This site is intended for healthcare professionals as a useful source of information on the diagnosis, treatment and support of patients with lupus and related connective tissue diseases.

Introduction

There is no doubt that lupus runs in families suggesting a genetic contribution to the disease. Family members of a patient with lupus have an estimated 3-10% chance of developing the disease themselves although, frequently, it is not lupus that develops but another connective tissue disease such as Sjögren's Syndrome or MCTD. Amongst identical twins the risk of lupus rises to 25%. The fact that the penetrance is not 100% suggests strongly that factors other than genetics are important in the development of the disease. Such factors could be either environmental or random. Random genetic events include recombination of T cell receptor and immunoglobulin genes which may contribute to the pathogenesis of the disease. This theory would be concordant with the observation that most twin studies have shown that the time of onset of disease can vary enormously between identical twins even though they effectively have identical genetic makeup and are exposed to the same environmental agents. The genes which are now known to be important in predisposing towards lupus are the DR genes, the complement genes, the X chromosome and race.

DR Genes

The DR genes are a set of polymorphic sequences located on chromosome 6. They are critically important in presenting antigen to responding T cells and there is now increasing evidence that different DR genes have particular preferences for different antigens.A number of epidemiological studies have examined associations between DR and lupus and all are agreed that DR2 and DR3 are increased compared to the general population.The reason for this association is not clear. Work from the late '70s has suggested that patients who are DR3 positive, in particular, have defective clearance of immune complexes, although more recent work suggesting a specific binding of individual peptides of autoantigens may be more important.

Complement

Complement has a central role in the pathogenesis of lupus. Patients with homozygous complement deficiencies have a very high frequency of lupus. For example, lupus or lupus-like syndromes occur in 80% of patients with total C1q deficiency, approximately 60% of those with C2 deficiency and about 30% of patients with C4 deficiency. Although the risk of lupus in patients with complement deficiency is high, C1q deficiency and C2 deficiency is extremely rare, with less than 100 patients with each being described in the world literature. Thus, it is extremely unlikely that the average patient will have a "knockout" for one of these genes. The role for complement deficiency in the pathogenesis in lupus has now been clarified by the "garbage disposal hypothesis". This hypothesis is based on the observation that complement components are important in the clearance of material from apoptotic or necrotic cells. Cell death results in the exposure of nuclear antigens, including DNA, nucleosomes and ribonuclear proteins, to the immune system.Therefore, the characteristic pattern of autoimmunity in lupus (antinuclear antibodies) is due, at least in part, to the failure to remove nuclear antigens due to the defective removal of cellular "garbage".

Other clearance mechanisms including DNAse and C-reactive protein are also defective in patients with lupus and the genetic basis for these has been demonstrated in animal models. Complement is also important in the clearance of immune complexes which themselves are thought to be involved in the pathogenesis of disease. The complement gene, C4, has two different loci, C4a and C4b. Absence of one of the loci, C4a, is quite common in the healthy population and is considerably more common in patients with lupus. However, those who lack this gene on one chromosome almost always have it on the other. In addition, any patients with C4a deficiency are likely to have both copies of C4b, so true C4 deficiency is extremely rare. The C4a null gene, however, is more common in lupus compared to the normal population though this may be because the C4 loci also lie on chromosome 6 and C4a null is in linkage disequilibrium with DR3.

Female sex

Lupus is approximately 9 times more common in women than men, though evidence suggests that this is due to an indirect effect associated with sex hormones rather than the presence of two X chromosomes. Lupus is uncommon before the menarche and, in most cases, also relatively mild when it occurs postmenopausally. Both in vitro and work in animal models suggest that estrogens, in particular, have a pro-inflammatory effect and are liable to make lupus worse, whereas the opposite is observed with androgens and, to a lesser extent, progesterones. Apart from conferring risk, the implication of this is that hormone replacement therapy (HRT) and oral contraceptives should be used with extreme caution with patients with lupus, though some recent studies have suggested that HRT is safe in patients with late onset disease. It is also possible that progesterone-only pills have a weak therapeutic effect providing they are tolerated.

Ethnic groups

Lupus is approximately 4 times more common in Afro-Caribbeans than in Western Caucasians. Precise figures are not available but it is likely that the same holds for Oriental races, particularly those derived from equatorial islands such as the Philippines and the Seychelles. In contrast to this, the frequency of lupus in rural Africa is reported to be low with a higher frequency in urban African populations. This is now thought to be due to interbreeding between different races, which has occurred particularly on tropical island populations, which result in a mixture of different risk factor genes being aggregated into the same population.

Conclusion

Although much remains unknown about genetic factors predisposing to lupus, there is no doubt that it is a polygenic rather than monogenic disease. As a rare disease, its relative risk is increased when there is an affected member of the family. However, it is still not considered worthwhile to screen all family members for evidence of lupus, particularly as some studies have shown that unaffected family members can be antinuclear antibody positive, in which case screening tests are difficult to interpret.Nevertheless, the familial tendency is such that any manifestations which could be interpreted as being due to lupus should be taken seriously and it should be considered as a possible diagnosis if another family member is affected. It is always worthwhile seeking a family history of other autoimmune diseases which may or may not be related to lupus. Sjögren's Syndrome is strongly associated with lupus and organ specific autoimmune diseases, such as thyroid disease and diabetes, are more common in families with lupus, probably because they are also associated with the DR3 gene.
In conclusion, family history of lupus or other autoimmune diseases, including organ-specific disease, should point the clinician towards lupus in the patient with the realisation that it is not, as such, genetic but a disease in which risk factors are inherited.

Prof Patrick Venables
Kennedy Institute of Rheumatology
1, Aspenlea Road
Hammersmith
London, W6 8LH