A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus

• Published in: Genes and immunity Vol. 13; no. 5; pp. 380 - 387
• Main Authors: Wang, S, Adrianto, I, Wiley, G B, Lessard, C J, Kelly, J A, Adler, A J, Glenn, S B, Williams, A H, Ziegler, J T, Comeau, M E, Marion, M C, Wakeland, B E, Liang, C, Kaufman, K M, Guthridge, J M, Alarcón-Riquelme, M E, Alarcón, G S, Anaya, J-M, Bae, S-C, Kim, J-H, Joo, Y B, Boackle, S A, Brown, E E, Petri, M A, Ramsey-Goldman, R, Reveille, J D, Vilá, L M, Criswell, L A, Edberg, J C, Freedman, B I, Gilkeson, G S, Jacob, C O, James, J A, Kamen, D L, Kimberly, R P, Martin, J, Merrill, J T, Niewold, T B, Pons-Estel, B A, Scofield, R H, Stevens, A M, Tsao, B P, Vyse, T J, Langefeld, C D, Harley, J B, Wakeland, E K, Moser, K L, Montgomery, C G, Gaffney, P M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2012; Nature Publishing Group
• Subjects: 631/208/205; 631/208/2490; 631/208/457/649; 692/699/249/1313/1613; Alleles; Arthritis; Asian People - genetics; Autoantibodies; Autoimmune diseases; Autoimmunity; Biomedical and Life Sciences; Biomedicine; Black or African American - genetics; Cancer Research; Cell growth; Cell proliferation; Disease; Enzymes; Female; Gene Expression; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic variation; Genome-wide association studies; Genomes; Haplotypes; Hispanic or Latino - genetics; Human Genetics; Humans; Immune response; Immunology; Inflammation; Joint diseases; Kidney; Linkage Disequilibrium; Lupus; Lupus Erythematosus, Systemic - ethnology; Lupus Erythematosus, Systemic - genetics; Male; Medical research; Medicin och hälsovetenskap; Medicine; original-article; Physiological aspects; Polymorphism, Single Nucleotide; Protein expression; Proteins; Rheumatology; Risk factors; Systemic lupus erythematosus; Ubiquitin; Ubiquitin-conjugating enzyme; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; White People - genetics; Los Angeles California; Puerto Rico; San Francisco California; United States > US; Oklahoma; Chicago Illinois; California; Spain; UBCH7 expression; systemic lupus erythematosus; multi-ethnic association study
• ISSN: 1466-4879; 1476-5470; 1476-5470
• DOI: 10.1038/gene.2012.6

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the
UBE2L3
region that are associated with SLE in subjects of European and Asian ancestry.
UBE2L3
encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of
UBE2L3
and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of
UBE2L3
and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (
P
<1 × 10
−4
). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both
UBE2L3
mRNA expression (
P
=0.0004) and UBCH7 protein expression (
P
=0.0068). The results suggest that variants carried on the SLE-associated
UBE2L3
risk haplotype influence autoimmunity by modulating UBCH7 expression.