Lupus (genetics)

In the article below lupus may sometimes be referred to as SLE (Systemic Lupus Erythematosus).

Around one in 3 of all identical twins with lupus have a twin who also has lupus. With non-identical twins it is 1 in 20. This indicates that the genes can play a significant role. Experts in the field currently think that more than 30 genes could play a role.

Does the genetics of lupus help us?

Understanding more about the genes that are associated with lupus can help us in a number of areas.

  1. Knowing the risk of getting lupus. Some changes to particular genes carry much more risk than others.
  2. Knowing which side effects of lupus you are most likely to develop.
  3. Understanding which drugs are likely to be most effective in controlling your lupus.

From an alternative medicine perspective the knowledge of which genes and therefore which immune pathways are most affected could help with the development of an optimised diet and lifestyle plan.

Below is an analysis of some of the areas of the immune system that are affected by lupus.

Immunological effects of lupus:

Problems clearing damaged cells

Proper clearance of dead and damaged cells from the immune system is known as apoptosis or programmed cell death. In people with lupus this apoptosis is defective, leading to something called cell necrosis. Cell necrosis, unlike apoptosis leads to cells spewing their contents out into the blood, including the self-reactive antigens that can cause lupus. There are at least two genes that are associated with this problem, and that may be altered in people with lupus.

Chromosome 1

Genes called FCGR3A and FCGR3B are found on this chromosome. They code for IgG antibody receptors that clear immune complexes (containing IgG molecules) from the blood. People with lupus can have problems with these genes that mean that they don't have the IgG receptors they need to clear immune complexes from their blood. The immune complexes get trapped in tissues causing the symptoms of lupus. 

Chromosome 16

The ITGAM gene on chromosome 16 codes for a protein called an integrin. The integrin in question helps white blood cells stick to the inside of blood vessels and dispose of damaged apoptotic cells. In European and African lupus patients this gene can have an altered base, leading to fewer white blood cells that can remove apoptotic cells from the blood vessels. This leaves more apoptotic cells to degrade by necrosis, creating inflammatory cytokines to damage blood vessels. This particular gene is associated with a greater incidence of kidney and neural problems in lupus patients.

Problems tagging proteins for destruction

The proteins produced by our genes are controlled in many ways. One way is by tagging them for destruction if there are too many of them. Pictured is a protein in green which is tagged by a tail of pink ubiquitin molecules. The whole assembly is then recognized and transported to a cylindrical proteasome in which it is broken up. This process is called ubiquitination, and in lupus it is quite common for this process to operate incorrectly.

Failure of ubiquitination in SLE seems to affect a protein called NF-kB (nuclear factor kappa B). This protein helps cells survive for longer. If the cell in question is a white blood cell that releases inflammatory chemicals then damaging symptoms may result. There are 3 known genes that affect this process, that have also been linked to some cases of lupus.

Chromosome 5

On chromosome 5 there is a gene called TNIP1 which helps damp down the effects of TNFAIP3 (see below).

Chromosome 6

The TNFAIP3 gene is stimulated into action by tumour necrosis factor - TNF. It produces a protein, the enzyme A20, that helps tag proteins for destruction (ubiquitination). It also inhibits apoptosis (see section above).

Chromosome 22

A gene called UBE2L3 codes a protein that attaches ubiquitin to proteins, enabling their destruction or transformation. In particular it helps transform a protein that becomes NF-kB (nuclear factor kappa B). NF-kB is a protein that controls gene activities that affect interferon levels. It has been found that this gene is more active in some lupus patients leading to increased levels of NF-kB, and potentially more inflammation due to increased levels of interferon and other cytokines(3).

Problems with white blood cell development

There are various types of white cells that protect us from infection. In particular one major type called lymphocytes come in two types, B and T. With SLE there is often a problem with the development of T lymphocytes, which fail to reach the correct part of the body and end up releasing more inflammatory chemicals than they should.

Chromosome 7

A gene called IKZF1 controls the development of white blood cells in the bone marrow. Variation in this gene in some SLE patients leads to an aggressive form of lupus in which proteins produced by the gene, increase production of some white blood cells. This can in some cases cause acute lymphoblastic leukaemia or Non-Hodgkin's Lymphoma to add to the burden of lupus.

Another gene on chromosome 7 called MAFB also affects white blood cell development. It codes for a protein called ETS1 that controls T cells called Th17. Th17 cells regulate other T cells. A lack of ETS1 as a result of faulty MAFB genes in lupus means that regulation of T-cells is lacking. 

Problems with B-cells

B-cells are white blood cells that produce antibody, to fight pathogens in our blood and lymphatic system. In SLE these B-cells are often over active, producing antibodies that attack our own cells and releasing inflammatory chemicals.

Chromosome 1

The NCF2 gene produces a protein called neutrophil cytosolic factor 2 that forms part of NADPH oxidase, an enzyme that is thought to increase the production of free radicals inside B-cells leading to increased levels of activation.

Chromosome 4

A gene called BANK1 is responsible for a protein that increases calcium levels in activated B-cells. As a consequence of the increased calcium, the B-cells remain in an activated state for far longer than normal.

Chromosome 8

Genes called BLK and LYN appear to react with BANK1 proteins and enhance the responsiveness of B-cells to BANK1 and thus activate them further.

Problems with T-cells

T-cells are white blood cells that help eliminate pathogens that are attacking our tissues, and stimulate other cells to fight infection. There are various types of T-cells and with SLE, regulation and survivability of these T-cells is altered, leading to inflammation and tissue damage.

