Evidence of linkage to chromosome 1 for early age of onset of rheumatoid arthritis and HLA marker DRB1 genotype in NARAC data

Focusing on chromosome 1, a recursive partitioning linkage algorithm (RP) was applied to perform linkage analysis on the rheumatoid arthritis NARAC data, incorporating covariates such as HLA-DRB1 genotype, age at onset, severity, anti-cyclic citrullinated peptide (anti-CCP), and life time smoking. All 617 affected sib pairs from the ascertained families were used, and an RP linkage model was used to identify linkage possibly influenced by covariates. This algorithm includes a likelihood ratio (LR)-based splitting rule, a pruning algorithm to identify optimal tree size, and a bootstrap method for final tree selection. The strength of the linkage signals was evaluated by empirical p-values, obtained by simulating marker data under null hypothesis of no linkage. Two suggestive linkage regions on chromosome 1 were detected by the RP linkage model, with identified associated covariates HLA-DRB1 genotype and age at onset. These results suggest possible gene × gene and gene × environment interactions at chromosome 1 loci and provide directions for further gene mapping.