More than 40 genes are now associated with risk of lupus. This brief overview describes what remains to be learned and what a future "risk of lupus" algorithm will look like.
We have had great success in mapping the genetic architecture of human lupus. Over 40 genes are now associated with risk of human lupus,1 thanks to the recent implementation of genome-wide screening methods and the ability to assemble large patient sample collections. We can no longer lament that we don’t know any of the factors that cause human lupus; we have a long list of names now.
1. Many genes conferring risk of lupus are now known.
• The HLA locus still represents the strongest population-level risk factor, and many non-HLA polymorphisms have been added to the list.
• Many polymorphisms associated with risk of lupus are in or near genes with known immune system function, which supports our concept of lupus as an autoimmune disease. Many of these fall within molecular pathways classically associated with human lupus, such as type I interferon, T and B cell activation, and pathways involved in apoptosis and cellular debris-handling.1,2
• The next major area of work is to understand how these polymorphisms change the molecular and cellular biology of the immune system to predispose an individual to develop lupus.
2. Both common and rare polymorphisms contribute to disease risk. Our ability to elucidate the genetic basis of the disease continues to evolve as our methods of study and technologies improve.
• Genome-wide screening techniques aim to identify common polymorphisms, and many of these have been associated with human lupus. Many of the risk alleles that have been identified occur in the general population at rates of 30% or more.
• Logically, this tells us that most cases of lupus must be genetically complex, because lupus is relatively infrequent, affecting less than 1% of the population. Clearly none of the common alleles carried by 30% of the population can be “sufficient” in themselves to cause lupus in fewer than one in 100 people. This strongly supports the idea that numerous genetic and other factors are involved in most cases of lupus. Our historical family studies examining the heritability of lupus support this polygenic or complex method of inheritance for most cases.
• However, there are rare forms of lupus in which a single gene results in lupus or a lupus-like disease, following a classical Mendelian pattern of inheritance. Genetic deficiencies of early complement components such as homozygous C1q are strongly associated with lupus. With the expanded use of next-generation sequencing techniques, we are identifying additional rare single gene mutations associated with lupus, such as TREX1, DNASE1L3, and others.3,43. We are still a long way from a complete map, but we understand some of the reasons for the gaps. It is estimated that currently we can explain less than 20% of the inherited liability of lupus. Here are some of our challenges:
• Undiscovered rare risk alleles are not likely to fill the gap completely. While it seems likely that we will continue to add more rare polymorphisms to our list, it seems unlikely that the addition of more rare alleles will contribute to our understanding of overall population risk sufficiently to make up the difference. If an allele is carried by very few individuals, it cannot explain a large proportion of the population risk.
• Interactions between genes that multiply their individual effects upon disease risk (1 + 1 = 20) would help to explain our gap in understanding, but we have not found many strong examples to date.5 Most geneticists believe that gene-gene interactions should exist in many complex diseases, and it would make biological sense, as these risk factors do not exist in a vacuum. So why have we found few of these gene-gene interactions for lupus? Perhaps we need to refine each association to a greater degree. It may be that many of the interacting partners are still undiscovered. Perhaps risk factors come together in complex higher-order interactions that are not as simple as additive or multiplicative.
• Clinical heterogeneity may be another major reason we are unable to explain the inheritance of lupus satisfactorily at the population level. We think it is likely that many combinations of different pathogenic pathways may all lead to one diagnosis we call lupus. If that is so, then the experimental models comparing all lupus cases with non-lupus controls will not work well. (For example, if one risk gene is highly relevant to only 10% of the patients, and not at all relevant to the other 90%, then it will never look like a strong risk factor, because the many patients for whom it is irrelevant will dilute its effect by a factor of 9 to 1.)
