Kathleen E. Sullivan, M.D., Ph.D.

A reprint from the Lupus Foundation of America Lupus News
(Originally appeared as a two part series )
Volume 19, Number 4, Fall 1999
Volume 20, Number 1, Winter 1999-2000

• Multiple genes involved in lupus
• Lupus varies in populations
• Lupus affects populations differently
• Genetic studies evaluate lupus families
• Identifying specific genes
• Defective complement genes found in every population
• MHC genes
• Cytokine genes
• Conclusions

It has been known for more than 20 years that the inheritance pattern of systemic lupus erythematosus (SLE) is complex. Studies on identical twins, where one of the twins has SLE, have shown that anywhere from 24 to 69 percent of the time, the second twin will have or will develop the disease. This suggests not only that inheritance plays a significant role in the development of SLE, but that other factors are important as well.

If genetics were the sole basis of the disease, both identical twins either would always have the disease or would not have the disease. Instead, it has been found that, for first-degree relatives of people with SLE, the risk of them developing SLE in their lifetime is about three percent. While this number is fairly low, it is much higher than the risk to the general population. The type of inheritance where a disease runs in a family, but has no direct inheritance pattern, is called polygenic. This reflects the belief that the genetic susceptibility is due to multiple genes, and that a certain threshold of genetic susceptibility must be reached before an external process is capable of triggering the disease. Many of the best known examples of polygenic inheritance occur in the rheumatic diseases.

Lupus varies in populations

Because the precise genes involved in the genetic susceptibility may vary from population to population, it is not surprising that the incidence of SLE varies in populations. In both Sweden and Iceland, the prevalence rates are 36 per 100,000 people. In Great Britain, the prevalence of SLE among Asian people is 40 per 100,000; for Caucasians, it is 20 per 100,000 people.

In the United States, the total prevalence of SLE is between 24 and 100 per 100,000 people. For Caucasian women between the ages of 15 and 64, the prevalence is one per 700 women. For African-American women between the ages of 15 and 64, the prevalence is one per 245 women. In each case the prevalence among men is approximately 10-fold lower. This prevalence rate for African-American women makes SLE one of the most common chronic diseases of this population.

Interestingly, SLE is felt to be rare in Africa. This suggests two possibilities: that there are environmental risk factors which are more common in the United States and Europe, compared to Africa; or that the mingling of ancestral African genes with Caucasian genes has resulted in an increased genetic susceptibility to lupus.

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Lupus affects populations differently

Not only is the prevalence different in different populations, but the natural history is different in different populations. This is also consistent with the idea that different combinations of genes play a role in the genetic susceptibility in different populations.

In a very general way, African-Americans with SLE and Asians with SLE have more aggressive disease. There is a broad range of severity of SLE in every ethnic group, but African-Americans and Asians have significantly more active disease as a population. Hispanics with SLE are more likely to have kidney involvement or cardiac involvement than Caucasians or African-Americans; while Caucasians are more likely as a population to have skin involvement and platelet destruction.

Genetic studies evaluate lupus families

There are several ongoing studies trying to directly identify the genes involved in SLE. High recruitment numbers are important as large numbers of people with the disease are required to perform these types of analyses.

Generally in these types of studies, families with more than one affected member are used. Many small pieces of DNA are taken from each of the chromosomes from each family member. These pieces then are amplified (increased in number) and characterized using a method called PCR (polymerase chain reaction). Statistical analyses are then used to compare the pieces of DNA from the affected family members and the unaffected family members. The idea is that if a particular gene is involved, the affected family members should share that segment of the chromosome containing the relevant gene.

When many families are evaluated, specific regions of the chromosome can be identified as being involved on a population basis. Doing this type of study is extremely labor-intensive but has been very revealing. More than 100 genes now are thought to be involved in the genetic susceptibility of SLE. It also is quite clear that the specific genes are indeed different in different ethnic groups.

Some of the chromosomal regions identified in these analyses have been implicated in other autoimmune diseases such as psoriasis (a skin disease) and Crohn's disease (a gastrointestinal disorder). This suggests that some genes predispose to autoimmunity in a general way.

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Identifying specific genes

The type of study described above defines regions of chromosomes that appear to be linked to the development of SLE. Sometimes a specific gene is identified through this type of study, but more often another type of study is performed to look for the specific gene within that region.

The Human Genome Project has produced a map of the locations of 50,000 genes on the individual chromosomes. This study was undertaken to identify all of the human genes and is approximately one-third complete. (There are two excellent Web sites describing this fascinating and important work: www.nhgri.nih.gov/HGP/and www.ncbi.nlm.nih.gov/genome/guide/). When a chromosome region is identified as being important in SLE, it sometimes is possible to go to the map and pick out a gene that seems likely to be involved in SLE, based on its function and chromosomal location.

