Sunday, January 22, 2006

Genetics and Lupus

Genetics and Lupus
Raphael J. DeHoratius, MD

The most frequently asked question about lupus is, "Is lupus inherited?" The answer to this question is both "yes" and "no"! Genes, those parts of our individual make-up that we inherit from our parents, are important in the development of lupus, but the answer is much more complicated than a simple "yes". Estimates are that from four to six or more genes must be combined for a person to inherit a susceptibility to acquire lupus.

It is nearly impossible to inherit all the genes necessary to develop lupus from a single parent, since an individual's genes come from both parents. This is one very important reason why it is unusual for lupus to occur in multiple generations of a family. If only some of the lupus genes are inherited, a person may not have lupus but may test positive for some of the immunologic tests, such as the antinuclear antibody (ANA).

A positive ANA occurs in up to one third of healthy family members of lupus patients.Genetic information is coded in chromosomes which are located in humans in a tiny part of the center (nucleus) of each cell. Humans have 46 chromosomes, each of which is made up of thousands of genes. Each chromosome is divided into a long and short arm. Most of the important genes in systemic lupus erythematosus are located on the short arm of chromosome #6. The genes on chromosome #6 have many complex functions.

Some regulate complement components (proteins important in acute and chronic inflammation and in the formation of immune complexes). When these complement components are missing, a milder form of lupus, which usually lacks kidney involvement, may develop. Complement genes are important but they are not the whole story in the development of this form of lupus.

For example, many susceptible individuals who lack these genes for complement never develop lupus at all.Another important area on the short arm of chromosome #6 is the HLA (human leukocyte antigen) region. It is located next to the area for complement genes. The HLA area has been very thoroughly studied since it is used to match donors genetically to recipients for organ transplants. it is further divided into smaller regions called HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ. In lupus patients there is an increased frequency of the HLA genes called Al, B8, Dr2, or Dr-3 and DQ1.Associations between genes and diseases such as lupus are established by comparing lupus patients to a normal or "control" population.

Particular HLA markers found in white lupus patients (on whom the majority of studies have focused) have not been shown to be present in black patients or Japanese patients with lupus. The reasons for these differences are not clear. There may be other as yet unknown genes or there may also be important genes on other chromosomes which play a part in making a person susceptible to developing lupus.

The newest research methods now being used to study genetics come from the field of molecular biology. They are redefining the way in which we look at the genetics of disease. When methods of molecular biology are used to study the HLA system in various diseases, we are finding that what looked like a specific HLA type, by our current standard tests, in reality is slightly different and Much more complex. This methodology should lead to new important findings, both in genetics and in lupus.

Another way of studying the genetics of lupus is by looking at families in which lupus occurs in more than one member. Familial cases are reported in approximately 10% of the lupus population. The most thoroughly studied family association is between twins. If one of a pair of identical twins (twins with exactly the same genes) has lupus, the other will develop it more than two thirds (69%) of the time. If a fraternal or non-identical twin (a twin with genes no more similar to his twin than to any other brother or sister) has lupus, the other twin has only a 5% chance of developing it. It is obvious that genetics are important, since the frequency of developing lupus is so much higher in identical twins than in fraternal twins when one of the twins already has lupus.

Genetic factors cannot be the only answers, however, or susceptible identical twins would both develop lupus 100% of the time. Environmental factors, therefore, must also be important. It appears that some people are genetically predisposed to develop lupus but then must be exposed to the proper environmental triggers in order to have the disease.In summary, heredity is involved in the development of lupus but it is rare to have more than one family member who has lupus.

Much is known about the genetics of lupus, yet even more needs to be discovered. It is only through careful family studies using molecular biological techniques that the answer to the genetic riddle of systemic lupus erythematosus and the relationship between heredity and environment will be solved.

=========================================================== This information is for "informational purposes" and is not meant to be used for medical diagnosis. Always consult your physician on matters such as this.

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