Genetics and Rheumatic Disease

Diseases that happen due to a mutation or normal variation in genes are usually classified as either unifactorial or multifactorial. Unifactorial diseases occur when a mutated gene or pair of genes is passed to a child by one or both parents. For example, sickle cell anemia is a unifactorial disease that happens if the same mutated gene is passed to a child by both parents. If the child inherits one mutated (sickle cell) gene from one parent and a normal gene from the other, the child has "sickle cell trait" but not the disease. However, with other unifactorial diseases, such as Marfan syndrome, the child can receive the abnormal gene from only one parent and inherit the disease, meaning one gene is enough to pass on the disease.

Multifactorial diseases are caused by a complicated interaction of multiple genes and environmental factors such as age, gender, infection, or nutrition. Most diseases like osteoarthritis or adult-onset diabetes are thought to be multifactorial. Because the predisposition to these diseases is caused by several genes, they are also called polygenic diseases. Most forms of arthritis are thought to be multifactorial and polygenic.

Studying twins has proven very helpful in examining the genetic and environmental influences that may cause rheumatic disease. Identical twins have exactly the same genes, while non-identical twins typically have about half of the same genes, like most siblings. Regardless of their genetic background, both identical and non-identical twins usually grow up in the same environment and share similar exposures during childhood. Therefore, a simple comparison of how frequently a disease affects identical versus non-identical twins can provide valuable information about to what extent a disease is influenced by genetic versus environmental factors.

If the disease is unifactorial, both identical twins nearly always will be affected, while a much smaller percentage of non-identical twins will both develop the disease. In multifactorial diseases, the frequency of both identical twins getting the disease is 5 - 70%, and for non-identical pairs, even lower.

Each rheumatic disease has its own cause(s), including a certain genetic background. One of the strongest examples of this genetic influence on a rheumatic disease is the connection between ankylosing spondylitis (AS) and a gene called HLA-B27. Ankylosing spondylitis is an inflammatory arthritis affecting primarily the spine that begins in teenagers and young adults.

More than 90% of Caucasian AS patients have the HLA-B27 gene, compared to the approximately 7% of the general population who carry this gene. This means only a small portion of the general population (approximately 5%) who carries the gene will develop the disease.

On the other hand, first-degree family members (parents, siblings and children) of AS patients with the HLA-B27 gene have a 20 percent chance of developing the disease. This is probably because they are also exposed to the same environmental factors as the patient and have inherited certain other important genes in addition to the HLA-B27 gene. ARTS 1 and IL23R are two newly identified non-HLA B27 susceptibility genes for ankylosing spondylitis.

Rheumatoid arthritis, a multifactorial disease, is a common type of inflammatory arthritis which affects many joints and occurs in approximately 1% of the population worldwide. In this case, the gene link with rheumatoid arthritis is to an immune system gene called HLA-DR4. In rheumatoid arthritis patients of European ancestry, as many as 60 - 70% carry the HLA-DR4 gene, compared with 30% in the general population.

Twin studies show that 12 - 15% of identical twins both develop rheumatoid arthritis compared to only 4% of non-identical twins. Further, the disease rate in the parents, siblings and children of rheumatoid arthritis patients is only 0.8% compared to 0.5% in the general population. This indicates that genes only slightly increase the risk for rheumatoid arthritis and that the environment factors (age, gender, etc.) are likely to play a stronger role. Recent studies have indicated a relationship between smoking and DR4 that leads to an increased rheumatoid arthritis risk.

Lupus (systematic lupus erythematosus) is a chronic inflammatory disease that can affect skin, joints, kidneys, lungs and/or other organs of the body. A study showed 8 percent of patients with SLE had at least one first-degree family member (parents, siblings and children) with the same diagnosis compared to 0.08% of the general population. This suggests SLE recurs to a modest degree in families.

A twin study showed that SLE recurs in the other sibling in 24% of identical twins and 2% non-identical twins, implying both genetic and environmental factors are important. Researchers have identified multiple gene alterations that contribute to a modestly increased risk for this disease.

It is thought that a combination of these genes leads to development of systemic lupus erythematosus.

Osteoarthritis (OA) or degenerative joint disease (DJD) is the most common type of arthritis. OA and DJD are not autoimmune diseases, and thus are unlikely to share the same genes as ankylosing spondylitis, rheumatoid arthritis, or systemic lupus erythematosus. In a study comparing identical to non-identical twins, an identical twin had a two-fold higher chance of developing OA of the hand or knee if the other twin had the same disease. This indicates that genetics may play an important role in the development of OA or DJD.

Another study investigating the role of genetics in hand OA showed that sisters of women with this disease had a two-fold increased risk of developing hand OA when compared to the general population. This risk was increased by five- to seven-fold if the diseased sibling had severe disease. Certain gene mutations have been linked only to a particular site of OA (e.g., knee, hip or hand) implying that each site might have its own genetic basis.

These recent findings about the genes contributing to the many forms of arthritis are leading to new knowledge about their cause that could potentially lead to new treatment strategies in the future.

The immune system protects us from harmful germs, but can become redirected and attack various parts of our own bodies. This creates a biological basis for autoimmune diseases. Rheumatoid arthritis and SLE along with a variety of other diseases, such as scleroderma, Sjögren’s syndrome, thyroid disorders, multiple sclerosis, and juvenile diabetes mellitus, belong to this group of “autoimmune diseases.”

Frequently, multiple and different autoimmune diseases are observed in the same families. As examples, 11% of SLE patients have one other relative with an autoimmune disease in their family indicating these diseases may share some of the same susceptibility genes. Recent technological advances have enabled a more comprehensive examination of the genetic basis of rheumatic diseases. Supporting the notion of common genetic basis, these studies have revealed that the same immune system genes, like PTPN22 and STAT4 are linked to different autoimmune diseases, including SLE, scleroderma, and rheumatoid arthritis.