerosis and many others. And oddly enough, here is a paper suggesting a correlation between certain genes associated with immune disorders, suggesting that they are associated with psychiatric disorders as well[6].

Some GWA studies have been done regarding food allergy, one cited risk is the self-reported nature of many food allergies and the variability of the symptoms, nonetheless here is a study that performed genome-wide analysis on 523 cases of food allergy and 2682 controls. Two of the genes most significantly associated with Peanut Allergy involve fillagrin, a protein responsible for binding keratin in the skin[7]. They also found this correlates with Hen’s egg and Cow’s Milk allergies. Additionally they found regulatory, non-coding DNA correlated with the hen’s egg and cow’s milk allergies, and cataloged hundreds of single-nucleotide polymorphisms(variants of a gene where a single nucleotide is changed) associated with each disease. Given the sheer number of associated genes, I’m starting to understand why there’s no cure for this yet.


1 = New Gene Discovered regulating Cytokine 6, involved in Cancer, Diabetes and Inflammatory disorders:
Genetic basis of autoimmunity – Alexander Marson, 1,2 William J. Housley, 3 and David A. Hafler 3,4 – The Journal of Clinical Investigation – June 2015 –
2 = Cellular and Molecular Immunology (page 433)
3 = Systematic Localization of Common Disease-Associated Variation in Regulatory DNA –
4 = Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls –
5 = Cellular and Molecular Immunology (pages 342-346)
6 = Pervasive pleiotropy between psychiatric disorders and immune disorders revealed by integrative analysis of multiple GWAS –
7 = Genome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy –