Top

28-07-2016 | Systemic lupus erythematosus | Article

Genetic risk and longitudinal disease activity in systemic lupus erythematosus using targeted maximum likelihood estimation

Journal: Genes & Immunity

Authors: M A Gianfrancesco, L Balzer, K E Taylor, L Trupin, J Nititham, M F Seldin, A W Singer, L A Criswell, L F Barcellos

Publisher: Nature Publishing Group UK

Abstract

Systemic lupus erythematous (SLE) is a chronic autoimmune disease associated with genetic and environmental risk factors. However, the extent to which genetic risk is causally associated with disease activity is unknown. We utilized longitudinal-targeted maximum likelihood estimation to estimate the causal association between a genetic risk score (GRS) comprising 41 established SLE variants and clinically important disease activity as measured by the validated Systemic Lupus Activity Questionnaire (SLAQ) in a multiethnic cohort of 942 individuals with SLE. We did not find evidence of a clinically important SLAQ score difference (>4.0) for individuals with a high GRS compared with those with a low GRS across nine time points after controlling for sex, ancestry, renal status, dialysis, disease duration, treatment, depression, smoking and education, as well as time-dependent confounding of missing visits. Individual single-nucleotide polymorphism (SNP) analyses revealed that 12 of the 41 variants were significantly associated with clinically relevant changes in SLAQ scores across time points eight and nine after controlling for multiple testing. Results based on sophisticated causal modeling of longitudinal data in a large patient cohort suggest that individual SLE risk variants may influence disease activity over time. Our findings also emphasize a role for other biological or environmental factors.

Genes Immun 2016;17:358–362. doi:10.1038/gene.2016.33

Deng Y, Tsao BP . Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol 2010; 6: 683–692.CrossRef

Morris DL, Taylor KE, Fernando MM, Nititham J, Alarcon-Riquelme ME, Barcellos LF et al. Unraveling multiple mhc gene associations with systemic lupus erythematosus: model choice indicates a role for hla alleles and non-hla genes in europeans. Am J Hum Genet 2012; 91: 778–793.CrossRef

Barcellos LF, May SL, Ramsay PP, Quach HL, Lane JA, Nititham J et al. High-density snp screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions. PLoS Genet 2009; 5: e1000696.CrossRef

Bentham J, Morris DL, Cunningham Graham DS, Pinder CL, Tomblesson P, Behrens TW et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet 2015; 47: 1457–1464.CrossRef

Taylor KE, Chung SA, Graham RR, Ortmann WA, Lee AT, Langefeld CD et al. Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes. PLoS Genet 2011; 7: e1001311.CrossRef

Gualtierotti R, Biggioggero M, Penatti AE, Meroni PL . Updating on the pathogenesis of systemic lupus erythematosus. Autoimmun Rev. 2010; 10: 3–7.CrossRef

Luijten KM, Tekstra J, Bijlsma JW, Bijl M . The systemic lupus erythematosus responder index (sri); a new SLE disease activity assessment. Autoimmun Rev 2012; 11: 326–329.CrossRef

Taylor KE, Remmers EF, Lee AT, Ortmann WA, Plenge RM, Tian C et al. Specificity of the stat4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet 2008; 4: e1000084.CrossRef

Yazdany J, Yelin EH, Panopalis P, Trupin L, Julian L, Katz PP . Validation of the systemic lupus erythematosus activity questionnaire in a large observational cohort. Arthritis Rheum 2008; 59: 136–143.CrossRef

10.

Blakemore AI, Tarlow JK, Cork MJ, Gordon C, Emery P, Duff GW . Interleukin-1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus. Arthritis Rheum 1994; 37: 1380–1385.CrossRef

11.

Garred P, Voss A, Madsen HO, Junker P . Association of mannose-binding lectin gene variation with disease severity and infections in a population-based cohort of systemic lupus erythematosus patients. Genes Immun 2001; 2: 442–450.CrossRef

12.

Podrebarac TA, Boisert DM, Goldstein R . Clinical correlates, serum autoantibodies and the role of the major histocompatibility complex in french canadian and non-french canadian caucasians with SLE. Lupus 1998; 7: 183–191.CrossRef

13.

Hanaoka H, Okazaki Y, Satoh T, Kaneko Y, Yasuoka H, Seta N et al. Circulating anti-double-stranded DNA antibody-secreting cells in patients with systemic lupus erythematosus: a novel biomarker for disease activity. Lupus 2012; 21: 1284–1293.CrossRef

14.

Chung SA, Taylor KE, Graham RR, Nititham J, Lee AT, Ortmann WA et al. Differential genetic associations for systemic lupus erythematosus based on anti-dsdna autoantibody production. PLoS Genet 2011; 7: e1001323.CrossRef

15.