4. Many lupus risk genes are linked to autoantibody profiles and molecular disturbances in the immune system, and some of these are associated with clinical manifestations. Our group and others have been exploring the idea that genetic risk factors may be relevant to specific immune system parameters or “molecular phenotypes.” Somewhat surprisingly, when creating subsets of patients for genetic studies, the clinical manifestations of lupus have not generally performed as well as autoantibody profiles, and in general genetic effects on immune system parameters are much greater than those observed upon the overall disease.6,7 Even genes that already demonstrate strong associations in overall case-control studies have shown stronger genetic effects within autoantibody subgroups in many studies.6,8 Other genes are being discovered not using case-control genetics, but rather due to their relevance to a molecular characteristic of lupus, such as high circulating interferon.9,10 And some lupus risk genes are strongly associated with clinical disease features, such as the STAT4 gene and lupus nephritis.11
These studies all support the idea that lupus is highly genetically heterogeneous. While it is still rational to think that the striking clinical heterogeneity observed in lupus will have some genetic basis, it seems that this will not be as simple as genes that go with “rash versus no rash” or “nephritis versus no nephritis”. Genetic influences on these clinical manifestations may play out through various intermediate steps-a complexity that may be preventing us from establishing direct and strong genetic correlations between genes and clinical manifestations.
5. As the field continues to develop, we expect that genetics will be useful in patient stratification and in predicting response/non-response to therapy. Currently, for reasons apparent from the discussion above, the genetic risk factors that are known in lupus are not widely useful in clinical practice. For the vast majority of families in which lupus inheritance does not follow a strong Mendelian pattern, we cannot use genetic markers to identify with reasonable certainty those individuals in whom the condition will develop. While we can test for C1q and early complement component deficiency, tests are not widely available for the other reported single-gene forms of lupus, and these tests would not help families that have their own unique risk polymorphism. Prognostication will continue to improve as the list of markers and, we hope, the number of known gene-gene interactions increases.
Ideally, a future “risk of lupus” prognostic algorithm will include not only genetic markers, but also family history, blood protein markers such as circulating cytokines, and tests for other multimodal biomarkers. Genetics should also contribute significantly to patient stratification in lupus. Because it is likely that different patients have “traveled along different roads” to arrive at lupus, genetic markers could be very useful to define the particular molecular pathways involved in a given patient, predict disease manifestations or severity, and (supplemented with immune system parameters such as levels of circulating cytokines), to predict which targeted therapy will succeed in a given patient.
Given the low cost of genotyping and the striking between-patient heterogeneity observed thus far in lupus genetics, it seems likely that gene panels will be part of our future clinical algorithms in lupus, helping us to define important differences between subgroups within this challenging clinical syndrome.
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2. Kariuki SN, Niewold TB. Genetic regulation of serum cytokines in systemic lupus erythematosus. Transl Res. (2010) 155:109-117.
3. Lee-Kirsch MA, Gong M, Chowdhury D, et al. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet. (2007) 39:1065-1067.
4. Al-Mayouf SM, Sunker A, Abdwani R, Abrawi SA, Almurshedi F, Alhashmi N, et al. Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet (2011) 43: 1186-1188.
5. Hughes T, Adler A, Kelly JA, Kaufman KM, Williams AH, Langefeld CD, et al. Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus. Arth Rheum (2012) 64: 485-492.
6. Niewold TB, Kelly JA, Kariuki SN, Franek BS, Kumar AA, Kaufman KM, et al. IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis ( 2012;71(3):463-8.
7. Salloum R, Niewold TB. Interferon regulatory factors in human lupus pathogenesis.Transl Res. (2011) 157:326-331.
8. Agik S, Franek BS, Kumar AA, et al. The autoimmune disease risk allele of UBE2L3 in African American patients with systemic lupus erythematosus: a recessive effect upon subphenotypes. J Rheumatol. (2012) 39:73-78.
9. Kariuki SN, Franek BS, Kumar AA, et al. Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus. Arthritis Res Ther. (2010) 12:R151.
10. Koldobskaya Y, Ko K, Kumar AA, et al.Gene-expression-guided selection of candidate loci and molecular phenotype analyses enhance genetic discovery in systemic lupus erythematosus. Clin Dev Immunol. (2012) 2012:682018.
11. Taylor KE, Remmers EF, Lee AT, et al.Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genetics (2008) 4:e1000084.