rs2230199

A retrospective cohort study of 282 patients with severe uncontrolled asthma treated with omalizumab, mepolizumab, or benralizumab for 12 months evaluated genetic variants in 11 genes (IL1RL1, IL5, GATA2, IKZF2, RAD50, C3, FCER1A, FCER1B, FCGR2A, FCGR2B, FCGR3A) as predictors of response. Key findings: FCGR2B rs3219018-C, GATA2 rs4857855-T, and FCGR2A rs1801274-AG associated with improved lung function in omalizumab (p=0.052, 0.052, 0.012); IL1RL1 rs17026974-AG/GG associated with reduced exacerbations in omalizumab (p=0.040, 0.041); FCER1B rs569108-AA and FCGR2A rs1801274-GG associated with corticosteroid reduction in benralizumab; FCER1A rs2427837-A associated with improved lung function in mepolizumab (p=0.023).

Cross-sectional study of 835 CATT participants with neovascular AMD genotyped for SNPs in CFH, ARMS2, C3, LIPC, CFB, and C2. ARMS2 risk alleles were associated with larger total lesions (p=0.03) and increased intraretinal fluid (p=0.008); C3 risk alleles were associated with decreased intraretinal fluid (p=0.001) and retinal thickness (p=0.02); CFH risk alleles were associated with decreased total thickness (p=0.01).

This study evaluated 835 neovascular age-related macular degeneration (nAMD) patients from the CATT trial for associations between 8 SNPs in the VEGF signaling pathway (7 in VEGF-A: rs699946, rs699947, rs833069, rs833070, rs1413711, rs2010963, rs2146323; 1 in VEGFR-2: rs2071559) and response to anti-VEGF therapy with ranibizumab or bevacizumab. While four VEGF-A SNPs showed nominal associations with retinal thickness (p=0.03-0.04 and p=0.006), adjusted p-values were not statistically significant (p=0.24-0.45). The study found no pharmacogenetic associations between these VEGF pathway SNPs and visual acuity, anatomical outcomes, or injection frequency, concluding that these variants do not substantially influence response to anti-VEGF therapy.

Prospective cohort study of 472 elderly French participants (mean age 81.9 years) from the ALIENOR study examining incident reticular pseudodrusen (RPD). Annual incidence was 2.047% with estimated 5-year cumulative incidence of 9.73%. Risk factors identified in multivariate analysis included ARMS2 rs10490924 (HR 3.36, p=0.0009), LIPC rs10468017 (HR 2.65, p=0.0029), and thinner choroidal thickness (HR 1.06, p=0.0085). Liposoluble statin medication was protective (HR 0.18, p=0.0448).

A prospective nested case-control study pooled from five large cohorts examining 15 CX3CR1 SNPs (including T280M and V249I) in 1,110 AMD cases (369 neovascular AMD) and 2,532 controls. No significant associations with AMD were found for the candidate variants T280M (RR=0.87, P=0.074) or V249I (RR=1.01, P=0.82) after multiple comparisons correction. Some CX3CR1 variants showed nominal associations with neovascular AMD in recessive models (rs2669845 RR=3.10 P=0.035, rs9868689 RR=0.31 P=0.017, rs2853707 RR=0.48 P=0.050), with possible gene-environment and gene-gene interactions identified.

This case-control study of 1844 unrelated white individuals examined the association between 8 SNPs in 5 genes (CFH, HTRA1/LOC387715, C2, CFB, C3) and advanced age-related macular degeneration (AMD), including geographic atrophy and choroidal neovascularization. All genetic variants showed strong associations with AMD, with odds ratios ranging from 0.44 (C2 rs9332739, protective) to 10.99 (HTRA1/LOC387715 rs10490924 TT). A combined predictive model including genetic variants and environmental factors (smoking, age, BMI) achieved 78.8% discrimination accuracy with ROC curve AUC of 0.82.

This cumulative PhD dissertation investigates genetic susceptibility factors for age-related macular degeneration (AMD). The study confirms weak associations of APOE coding variants with AMD risk (P < 0.05) but finds no association with HMCN1 variants. Large replication studies of candidate genes TLR3 and SERPING1 (1,080-4,881 cases and 2,669-2,842 controls) show no association. The authors identified 15 high-risk variants in ARMS2/HTRA1 region on chromosome 10q23.33-10qter, with the ARMS2 A69S variant showing 2.7-fold increased risk heterozygously and 8.2-fold increased risk homozygously, comparable in strength to CFH Y402H. An indel variant (c.*372_815del443ins54) in ARMS2 3' UTR causes mRNA destabilization.