title: Estimation of heritability of different outcomes for genetic studies of TNFi response in patients with rheumatoid arthritis.
abstract: OBJECTIVE
  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 (h(2)gbayz=0.76 and h(2)gGCTA=0.87) and ΔTJC (h(2)gbayz=0.62 and h(2)gGCTA=0.82); lower heritability was found for ΔDAS28 (h(2)gbayz=0.59 and h(2)gGCTA=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.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Maša
authors.initials: M
authors.lastname: Umićević Mirkov
authors.affiliation: Faculty of Science and Technology, Department of Molecular Biology and Genetics, University of Aarhus, Tjele, Denmark.
authors.forename: Luc
authors.initials: L
authors.lastname: Janss
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.affiliation: Department of Rheumatology, University Twente&Medisch Spectrum Twente, Enschede, The Netherlands.
authors.forename: Mart A F J
authors.initials: MA
authors.lastname: van de Laar
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Piet L C M
authors.initials: PL
authors.lastname: van Riel
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Cornelis A
authors.initials: CA
authors.lastname: Albers
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D004247:DNA
keywords: Anti-TNF; DAS28; Gene Polymorphism; Pharmacogenetics; Rheumatoid Arthritis