Analysis of association of <i>PTPN22</i> ‘haplotype 6–10’ group (<i>rs12144309</i>: C&gt;T) with rheumatoid arthritis.

<p>1. Cases top line, controls bottom line. The NZ controls deviated mildly from HWE (<i>P</i> = 0.02).</p><p>2. Imputed genotypes were taken from <a href="http://www.wtccc.org.uk" target="_blank">www.wtccc.org.uk</a>.</p><p>3. The Mantel-Haenszel combined OR = 0.90 [0.82–0.98], <i>P</i> = 0.021. The Breslow-Day test for heterogeneity <i>P</i> = 0.90.</p

Analysis of association of <i>PTPN22</i> ‘haplotype 4’ (<i>rs3811021</i>: A&gt;G) with rheumatoid arthritis.

<p>1 Cases top line, controls bottom line.</p><p>2 Imputed genotypes were taken from <a href="http://www.wtccc.org.uk" target="_blank">www.wtccc.org.uk</a>.</p><p>3 The Mantel-Haenszel combined OR  = 0.85 [0.72–1.01], <i>P</i> = 0.071. The Breslow-Day test for heterogeneity <i>P</i>&lt;0.001.</p

Haplotype structure of structure of a portion of the <i>PTPN22</i> haplotype block.

<p>The figure was generated by Haploview using Phase 2 CEPH CEU HapMap data downloaded from <a href="http://www.hapmap.org" target="_blank">www.hapmap.org</a>, with the boundaries being <i>rs4145859</i> (114.312 Mb) and <i>rs10745340</i> (114.437 Mb).</p

Analysis of association of <i>PTPN22</i> ‘haplotype 5’ (<i>rs3789607</i>: T&gt;C) with rheumatoid arthritis.

<p>1 Cases top line, controls bottom line. The Carlton Set 2 cases and controls, the combined other cases and total cases deviated mildly from HWE (<i>P</i> = 0.02, 0.03, 0.05 and 0.02, respectively).</p><p>2 Allele 2; number of chromosomes (frequency).</p><p>3 Genotype data from <i>rs17274634</i> were used (r² = 1 with <i>rs3789607</i> in CEPH CEU (<a href="http://www.hapmap.org" target="_blank">www.hapmap.org</a>)).</p><p>4 The Mantel-Haenszel pooled OR = 0.87 [0.82–0.93], <i>P</i> = 7.5×10⁻⁶; Breslow-Day test for heterogeneity <i>P</i> = 0.083. The Mantel-Haenszel pooled OR excluding Carlton et al data was 0.91 [0.85–0.98], <i>P</i> = 0.016; Breslow-Day <i>P</i> = 0.50.</p

<i>Rs2476601-rs12566340</i> haplotypic analysis.

<p>1. Within each cell in the RA half, NZ data are top, WTCCC data middle and combined bottom.</p

A genome-wide association study of gout in people of European ancestry

Background/Purpose: Genome wide association studies (GWAS) have provided considerable insight into the molecular control of urate levels. However, less is known about the progression from asymptomatic hyperuricemia to gout. Our aim was to conduct a GWAS for gout in people of European ancestry using the largest number of cases of gout to date. Methods: This GWAS (7,431 cases and 105,631 controls) was comprised of three data sets: a mixed New Zealand (NZ), Eurogout, and Ardea Biosciences group (3,961 cases; 1,547 controls; genotyped using the Illumina CoreExome v24 array, 547,644 markers), a composite set from the Health Professionals Follow-Up (HPFS) and NursesÕ Health Studies (NHS) (1,038 cases; 1,095 controls; genotyped using the Illumina OmniExpress v12 array, 730,525 markers), and UK Biobank (2,432 cases; 102,989 controls; genotyped using an Affymetrix Axiom array, 820,967 markers). The UK Biobank genotypes were imputed to ~73.3M SNPs. Neither the NZ/Eurogout/Ardea nor NHS/HPFS genotype sets were imputed. Markers found within all three data sets (234,062) were identified and associated with gout (adjusted for sex and age), within each data set separately, using PLINK v1.9. An inverse-variance weighted meta-analysis of the results was then performed using the meta v4.4 package within R v3.2.3. The overall genome inflation factor was 0.90. Results: There were nine loci with experiment-wide significance (0.05/234,062; P < 2×10-7) for association with gout: ABCG2 (OR=1.77), SLC2A9 (OR=1.69), GCKR (OR=1.24), MLXIPL (OR=1.18), SLC17A1-A4 (OR=1.22), SLC16A9 (OR=1.18), SLC22A12 (OR=1.16), PDZK1 (OR=1.16), TRIM46 (OR=1.15). All nine of these loci have been previously associated with serum urate levels in genome-wide studies with the urate-increasing alleles also associated with increased risk of gout in this study. Conclusion: Our data emphasize the central importance of genetic involvement in serum urate levels, compared to the genetic involvement in MSU crystal formation, or the innate immune response, in determining gout.</p