Risk Alleles for Systemic Lupus Erythematosus in a Large Case-Control Collection and Associations with Clinical Subphenotypes

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Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p<5×10⁻⁸) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p = 4×10⁻¹²⁸. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8–5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (OR_high-low = 2.36, p = 9e−9), the immunologic criterion (OR_high-low = 2.23, p = 3e−7), and age at diagnosis (OR_high-low = 1.45, p = 0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR = 1.37, 95% CI 1.14–1.64) and arthritis (ITGAM, OR = 0.72, 95% CI 0.59–0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci.

Vyšlo v časopise: Risk Alleles for Systemic Lupus Erythematosus in a Large Case-Control Collection and Associations with Clinical Subphenotypes. PLoS Genet 7(2): e32767. doi:10.1371/journal.pgen.1001311
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001311

Souhrn

Zdroje

1. HarleyIT

KaufmanKM

LangefeldCD

HarleyJB

KellyJA

2009 Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat Rev Genet 10 285 290

2. GrahamRR

HomG

OrtmannW

BehrensTW

2009 Review of recent genome-wide association scans in lupus. J Intern Med 265 680 688

3. HomG

GrahamRR

ModrekB

TaylorKE

OrtmannW

2008 Association of Systemic Lupus Erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 358 900 909

4. HarleyJB

Alarcon-RiquelmeME

CriswellLA

JacobCO

KimberlyRP

2008 Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40 204 210

5. GrahamRR

CotsapasC

DaviesL

HackettR

LessardCJ

2008 Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 40 1059 1061

6. GatevaV

SandlingJK

HomG

TaylorKE

ChungSA

2009 A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 41 1228 1233

7. KozyrevSV

AbelsonAK

WojcikJ

ZaghloolA

Linga ReddyMV

2008 Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 40 211 216

8. TaylorKE

RemmersEF

LeeAT

OrtmannWA

PlengeRM

2008 Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet 4 e1000084 doi:10.1371/journal.pgen.1000084

9. PodrebaracTA

BoisertDM

GoldsteinR

1998 Clinical correlates, serum autoantibodies and the role of the major histocompatibility complex in French Canadian and non-French Canadian Caucasians with SLE. Lupus 7 183 191

10. ZhengSL

SunJ

WiklundF

SmithS

StattinP

2008 Cumulative association of five genetic variants with prostate cancer. N Engl J Med 358 910 919

11. KarlsonEW

ChibnikLB

KraftP

CuiJ

KeenanBT

2010 Cumulative association of 22 genetic variants with seropositive rheumatoid arthiritis risk. Ann Rheum Dis 69 1077 1085

12. PurcellSM

WrayNR

StoneJL

VisscherPM

O'DonovanMC

2009 Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460 748 752

13. TanEM

CohenAS

FriesJF

MasiAT

McShaneDJ

1982 The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25 1271 1277

14. HochbergMC

1997 Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [letter]. Arthritis Rheum 40 1725

15. HunterDJ

KraftP

JacobsKB

CoxDG

YeagerM

2007 A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39 870 874

16. BenjaminiY

HochbergY

1995 Controlling the false discovery rate - a practical and powerful approach to multiple testing. J R Stat Soc Ser B 57 289 300

17. MusoneSL

TaylorKE

LuTT