European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus.
OBJECTIVE
To determine whether genetic substructure in European-derived populations is associated with specific manifestations of systemic lupus erythematosus (SLE), including mucocutaneous phenotypes, autoantibody production, and renal disease.


METHODS
SLE patients of European descent (n=1,754) from 8 case collections were genotyped for >1,400 ancestry informative markers that define a north-south gradient of European substructure. Using the Structure program, each SLE patient was characterized in terms of percent Northern (versus percent Southern) European ancestry based on these genetic markers. Nonparametric methods, including tests for trend, were used to identify associations between Northern European ancestry and specific SLE manifestations.


RESULTS
In multivariate analyses, increasing levels of Northern European ancestry were significantly associated with photosensitivity (Ptrend=0.0021, odds ratio for highest quartile of Northern European ancestry versus lowest quartile [ORhigh-low] 1.64, 95% confidence interval [95% CI] 1.13-2.35) and discoid rash (Ptrend=0.014, ORhigh-low 1.93, 95% CI 0.98-3.83). In contrast, increasing levels of Northern European ancestry had a protective effect against the production of anticardiolipin autoantibodies (Ptrend=1.6x10(-4), ORhigh-low 0.46, 95% CI 0.30-0.69) and anti-double-stranded DNA autoantibodies (Ptrend=0.017, ORhigh-low 0.67, 95% CI 0.46-0.96).


CONCLUSIONS
This study demonstrates that specific SLE manifestations vary according to Northern versus Southern European ancestry. Thus, genetic ancestry may contribute to the clinical heterogeneity and variation in disease outcomes among SLE patients of European descent. Moreover, these results suggest that genetic studies of SLE subphenotypes will need to carefully address issues of population substructure based on genetic ancestry.
Chung
Sharon A
SA
Division of Rheumatology, University of California, San Francisco, CA 94143-0500, USA. sharon.chung@ucsf.edu
Tian
Chao
C
Taylor
Kimberly E
KE
Lee
Annette T
AT
Ortmann
Ward A
WA
Hom
Geoffrey
G
Graham
Robert R
RR
Nititham
Joanne
J
Kelly
Jennifer A
JA
Morrisey
Jean
J
Wu
Hui
H
Yin
Hong
H
Alarcón-Riquelme
Marta E
ME
Tsao
Betty P
BP
Harley
John B
JB
Gaffney
Patrick M
PM
Moser
Kathy L
KL
Manzi
Susan
S
Petri
Michelle
M
Gregersen
Peter K
PK
Langefeld
Carl D
CD
Behrens
Timothy W
TW
Seldin
Michael F
MF
Criswell
Lindsey A
LA
D000328:Adult; D017153:Antibodies, Anticardiolipin / Q000097:blood*; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous / Q000097:blood / Q000150:complications / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000150:complications / Q000235:genetics*; D008297:Male; D010641:Phenotype; D010787:Photosensitivity Disorders / Q000097:blood / Q000209:etiology / Q000235:genetics*; D044465:White People / Q000235:genetics*; D055815:Young Adult
D017153:Antibodies, Anticardiolipin