Computational protocol: CRP genotype and haplotype associations with serum C reactive protein level and DAS28 in untreated early rheumatoid arthritis patients

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Protocol publication

[…] CRP concentrations in serum were log-normally distributed and, therefore, log-transformed before analysis. The genotype distribution was tested for deviation from Hardy-Weinberg equilibrium using Haploview software [], which was also used for population-based haplotype analysis. Analysis of variance based on multiple linear regression models was used to investigate the association between CRP and genotypes with age, sex and treatment as covariates. The genotype was modeled as an additive allelic effect. The two cohorts were combined in the analysis of the genotype and haplotype effects.Tests of haplotype association with protein levels were performed by using haplo.stats in the R statistical software package, version 1.6.3 []. For all analyses, we assumed additive haplotype effects and Gaussian distribution of traits and phenotypes. First, the haplo.score was used to study associations between the combined haplotypes and CRP levels by calculating global P-values. Next, the haplo.glm function was used to account for ambiguity of haplotype estimation and multiple comparisons so that we could estimate the effect of each haplotype compared to the most frequent haplotype (H3) by linear regression analysis. Age, sex and treatment were added as covariates in all haplotype analyses. In contrast to assigning the most likely haplotype phase resolution to each sample, the haplo.glm function estimates a generalized linear model by incorporating the haplotype phase uncertainty by inferring a probability matrix of haplotype likelihoods for each individual by use of the expectation-maximization haplotype inference algorithm.Results with P-values below 0.05 were considered significant, and 95% confidence intervals (CI) are used throughout. Data are presented as medians (5th to 95th percentile ranges), unless otherwise stated. Fisher’s exact test, the Mann–Whitney rank-sum test and Student’s t-test were used to test population differences. Stata 12.1 software (StataCorp, College Station, TX, USA) was used for analysis. […]

Pipeline specifications

Software tools Haploview, haplo.stats
Application GWAS
Organisms Homo sapiens
Diseases Arthritis, Rheumatoid