Risk factors for developing SLE

What are some risk factors for developing SLE?

As with most autoimmune diseases, SLE probably occurs from a genetic predisposition (two-third of risk) with environmental influences (one-third of risk).

  • a) Environmental: tobacco, viral infection (Epstein–Barr virus [EBV], cytomegalovirus [CMV], and others), silica exposure, ultraviolet (UV) light, pesticides, gut microbiome, and demethylating drugs.
  • b) Genetic: Risk of SLE increases with affected family members, notably first-degree relatives and identical twins. SLE is likely polygenetic which helps explain its varied disease manifestations.
    • • Family aggregation studies show an increased risk when family members have the disease:
      • – Monozygotic twin concordance for SLE: 24% to 35%
      • – Dizygotic twin concordance for SLE: 2% to 5%
      • – First-degree relatives with family history of SLE have a 16-fold increased risk of developing SLE (4%–8%) and a 5-fold increased risk of developing any other autoimmune disease.
    • • Histocompatibility complex (HLA) DR2 ( DRB1∗1501 ) and DR3 ( DRB1:0301 ) increase the relative risk of SLE two to three fold. The presence of these genes may allow more efficient presentation of self-antigens to self-reactive T and B cells.
    • • Complement component deficiencies (C1q, C2, and C4) increase the risk of SLE 5–10-fold presumably due to defective clearance of apoptotic debris and production of interferon (IFN) alpha.
    • • There are a large number of other genetic risk loci (>90) identified in genome-wide association studies that each confer modest risk (odds ratio <2x) for SLE. The non-major histocompatibility complex genes are more likely to be regulatory than effector genes. These include genes involved in aberrant clearance of nuclear material (e.g., CRP, Fc γ receptors IIa and IIIa ITGAM), excessive innate immune activation (e.g., Type I IFNs, IRF5, IRF7, TNFAIP3, TREX1), and abnormal T and B cell activation/signaling (e.g., STAT4, PTPN22, PCDCD1, BLK, BANK1).
    • • It is estimated that it takes 10 to 20 genetic risk alleles to predispose a patient to develop SLE. The more risk alleles a person has, the earlier the onset and more severe the disease will be. Epigenetic effects on the different risk alleles likely account for different disease manifestations and severity.
  • c) Gender/hormonal:
    • • SLE is approximately 10 to 15 times more common in women of childbearing age as than in men. Some predisposing genes are located on the X chromosome (IRAK1, MECP2, and TLR7).
    • • Interestingly, men with Klinefelter’s syndrome (47 XXY) have a 14-fold risk of SLE.
    • • SLE is rare in Turner’s syndrome (XO).
    • • Androgenic medication such as dehydroepiandrosterone (DHEA) has been used to treat SLE.
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