Genetics of Systemic Lupus Erythematosus 

  • Author: R Hal Scofield, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Jun 20, 2011
 

Overview

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder associated with a wide range of physical findings. The risk of developing SLE is, at least in part, genetic, but it is a complex genetic illness with no clear mendelian pattern of inheritance. The disease tends to occur in families. Siblings of SLE patients have a risk of disease of about 2%. However, even identical twins with SLE are concordant for disease in only 25% of cases and are therefore discordant (ie, where one twin has SLE and one does not) in about 75% of cases.[1]

The major histocompatibility complex (MHC) on chromosome 6, which contains the human lymphocyte antigens (HLA), was the first described genetic link to SLE.[1] The protein products of the HLA genes are critical components of cell-to-cell communication in the immune system. Indeed, in some cases, HLA genes are more highly related to lupus-associated autoantibodies than to the disease itself. Nonetheless, carriage of specific alleles of HLA imparts about a 2-fold risk of SLE above the general population.

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Clinical Implications

Although SLE is generally a complex genetic illness, there are several examples of mutations that can produce a monogenetic form of the illness. Complete deficiency of the early complement components C2, C4, and C1q results in SLE in 75%, 10%, and 90% of cases, respectively.[2] However, complete complement deficiencies are quite rare and account for only a tiny percentage of SLE cases.[3] More commonly, a low gene copy number of C4 is seen as a risk factor for SLE, whereas a high copy number of C4 is protective against SLE.[4]

Sex-chromosome copy number variations are also implicated in the risk of SLE. SLE is about 10 times more common in women than in men. However, men with SLE have 15 times the risk of Klinefelter syndrome (47,XXY) as compared with the average population, and the risk of SLE among men with 47,XXY is equal to that of women.[5] These data suggest that the predisposition of women to developing SLE is related to X chromosome copy number, not to sex.

Genome-wide genetic association studies (GWAS) have been performed in large collections of SLE patients and controls. These genome-wide studies of up to 500,000 single-nucleotide polymorphisms (SNPs) have identified at least 30 and perhaps up to 50 genetic associations for SLE,[6, 7] and replication studies have confirmed these findings, in nonwhite as well as white cohorts.[8, 9, 10, 11, 12]

However, only a fraction of the genetic risk for SLE has so far been identified. Rare alleles and mutations that impart a moderate risk of SLE remain undiscovered and cannot be found by GWAS. Gene-gene interaction is virtually unexplored. Nevertheless, although few of GWAS have identified actual causative alleles that impart risk of SLE, the findings do have common themes.

Many of the genes implicated thus far can be categorized as involved in B lymphocyte activation, apoptosis, or the interferon signaling pathway. Such insight into the genetic pathogenesis of SLE may suggest new therapeutic targets for the disease down the road.[13]

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Contributor Information and Disclosures
Author

R Hal Scofield, MD  Professor, Department of Medicine, Section of Endocrinology, Associate Dean for Clinical and Translational Research, College of Medicine, University of Oklahoma Health Sciences Center; Associate Member, Arthritis and Immunology Program, Oklahoma Medical Research Foundation

R Hal Scofield, MD is a member of the following medical societies: American Association of Immunologists, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American College of Rheumatology, American Diabetes Association, American Federation for Medical Research, Endocrine Society, and Oklahoma State Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

  1. Schur PH. Genetics of systemic lupus erythematosus. Lupus. Dec 1995;4(6):425-37. [Medline].

  2. Walport MJ. Complement. Second of two parts. N Engl J Med. Apr 12 2001;344(15):1140-4. [Medline].

  3. Aggarwal R, Sestak AL, D'Sousa A, Dillon SP, Namjou B, Scofield RH. Complete complement deficiency in a large cohort of familial systemic lupus erythematosus. Lupus. Jan 2010;19(1):52-7. [Medline]. [Full Text].

  4. Yang Y, Chung EK, Wu YL, Savelli SL, Nagaraja HN, Zhou B, et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet. Jun 2007;80(6):1037-54. [Medline]. [Full Text].

  5. Scofield RH, Bruner GR, Namjou B, Kimberly RP, Ramsey-Goldman R, Petri M, et al. Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. Aug 2008;58(8):2511-7. [Medline]. [Full Text].

  6. Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. Feb 2008;40(2):204-10. [Medline].

  7. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med. Feb 28 2008;358(9):900-9. [Medline].

  8. Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet. Nov 2009;41(11):1228-33. [Medline].

  9. Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. Nov 2009;41(11):1234-7. [Medline].

  10. Ito I, Kawasaki A, Ito S, Hayashi T, Goto D, Matsumoto I, et al. Replication of the association between the C8orf13-BLK region and systemic lupus erythematosus in a Japanese population. Arthritis Rheum. Feb 2009;60(2):553-8. [Medline].

  11. Molineros JE, Kim-Howard X, Deshmukh H, Jacob CO, Harley JB, Nath SK. Admixture in Hispanic Americans: its impact on ITGAM association and implications for admixture mapping in SLE. Genes Immun. Jul 2009;10(5):539-45. [Medline]. [Full Text].

  12. Han S, Kim-Howard X, Deshmukh H, Kamatani Y, Viswanathan P, Guthridge JM, et al. Evaluation of imputation-based association in and around the integrin-alpha-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE). Hum Mol Genet. Mar 15 2009;18(6):1171-80. [Medline]. [Full Text].

  13. Perl A. Emerging new pathways of pathogenesis and targets for treatment in systemic lupus erythematosus and Sjogren's syndrome. Curr Opin Rheumatol. Sep 2009;21(5):443-7. [Medline].

 
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