Cytokines mapping for tissue-specific expression, eQTLs and GWAS traits.

Dysregulation in cytokine production has been linked to the pathogenesis of various immune-mediated traits, in which genetic variability contributes to the etiopathogenesis. GWA studies have identified many genetic variants in or near cytokine genes, nonetheless, the translation of these findings into knowledge of functional determinants of complex traits remains a fundamental challenge. In this study we aimed at collection, analysis and interpretation of data on cytokines focused on their tissue-specific expression, eQTLs and GWAS traits. Using GO annotations, we generated a list of 314 cytokines and analyzed them with the GTEx resource. Cytokines were highly tissue-specific, 82.3% of cytokines had Tau expression metrics ≥ 0.8. In total, 3077 associations for 1760 unique SNPs in or near 244 cytokines were mapped in the NHGRI-EBI GWAS Catalog. According to the Experimental Factor Ontology resource, the largest numbers of disease associations were related to 'Inflammatory disease', 'Immune system disease' and 'Asthma'. The GTEx-based analysis revealed that among GWAS SNPs, 1142 SNPs had eQTL effects and influenced expression levels of 999 eGenes, among them 178 cytokines. Several types of enrichment analysis showed that it was cytokines expression variability that fundamentally contributed to the molecular origins of considered immune-mediated conditions.

Verification of the Chromosome Region 9q21 Association with Pelvic Organ Prolapse Using RegulomeDB Annotations.

Pelvic organ prolapse (POP) is a common highly disabling disorder with a large hereditary component. It is characterized by a loss of pelvic floor support that leads to the herniation of the uterus in or outside the vagina. Genome-wide linkage studies have shown an evidence of POP association with the region 9q21 and six other loci in European pedigrees. The aim of our study was to test the above associations in a case-control study in Russian population. Twelve SNPs including SNPs cited in the above studies and those selected using the RegulomeDB annotations for the region 9q21 were genotyped in 210 patients with POP (stages III-IV) and 292 controls with no even minimal POP. Genotyping was performed using the polymerase chain reaction with confronting two-pair primers (PCR-CTPP). Association analyses were conducted for individual SNPs, 9q21 haplotypes, and SNP-SNP interactions. SNP rs12237222 with the highest RegulomeDB score 1a appeared to be the key SNP in haplotypes associated with POP. Other RegulomeDB Category 1 SNPs, rs12551710 and rs2236479 (scores 1d and 1f, resp.), exhibited epistatic effects. In this study, we verified the region 9q21 association with POP in Russians, using RegulomeDB annotations.

Fibulin-5 (FBLN5) gene polymorphism is associated with pelvic organ prolapse.

OBJECTIVE: FBLN5 encodes a key protein of elastic fiber matrix assembly and function that contributes to maintaining pelvic support and plays the important role in the pathophysiology of pelvic organ prolapse (POP). The aim of the study was to investigate whether there is an association between common single-nucleotide polymorphisms (SNPs) of the FBLN5 gene and POP. STUDY DESIGN: A total of eleven tag SNPs of the FBLN5 gene were genotyped using the polymerase chain reaction with confronting two-pair primers (PCR-CTPP) in 210 patients with POP (stages III-IV) and 292 controls with no even minimal POP. RESULTS: We revealed significant associations of tag SNPs rs2018736 and rs12589592 with POP. The top association signal was found for SNP rs2018736 (protective effect for the minor allele A) in the entire set: p=0.0026, OR=0.42, 95% CI: 0.24-0.75; in the stratum with pelvic floor trauma: p=0.0018, OR=0.27, 95% CI: 0.11-0.64; and in the stratum with fetal macrosomia: p=0.013, OR=0.14, 95% CI: 0.03-0.71. The results of the haplotype analyses were consistent with the single SNP analysis. In the strata without perineal trauma and fetal macrosomia effects were non-significant, possibly, due to the smaller effect sizes. CONCLUSIONS: Current data provide, for the first time, strong evidence that common SNPs of the FBLN5 gene are associated with POP especially after pelvic floor injury.