rs4950928

A genome-wide association study of 83 plasma proteins relevant to cardiovascular disease in 3,394 European subjects identified 79 genome-wide significant loci (p<5e-8), with 55 replicating in independent cohorts (n=2,639). Using eQTL analysis and network methods, the authors proposed plausible causal mechanisms for 25 trans-acting loci including post-translational regulation of KITLG by MMP9 and several receptor-ligand pairs. Multiple loci showed evidence of causal association with coronary artery disease risk.

This association study examined genetic variants in chitinase genes (CHIA, CHIT1, CHI3L1) and their relationship to lung function in COPD. In the Lung Health Study cohort (4,344 smokers), CHIA rs3818822 (Gly102Arg) was associated with baseline FEV1 level in Caucasians (p=0.0291), with AA genotype showing ~3% lower FEV1 compared to GG genotype. The GG genotype was associated with 2.4-fold higher AMCase protein levels and 4-fold higher chitinase activity. CHIT1 rs2494303, in perfect linkage disequilibrium with a 24-bp duplication, was significantly associated with rate of FEV1 decline in Caucasians (p=0.0083), and CHIA G339T was associated with FEV1 decline rate in African Americans (p=0.0021). However, these associations did not replicate in four independent COPD case-control populations.

This case-control study examined two functional SNPs of the CHI3L1 gene (rs4950928 and rs10399931) in 182 Hungarian rheumatoid arthritis patients and 194 healthy controls. Despite CHI3L1's known elevated levels in RA and prior associations with schizophrenia and sarcoidosis, no significant association was found between either SNP and rheumatoid arthritis susceptibility (all p > 0.05, ORs 0.95-1.09 with 95% CIs overlapping 1.0).

This case-control study examined two functional SNPs in the CHI3L1 gene (rs4950928 and rs10399931) previously associated with schizophrenia and sarcoidosis to determine if they associate with rheumatoid arthritis. In 182 Hungarian RA patients and 194 healthy controls, no significant associations were found between either SNP and RA risk (all p > 0.05), suggesting that CHI3L1 polymorphisms may not confer RA susceptibility despite elevated CHI3L1 levels observed in RA patients.

This PhD thesis comprises four association studies examining inherited variations in inflammatory cytokine genes and their pathogenetic role in rheumatoid arthritis (RA), multiple myeloma (MM), and B-cell non-Hodgkin's lymphoma (B-NHL). Paper I found that CHI3L1 promoter polymorphisms (rs4950928) were significantly associated with serum YKL-40 concentrations in 238 RA patients (P < 2.0e-16) and 605 controls. Paper IV reported CHI3L1 rs4950928 associated with follicular lymphoma 10-year overall survival (HRCG = 2.04, 95% CI 1.17-3.54). Papers II and III examined gene-gene interactions in MM and B-NHL risk and prognosis.