Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.).

Crohn disease is a chronic, inflammatory disease of the gastrointestinal tract. A locus of ∼250 kb at 5q31 (IBD5) 1,2 was previously associated with susceptibility to Crohn disease, as indicated by increased prevalence of a risk haplotype of 11 single-nucleotide polymorphisms 3 among individuals with Crohn disease, but the pathogenic lesion in the region has not yet been identified. We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a G→C transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease. These variants alter transcription and transporter functions of the organic cation transporters and interact with variants in another gene associated with Crohn disease, CARD15, to increase risk of Crohn disease. These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease.By resequencing the five genes in the IBD5 interval, we identified ten new single-nucleotide polymorphisms (SNPs; Supplementary Table 1 online), including two in the organic cation transporter (OCTN) gene cluster (SLC22A4 and SLC22A5, encoding OCTN1 and OCTN2, respectively) that are predicted to have functional effects. The first is a C→T substitution in SLC22A4 exon 9 (1672C→T; numbered according to the cDNA sequence for SLC22A4 in GenBank) that causes the amino acid substitution L503F. Leucine or isoleucine is conserved at this position in most OCTNs and other related transporters 4 (Fig. 1a), and its substitution with phenylalanine is predicted computationally (by PolyPhen 5 , TMHMM2 (ref. 6) and PHAT transmembrane database 7 ) to be nonconservative. The second SNP is a G→C transversion in the SLC22A5 promoter (-207G→C), which disrupts a heat shock element (HSE) 207 bp upstream of the start codon (Fig. 1b).1672C→T and -207G→C are in strong linkage disequilibrium and create a two-allele risk haplotype (TC) enriched in individuals with Crohn disease (frequency = 0.54 in affected individuals versus 0.42 in controls, P = 0.0003;

Linkage disequilibrium (LD) mapping provides a powerful method for fine-structure localization of rare disease genes, but has not yet been widely applied to common disease. We sought to design a systematic approach for LD mapping and apply it to the localization of a gene (IBD5) conferring susceptibility to Crohn disease. The key issues are: (i) to detect a significant LD signal (ii) to rigorously bound the critical region and (iii) to identify the causal genetic variant within this region. We previously mapped the IBD5 locus to a large region spanning 18 cM of chromosome 5q31 (P<10(-4)). Using dense genetic maps of microsatellite markers and single-nucleotide polymorphisms (SNPs) across the entire region, we found strong evidence of LD. We bound the region to a common haplotype spanning 250 kb that shows strong association with the disease (P< 2 x 10(-7)) and contains the cytokine gene cluster. This finding provides overwhelming evidence that a specific common haplotype of the cytokine region in 5q31 confers susceptibility to Crohn disease. However, genetic evidence alone is not sufficient to identify the causal mutation within this region, as strong LD across the region results in multiple SNPs having equivalent genetic evidence-each consistent with the expected properties of the IBD5 locus. These results have important implications for Crohn disease in particular and LD mapping in general.