The Role of HLA Genes in Ankylosing Spondylitis, RA, and Lyme Disease

Is There a Genetic Predisposition to These Conditions?

Genetics lab
TEK Image/Science Photo Library/Getty Images

Researchers and scientists are focused on what causes rheumatoid arthritis or what may predispose certain people to the disease. There may be many contributing factors, including environmental factors, genetics, and a triggering event.

Genetics has become a focal point of arthritis research. A major genetic link was discovered back in the 1960's between the gene HLA-B27 and the spondyloarthropathies, a group of diseases affecting the spine and other joints.

  • 90 percent of people with ankylosing spondylitis have the HLA-B27 gene.
  • 7 percent of the general population have the HLA-B27 gene.

During the decade following the discovery of HLA-B27, scientists found an association between carriers of the HLA-DR genes and increased risk of rheumatoid arthritis. It is believed that HLA-DR contributes to autoimmune disease (caused by the immune system going awry and fighting a person's own body). Other genes are suspected of playing a role in the evolution of rheumatoid arthritis.

HLA-DR and Rheumatoid Arthritis

The North American Rheumatoid Arthritis Consortium (consisting of medical centers across the country, established and sponsored by the Arthritis Foundation, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute of Allergy and Infectious Diseases) has been analyzing clinical findings and genetic material from 1,000 pairs of siblings who both have rheumatoid arthritis.

By testing many different genetic regions, researchers hoped to identify specific genes associated with the rheumatoid arthritis.

It was found that, while there is a genetic predisposition to rheumatoid arthritis, it is modest. Studies revealed that among twins, if one twin has rheumatoid arthritis, there is only a 25 percent chance the other twin will develop rheumatoid arthritis.

 Fraternal twins and first-degree relatives of someone with rheumatoid arthritis have a 4-fold risk (2 percent to 5 percent) of developing rheumatoid arthritis compared to the risk that exists in the general population (0.8 percent).

The greatest genetic association which accounts for half of the genetic risk associated with rheumatoid arthritis is thought to be in certain variants of the class II MHC genes. MHC is located on the short arm of chromosome 6. It includes class I, II, and III MHC genes and each of those have immunologic functions.

Class II genes play a role in generating antigen-specific T cell responses. There are specific Class II HLA gene variants (genotypes)—HLA-DR4 and HLA-DR1—which have been linked to and increased risk of rheumatoid arthritis, as well as increased severity of rheumatoid arthritis. But, there are other HLA-DR genotypes which show no connection to rheumatoid arthritis. 

HLA-DR4 and Lyme Disease

The HLA-DR4 genotype, which has been associated with rheumatoid arthritis, has also shown involvement in Lyme disease. Lyme disease is caused by a microorganism which is transmitted to humans via deer ticks.

People who have the disease more severely and do not respond well to the antibiotic treatment are more often found to have the HLA-DR4 genotype.

It has been theorized that once the microorganism moves to the joints, the immune response against it cross reacts with the person's own joint tissue in people who have HLA-DR4, leading to an autoimmune reaction.


Rheumatoid Arthritis: Early Diagnosis and Treatment. Third edition. Page 21 - Immunogenetics. Cush, Weinblatt, Kavanaugh. Professional Communications, Inc.

Kelley's Textbook of Rheumatology. Ninth edition. Elsevier. Chapter 21. Genetics of Rheumatic Diseases. Human Leukocyte Antigen Associations With Rheumatic Disease. 

Lack of replication of interactions between polymorphisms in rheumatoid arthritis susceptibility: case control study. Arthritis Research and Therapy. 2014 Ferreiro-Iglesias et al.

Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi. Infection and Immunity. 1993 Jul; 61(7): 2774–2779.