RT Journal Article
SR Electronic
T1 Estimation of heritability of different outcomes for genetic studies of TNFi response in patients with rheumatoid arthritis
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 2183
OP 2187
DO 10.1136/annrheumdis-2014-205541
VO 74
IS 12
A1 Maša Umićević Mirkov
A1 Luc Janss
A1 Sita H Vermeulen
A1 Mart A F J van de Laar
A1 Piet L C M van Riel
A1 Henk-Jan Guchelaar
A1 Han G Brunner
A1 Cornelis A Albers
A1 Marieke J H Coenen
YR 2015
UL http://ard.bmj.com/content/74/12/2183.abstract
AB Objectives Pharmacogenetic studies of tumour necrosis factor inhibitors (TNFi) response in patients with rheumatoid arthritis (RA) have largely relied on the changes in complex disease scores, such as disease activity score 28 (DAS28), as a measure of treatment response. It is expected that genetic architecture of such complex score is heterogeneous and not very suitable for pharmacogenetic studies. We aimed to select the most optimal phenotype for TNFi response using heritability estimates.Methods Using two linear mixed-modelling approaches (Bayz and GCTA), we estimated heritability, together with genomic and environmental correlations for the TNFi drug-response phenotype ΔDAS28 and its separate components: Δ swollen joint count (SJC), Δ tender joint count (TJC), Δ erythrocyte sedimentation rate (ESR) and Δ visual-analogue scale of general health (VAS-GH). For this, we used genome-wide single nucleotide polymorphism (SNP) data from 878 TNFi-treated Dutch patients with RA. Furthermore, a multivariate genome-wide association study (GWAS) approach was implemented, analysing separate DAS28 components simultaneously.Results The highest heritability estimates were found for ΔSJC (=0.76 and =0.87) and ΔTJC (=0.62 and =0.82); lower heritability was found for ΔDAS28 (=0.59 and =0.71) while estimates for ΔESR and ΔVASGH were near or equal to zero. The highest genomic correlations were observed for ΔSJC and ΔTJC (0.49), and the highest environmental correlation was seen between ΔTJC and ΔVASGH (0.62). The multivariate GWAS did not generate excess of low p values as compared with a univariate analysis of ΔDAS28.Conclusions Our results indicate that multiple SNPs together explain a substantial portion of the variation in change in joint counts in TNFi-treated patients with RA. In conclusion, of the outcomes studied, the joint counts are most suitable for TNFi pharmacogenetics in RA.