rs3184504

This eQTL study examined 137 ischemic stroke patients and 138 controls to identify SNP-gene associations affecting blood gene expression. The analysis identified 4 significant cis-eQTLs and 70 trans-eQTLs with genotype-diagnosis interactions. Key findings include rs56348411 (NRGN, p=2.10×10⁻⁸), rs78046578 (CXCL10), rs975903 (SMAD4), and rs62299879 (CD38) affecting inflammatory response genes, plus rs148791848 as a strong trans-eQTL for ANOS1 involved in neural cell adhesion.

A genome-wide association study (GWAS) of platelet count (PLT) and mean platelet volume (MPV) in 13,582 and 6,291 participants respectively from the eMERGE network identified 5 chromosomal regions associated with PLT and 8 with MPV at genome-wide significance (P<5E-8). Key findings include variants in ARHGEF3 (rs1354034, P=6E-24 for PLT; P=9E-34 for MPV), SH2B3 (rs3184504, P=5E-12), and multiple other loci. The study replicated 20 SNPs for PLT and 22 for MPV from prior meta-analyses and demonstrated pleiotropic effects with myocardial infarction, autoimmune, and hematologic disorders through phenome-wide association study (PheWAS).

This dense genotyping study identified 12 genome-wide significant susceptibility loci for primary sclerosing cholangitis (PSC) outside the HLA complex in 3,789 European PSC cases and 25,079 controls using the Immunochip array. Nine loci were novel, including rs7426056 (CD28; OR=1.30), rs3197999 (MST1; OR=1.33), rs13140464 (IL2/IL21; OR=1.30), rs56258221 (BACH2; OR=1.23), and rs2836883 (PSMG1; OR=1.28). The study found overlapping yet distinct genetic architecture between PSC and inflammatory bowel disease, with PSC being genetically more similar to ulcerative colitis than Crohn's disease.

Genome-wide association study of plasma beta-2 microglobulin (B2M) levels in 6,738 European Americans identified two genome-wide significant loci: the HLA region on chromosome 6 (rs9264638, p=1.8×10⁻²³) and SH2B3 on chromosome 12 (rs3184504, p=3.1×10⁻⁸). Six index SNPs in the HLA region accounted for 3.2% of log(B2M) variance and their associations were largely explained by imputed classical HLA alleles (HLA-A, HLA-B, HLA-C). The HLA locus was not associated with estimated glomerular filtration rate, while the SH2B3 locus had previously been implicated as an eGFR locus, confirming B2M as a kidney function biomarker.

A study of 1,115 UK rheumatoid arthritis patients receiving anti-TNF biologic therapy found that rs10919563 in the PTPRC gene was associated with improved treatment response (regression coefficient 0.19, 95% CI 0.09-0.37, P=0.04 for continuous DAS28 outcome; OR 0.62, 95% CI 0.40-0.95, P=0.03 for good EULAR response). Meta-analysis with a previous study strengthened evidence (P=5.13×10⁻⁵). Secondary analysis identified rs11594656 in IL2RA associated with good EULAR response (OR 1.47, P=0.02).

Genetic association study in 23,439 Caucasians and 7,112 African Americans identified novel loci modulating hematological traits. G6PD rs1050828 (Val68Met) shows strong association with red blood cell count, hemoglobin, hematocrit, and mean corpuscular volume in African Americans (P < 2.0 × 10^−13), while TPM4 rs8109288 associates with platelet count in both Caucasians and African Americans (P = 3.0 × 10^−7). HBA2-HBA1 rs1211375 associates with red blood cell traits specifically in African Americans (P < 7 × 10^−8). Study replicated 36 previously reported associations and highlights ethnic differences in genetic architecture of blood traits.

This study confirmed association between rs6822844 in the IL2-IL21 region and multiple autoimmune diseases in non-European populations, with significant associations in Colombian samples for systemic lupus erythematosus (OR 0.50, P=0.008), type 1 diabetes (OR 0.43, P=0.014), rheumatoid arthritis (OR 0.61, P=0.019), and primary Sjögren's syndrome (OR 0.46, P=0.033). Meta-analysis of 23 populations showed highly significant overall association (P=2.61×10⁻²⁵, OR 0.73) and disease-specific associations with inflammatory bowel disease (P=3.48×10⁻¹², OR 0.74), rheumatoid arthritis (P=3.61×10⁻⁶, OR 0.77), type 1 diabetes (P=5.33×10⁻⁵, OR 0.61), and celiac disease (P=5.30×10⁻³, OR 0.72).

PhD thesis describing comprehensive genome-wide association studies of acute anterior uveitis (AAU) in European (2,752 cases, 3,836 controls) and East Asian (821 cases, 4,898 controls) populations. European descent GWAS identified HLA-B at genome-wide significance plus 11 suggestive loci (ERAP1, NOS2, MERTK). East Asian GWAS identified HLA-B and ERAP1 at genome-wide significance plus 12 suggestive loci (GPR68, RHBDD2). Mendelian randomization confirmed ERAP1 as functionally relevant and showed genetically predicted CRP levels positively associated with AAU risk.

This study characterized an Ashkenazi Jewish (AJ) population-specific genetic signature using genome-wide SNP data from 1,312 AJ individuals. Using ADMIXTURE and principal components analysis, the authors identified allelic patterns that differentiate AJ from European and Middle Eastern populations. Gene Ontology enrichment analysis of the AJ-specific genetic signature revealed enrichment in genes involved in transepithelial chloride transport (including CFTR with rs213950 showing V158M variant) and equilibrioception (PCDH15, CLRN1), implicating these pathways in the elevated prevalence of cystic fibrosis and Usher syndrome in Ashkenazi Jews. The study also identified disease-relevant alleles including MTHFR C677T (rs1801133), SH2B3 rs3184504 associated with type 1 diabetes/celiac disease, and MC1R rs1805005, and provided a validated set of 103 ancestry informative markers (AIMs) for population stratification correction.

This review examines slowly progressive type 1 diabetes mellitus (SPIDDM), also known as latent autoimmune diabetes in adults (LADA), discussing its pathogenesis, diagnostic markers, and genetic associations. Key findings include T-cell-mediated insulitis and pseudoatrophic islets characteristic of type 1 diabetes, absence of amyloid deposition seen in type 2 diabetes, and identification of multiple genetic susceptibility loci including HLA haplotypes, PTPN22 rs2476601, INS rs689, CTLA4, TCF7L2 rs7903146, ZMIZ1 rs12571751, SH2B3 rs7310615, and PFKFB3 rs1983890. GAD autoantibodies and HLA genotypes are important risk factors for beta-cell failure progression.

This LD mapping study identified significant associations between bipolar affective disorder and genetic markers on chromosome 12q23-q24. Two SNPs (rs3847953, P=0.002 and rs933399, P=0.004) and an insertion/deletion (rs3840795, P=0.005) in regions containing CUX2 and FLJ32356 genes showed significant association after Bonferroni correction in 347 bipolar cases and 374 controls.