title: A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.
abstract: 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.
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: I
authors.initials: I
authors.lastname: Adrianto
authors.forename: G B
authors.initials: GB
authors.lastname: Wiley
authors.forename: C J
authors.initials: CJ
authors.lastname: Lessard
authors.forename: J A
authors.initials: JA
authors.lastname: Kelly
authors.forename: A J
authors.initials: AJ
authors.lastname: Adler
authors.forename: S B
authors.initials: SB
authors.lastname: Glenn
authors.forename: A H
authors.initials: AH
authors.lastname: Williams
authors.forename: J T
authors.initials: JT
authors.lastname: Ziegler
authors.forename: M E
authors.initials: ME
authors.lastname: Comeau
authors.forename: M C
authors.initials: MC
authors.lastname: Marion
authors.forename: B E
authors.initials: BE
authors.lastname: Wakeland
authors.forename: C
authors.initials: C
authors.lastname: Liang
authors.forename: K M
authors.initials: KM
authors.lastname: Kaufman
authors.forename: J M
authors.initials: JM
authors.lastname: Guthridge
authors.forename: M E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.forename: G S
authors.initials: GS
authors.lastname: Alarcón
authors.forename: J-M
authors.initials: JM
authors.lastname: Anaya
authors.forename: S-C
authors.initials: SC
authors.lastname: Bae
authors.forename: J-H
authors.initials: JH
authors.lastname: Kim
authors.forename: Y B
authors.initials: YB
authors.lastname: Joo
authors.forename: S A
authors.initials: SA
authors.lastname: Boackle
authors.forename: E E
authors.initials: EE
authors.lastname: Brown
authors.forename: M A
authors.initials: MA
authors.lastname: Petri
authors.forename: R
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.forename: J D
authors.initials: JD
authors.lastname: Reveille
authors.forename: L M
authors.initials: LM
authors.lastname: Vilá
authors.forename: L A
authors.initials: LA
authors.lastname: Criswell
authors.forename: J C
authors.initials: JC
authors.lastname: Edberg
authors.forename: B I
authors.initials: BI
authors.lastname: Freedman
authors.forename: G S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: C O
authors.initials: CO
authors.lastname: Jacob
authors.forename: J A
authors.initials: JA
authors.lastname: James
authors.forename: D L
authors.initials: DL
authors.lastname: Kamen
authors.forename: R P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: J
authors.initials: J
authors.lastname: Martin
authors.forename: J T
authors.initials: JT
authors.lastname: Merrill
authors.forename: T B
authors.initials: TB
authors.lastname: Niewold
authors.forename: B A
authors.initials: BA
authors.lastname: Pons-Estel
authors.forename: R H
authors.initials: RH
authors.lastname: Scofield
authors.forename: A M
authors.initials: AM
authors.lastname: Stevens
authors.forename: B P
authors.initials: BP
authors.lastname: Tsao
authors.forename: T J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: C D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: J B
authors.initials: JB
authors.lastname: Harley
authors.forename: E K
authors.initials: EK
authors.lastname: Wakeland
authors.forename: K L
authors.initials: KL
authors.lastname: Moser
authors.forename: C G
authors.initials: CG
authors.lastname: Montgomery
authors.forename: P M
authors.initials: PM
authors.lastname: Gaffney
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D044466:Asian People / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: C079437:UBE2L3 protein, human; D044763:Ubiquitin-Conjugating Enzymes