Trupin L, Tonner MC, Yazdany J, Julian LJ, Criswell LA, Katz PP et al. The role of neighborhood and individual socioeconomic status in outcomes of systemic lupus erythematosus. J Rheumatol 2008; 35: 1782–1788.PubMedPubMedCentral

16.

Robins JM . A new approach to causal inference in mortality studies with a sustained exposure period-application to control of the healthy worker survivor effect. Math Model 1986; 7: 1393–1512.CrossRef

17.

Thorburn CM, Prokunina-Olsson L, Sterba KA, Lum RF, Seldin MF, Alarcon-Riquelme ME et al. Association of pdcd1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort. Genes Immun 2007; 8: 279–287.CrossRef

18.

Yelin E, Trupin L, Katz P, Criswell L, Yazdany J, Gillis J et al. Work dynamics among persons with systemic lupus erythematosus. Arthritis Rheum 2007; 57: 56–63.CrossRef

19.

Panopalis P, Julian L, Yazdany J, Gillis JZ, Trupin L, Hersh A et al. Impact of memory impairment on employment status in persons with systemic lupus erythematosus. Arthritis Rheum 2007; 57: 1453–1460.CrossRef

20.

Yazdany J, Trupin L, Gansky SA, Dall'era M, Yelin EH, Criswell LA et al. Brief index of lupus damage: a patient-reported measure of damage in systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2011; 63: 1170–1177.CrossRef

21.

Parkes M, Cortes A, van Heel DA, Brown MA . Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet 2013; 14: 661–673.CrossRef

22.

Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S et al. Association of systemic lupus erythematosus with c8orf13-blk and itgam-itgax. N Engl J Med 2008; 358: 900–909.CrossRef

23.

Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in itgam, pxk, kiaa1542 and other loci. Nat Genet 2008; 40: 204–210.CrossRef

24.

Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z et al. Genome-wide association study in a chinese han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 2009; 41: 1234–1237.CrossRef

25.

Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 2009; 41: 1228–1233.CrossRef

26.

Yang J, Yang W, Hirankarn N, Ye DQ, Zhang Y, Pan HF et al. Elf1 is associated with systemic lupus erythematosus in Asian populations. Hum Mol Genet 2011; 20: 601–607.CrossRef

27.

Orozco G, Eyre S, Hinks A, Bowes J, Morgan AW, Wilson AG et al. Study of the common genetic background for rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis 2011; 70: 463–468.CrossRef

28.

Kozyrev SV, Abelson AK, Wojcik J, Zaghlool A, Linga Reddy MV, Sanchez E et al. Functional variants in the b-cell gene bank1 are associated with systemic lupus erythematosus. Nat Genet 2008; 40: 211–216.CrossRef

29.

Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM et al. Genetic variants near tnfaip3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 2008; 40: 1059–1061.CrossRef

30.

Eaton W, Muntaner C, Smith C, Tien A, Ybarra M . Center for Epidemiologic Studies Depression Scale: Review and Revision (CESD and CESD-R). In: Maruish ME (ed.). The Use of Psychological Testing for Treatment Planning and Outcomes Assessment, 3rd ed. Lawrence Erlbaum: Mahwah, 2004, pp 363–377.

31.

Petersen M, Schwab J, Gruber S, Blaser N, Schomaker M, van der Laan M . Targeted maximum likelihood estimation for dynamic and static longitudinal marginal structural working models. J Causal Inference 2014; 2: 147–185.CrossRef

32.

van der Laan MJ, Gruber S . Targeted minimum loss based estimation of causal effects of multiple time point interventions. Int J Biostat 2012; 8.

33.

Pearl J . Causality: Models, Reasoning and Inference. 2nd edn. Cambridge University Press: : New York, NY, USA, 2009.CrossRef

34.

Taubman SL, Robins JM, Mittleman MA, Hernan MA . Intervening on risk factors for coronary heart disease: an application of the parametric g-formula. Int J Epidemiol 2009; 38: 1599–1611.CrossRef

35.

Robins JM, Hernan MA, Brumback B . Marginal structural models and causal inference in epidemiology. Epidemiology 2000; 11: 550–560.CrossRef

36.

van der Laan MJ, Polley EC, Hubbard AE . Super learner. Stat Appl Genet Mol Biol 2007; 6: Article 25.CrossRef

37.

Mikdashi J, Nived O . Measuring disease activity in adults with systemic lupus erythematosus: the challenges of administrative burden and responsiveness to patient concerns in clinical research. Arthritis Res Ther 2015; 17: 183.CrossRef

38.

Schwab J, Lendle S, Petersen M, van der Laan M ltmle: Longitudinal targeted maximum likelihood estimation. R package version 0.9.3-1. http://CRAN.R-project.org/package=ltmle Published 22 April 2014.

Medicine Matters Rheumatology

Abstract