Chromosome 1

A gene called PTPN22 is found here. It produces a protein called LYP, that calms down T-cells. In SLE patients the gene may be changed and there is conflicting evidence as to whether this causes hyperactive T-cells and consequent inflammation or less active T-cells(4).

Another gene called TNFSF4 on chromosome 1 creates the protein OX40L, which is displayed on the surface of immune system cells called APCs. These APCs stick to T-cells displaying the OX40 protein increasing their activity level. In SLE more OX40L may be produced, leading to reduced activity of T regulatory cells, and greater interaction between APCs and T-cells, both of these effects increasing T-cell activity.

Chromosome 2

A gene called STAT4 is found on this chromosome. It codes the STAT4 protein that helps the Th1 T-cell clear foreign invaders from the body. With SLE patients this gene is sometimes overactive, leading to an increased release of interferon. Increased interferon is associated with lupus nephritis, (kidney inflammation).

Problems with Interferon

It is reported that more than half of people with SLE have problems with excess levels of interferon. This is an anti-viral chemical that can produce a lot of inflammation. It helps activate B and T-cells and sustain their activities. This increased level and persistance of immune system activity increases inflammation and tissue damage.

Chromosome 2

A gene called IFIH1 on this chromosome produces proteins called "DEAD box" that alter the structure of RNA - ribonucleic acid. These DEAD box proteins also sense excess RNA levels and as a result respond by triggering interferon release. In SLE more DEAD box proteins are produced leading to higher interferon levels and more inflammation.

Chromosome 7

IRF5, a gene on this chromosome, produces Interferon Regulatory Factor 5. This IRF5 protein regulates levels of interferon and other immune system chemicals. In SLE it seems that this regulatory factor does not do its job properly leading to increased levels of interferon.

Chromosome 19

The TYK2 gene codes for a protein called a Janus kinase, which helps to make some cells more sensitive to the effects of interferon. In SLE it is also associated with increased levels of inflammatory T-cells and interferon.

Other genes associated with lupus

Chromosome 1

Another gene called CRP (C-reactive protein) is found here. It sticlks to microbes and damaged cells allowing cells from our immune system to mop them up via phagocytosis. 

Chromosome 6

Chromosome 6 contains what are called the Human Leucocyte Antigen (HLA) genes, which can belong to one of three classes. Class II genes typically create receptors for white blood cell surfaces. These receptors interact strongly with other components of the immune system. Their strength of association with lupus depends on your ethnicity. Class III genes typically create proteins that are used to attack invading microbes and remove the immune complexes that are formed in lupus.

A version of the HLA-DRB1 gene, called 0301, which only about 3 in every 1,000 people have, makes an antibody called anti-ro. This antibody attacks the nucleus of our cells. Another antibody called anti-la is sometimes involved, often when lupus is present in newborns (neonatal lupus) or when lupus is present with another autoimmune disease called Sjogren's syndrome. Another version of this gene called 1501, makes an antibody called anti-sm. This is present in about 1 in 5 of all lupus patients. It could be induced by having suffered previously from glandular fever (Epstein Barr virus).

Between gene PRDM1 and ATG5 is a part of the DNA that is often changed in people with lupus. Both neighbouring genes may be affected by the change, with PRDM1 increasing B-cell propagation, leading to production of more lupus like auto-antibodies (those that attack our own tissues). ATG5 encourages cells to consume their own organelles, and consequently produces more inflammatory cytokines such as interferon-a and NF-kB(6). 

Chromosome 10

The MBL2 gene (mannose binding lectin) codes for a protein that sticks to invading microbes and allows cells from our immune system to mop them up (phagocytosis). In lupus a change in ths gene is associated with increased risk(7).

Chromosome 11

Between gene PDHX and CD44 is a part of the DNA that is often changed in people with lupus. The change is small consisting of 2 single nucleotide replacements. It appears that this change may affect the neighbouring gene CD44, which produces interferon-y, an inflammatory chemical that can worsen symptoms(8).

Chromosome 16

The APRIL/TNFRSF17 gene codes for a tumour necrosis factor (TNF) receptor that allow white blood cells called B-cells to survive for longer and controls their proliferation. In a study with Japanese lupus patients there were 91% with a particular version of this gene. However this gene version was also present in 80% of the Japanese population, so its significance doesn't seem that great.

Chromosome 22

The BAFF gene is similar to the APRIL gene, but probably more closely associated with lupus. The BA in BAFF stands for B-cell activating, and so this gene creates a TNF receptor that helps B cells to survive for longer. In the case of lupus this means that more white blood cells can attack their system as they survive for longer in the blood.

References

1) http://arthritis-research.com/content/14/3/211 Review of genetics in lupus

2) http://ghr.nlm.nih.gov/BrowseGenes 

3) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411915/ ubiquitination rates affecting lupus

4) http://www.nature.com/ng/journal/v37/n12/full/ng1673.html T-cells affected by the gene PTPN22

6) http://www.ncbi.nlm.nih.gov/pubmed/21622776 Intergenic risk locus between genes PRDM1 and ATG5 on chromosome 6

7) http://www.ncbi.nlm.nih.gov/pubmed/21510992 MBL gene and risk of SLE from chromosome 10.

8) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014359/ Intergenic risk locus between genes CD44 and PDHX on chromosome 11