rs2542151

Meta-analysis of 17 studies examining associations between three PTPN2 polymorphisms (rs2542151, rs1893217, rs7234029) and susceptibility to ulcerative colitis and Crohn's disease, involving 18,308 cases and 20,406 controls. The rs2542151 G allele was associated with increased CD risk (OR=1.22, 95% CI 1.15-1.30) and UC risk (OR=1.16, 95% CI 1.07-1.25), with stronger associations in Caucasians than Asians. The rs1893217 C allele showed association with CD (OR=1.45, 95% CI 1.23-1.70), particularly in children (OR=1.56, 95% CI 1.28-1.89), and rs7234029 G allele was associated with CD (OR=1.36, 95% CI 1.16-1.59).

This case-control study in a Chinese Han population evaluated eight IBD susceptibility loci previously identified in European GWAS. The study found that NOD2 P268S contributed to Crohn's disease susceptibility (P=0.025), IL23R rs11805303 conferred protective effect against ulcerative colitis (P=0.010), and PTPN2 rs2542151 was associated with increased UC risk (P=0.001). Phenotype-genotype analysis showed P268S was associated with early-onset disease and ileal involvement in CD patients.

This study identified a novel association between the PTPN2 SNP rs1893217 (intronic variant) and Crohn's disease in a combined German, Swiss, and Polish cohort (343 CD patients, 663 controls). Homozygous carriers of the variant showed significantly increased disease association (OR=2.653, 95% CI=1.147-6.136, P=0.018). Functionally, the variant impaired PTPN2 phosphatase activity, leading to increased MAPK phosphorylation, elevated T-bet expression and IFN-γ secretion in monocytes and impaired autophagosome formation in response to the NOD2 ligand MDP.

This case-control study of 439 Spanish type 1 diabetes (T1D) patients and 861 controls examined the association of PTPN2 polymorphisms with T1D and age at disease onset. The rs2542151*G allele was significantly associated with early-onset T1D (≤16 years) with OR=1.61 (p=0.005) and was linked to earlier disease debut compared to TT homozygotes (mean 16.6 vs 19.1 years, p=0.034), while the rs478582 polymorphism showed no significant association with age at onset.

This study examined 40 SNPs (34 CD-associated and 6 UC-associated) in 2374 Canadian IBD patients (1144 CD, 1230 UC/IBDU) and 1057 healthy controls. While most immune-related variants showed similar frequencies between CD and UC, the two diseases diverged significantly in genes related to innate immunity and autophagy (NOD2, ATG16L1, IRGM), which were more prevalent in CD. In patients with colon-only CD, genetic overlap with UC was nearly complete, suggesting a shared genetic basis for colonic disease.

This paper applies a bias correction method for odds ratio estimates from GWAS discovery data, demonstrating that the 'winner's curse' affects initial effect size estimates. The authors applied conditional maximum likelihood estimation to correct bias in GWAS findings from multiple complex diseases (breast cancer, colorectal cancer, lung cancer, prostate cancer, type I and II diabetes) and show that bias-adjusted odds ratios are substantially more consistent with subsequent replication studies, with selection-adjusted confidence intervals providing better uncertainty quantification than uncorrected estimates.

This case-control association study of juvenile idiopathic arthritis (JIA) in 809 JIA cases and 3,521 controls identified susceptibility loci shared with other autoimmune diseases. Three novel loci were identified: PTPN2 (strongest signals rs7234029, p=7.19×10⁻¹¹, OR=1.59; rs1893217, p=3.48×10⁻⁸, OR=1.52; rs2542151, p=3.05×10⁻⁷, OR=1.45), COG6 (rs7993214, p=3.98×10⁻³, OR=0.79), and ANGPT1 (rs1010824, p=4.93×10⁻³, OR=0.77). Four previously reported JIA loci were confirmed: PTPN22, STAT4, C12orf30, and IL2-IL21. Odds ratios ranged from 1.20 to 1.65 in meta-analysis of initial and independent replication cohorts (n=1,015 cases and 1,568 controls).

This paper presents a statistical method for unbiased estimation of odds ratios from genome-wide association scans combined with replication studies. The authors develop a Uniformly Minimum Variance Conditionally Unbiased Estimator (UMVCUE) that corrects for selection bias arising from both rank ordering and significance thresholding in initial scans. Applied to type 1 diabetes and Crohn's disease data from the Wellcome Trust Case Control Consortium, the method shows improved efficiency over replication-only estimates, particularly when replication sample sizes are smaller.

A case-control association study found that genetic variants in TNFAIP3 (rs10499194, OR 0.74; rs6920220, OR 1.3), STAT4 (rs7574865, OR 1.24), and C12ORF30 (rs17696736, OR 1.2) loci previously associated with other autoimmune diseases are also significantly associated with juvenile idiopathic arthritis, supporting shared genetic susceptibility among clinically distinct autoimmune phenotypes.

This comprehensive review article traces the evolution of pharmacogenetics from single-gene analysis to whole-genome approaches. It discusses validated pharmacogenetic biomarkers with clinical impact including CYP2D6, CYP2C9, CYP2C19, TPMT, DPD, VKORC1, UGT1A1, and ADRB1/ADRB2, providing examples of how genetic variants affect drug metabolism and response. The paper emphasizes the importance of integrating pharmacogenetic information into clinical practice and drug development.

A meta-analysis of 4,107 type 2 diabetes cases and 5,187 controls from three GWA studies found no evidence that common variants altering circulating inflammatory protein levels (IL-18, IL-6R, CRP, IL1RN, PAI1, MIF) or variants predisposing to autoimmune diseases (type 1 diabetes, rheumatoid arthritis, Crohn's disease, celiac disease, multiple sclerosis, SLE) are associated with type 2 diabetes risk. For example, rs2250417 in IL18 showed OR=1.00 (95% CI 0.99-1.03) versus the expected OR of ~1.15 if inflammation were causal, suggesting inflammatory markers are likely secondary rather than causative in type 2 diabetes.