Other times, genes are suspected of being involved in the development of SLE purely because of their function. One common type of study is to look for a genetic variation in a gene that is thought to be involved in SLE, and then to define the frequency of that genetic variation in an SLE population and a control population. If that variation is important in the development of SLE, it will be found more frequently in the SLE population compared to the control population.

Studies like these are very powerful in identifying genetic susceptibility factors, but they cannot reveal unknown genes. To perform the study the gene must already be known and the variation have been recognized. This is in contrast to the family studies which can identify new genes.

Defective complement genes found in every population

Genetic variations in the complement genes that direct the removal of antibody complexes have been identified in all ethnic groups examined-African-American, Asian, Hispanic, and Caucasian-although the specific genes often vary from group to group. This is not unexpected, since one of the hallmarks of SLE is antibody complexes being deposited into the kidneys and skin. Sometimes this occurs because the complement genes are not functioning to remove the antibody complexes efficiently. Therefore, defects in complement genes predispose to the depositing of antibody complexes and to SLE.

The most common type of defect is C4A deficiency. C4A is the name of one of the complement genes. Although C4 deficiency is found in all ethnic groups examined thus far, the exact defect leading to C4A deficiency has been different in different ethnic groups.

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MHC genes

Another family of genes where many ethnic-specific differences are found are the major histocompatibility complex (MHC) genes. These genes mold the body's immune response to any particular foreign agent and determine our ability to recognize an infection as foreign, requiring an effective immune response. The specific autoantibodies produced by any individual with SLE are determined by their MHC genes.

Because genetic variation (polymorphism) is very high in MHC genes, different ethnic groups have very different MHC gene mixtures. MHC genetic risk factors have been identified in Asian, Hispanic, African-American, and Caucasian populations. In each case the specific genes are different and are associated with a different autoantibody profile. In some cases, these genes are associated with a different natural history, as well. One example is the presence of the HLA-DQB1*0201 MHC gene that predicts more aggressive SLE in African-Americans.

Cytokine genes

The last well-characterized group of genes to be evaluated in this way are the cytokine genes. These genes produce hormones that allow the cells of the immune system to talk to each other. Some of these cytokines are predominantly involved in inflammation; others regulate the production of antibodies; and still others are more directly involved in defending against infection.

One of these hormones, called TNFa (TNF alpha), plays an important role in the inflammatory response. A particular genetic variation of this hormone, associated with an inherited ability to make too much TNFa , is seen with increased frequency in African-American and Caucasian people with SLE.

Many other genetic variations in cytokine genes have been discovered, but have only been evaluated in Caucasians thus far. The next few years should bring information on additional ethnic groups to the forefront.

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Conclusions

• The recognition that genetics plays a role in the development of SLE has led to an aggressive search for the specific genes through two strategies-the family studies and the studies designed to show disease association on a population basis. However, these two types of studies have complementary approaches.
• Although genetic studies are in their infancy, it is clear from both strategies that there are significant differences in the genetic susceptibility to SLE in different populations. These analyses also have demonstrated the enormous complexity of the development of SLE.
• Once the power of the genetic analyses is correlated with the differences in the disease symptoms in different populations, we may have the ability to identify particular individuals as belonging to a specific subgroup with a predictable disease course.
• Understanding the genetics of SLE also should lead to more specific therapeutic interventions.
  • For example, recognizing that defects in immune complex clearance genes are fairly universal has led to the clinical trial of a synthetic immune complex clearance strategy, which has been a very effective therapy.
  • Similarly, the finding that one of the immunological hormones is overproduced, due to inherited gene variations, has led to a clinical trial of a blocking agent. In this case, antibodies to the hormone IL-10 were used for brief periods in the SLE group, and significant improvement in skin lesions were seen.

Kathleen E. Sullivan, M.D., Ph.D., is an Assistant Professor of Pediatrics and practicing physician in the Division of Immunologic and Infectious Diseases at The Children's Hospital of Philadelphia, PA. In 1997 Dr. Sullivan was the recipient of a two-year research grant from the LFA for her project entitled, "Partial early complement component deficiency in SLE."

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© 1999-2000 Lupus Foundation of America, Inc. All rights reserved. No material in this issue may be copied or published without the express written consent of the Lupus Foundation, Inc.

Related Information
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Clinical Trials: List of contact information for genetic and other ongoing lupus research studies.