rs4149584

Whole genome sequencing of 44 Ashkenazi Jewish centenarians identified 216 coding variants annotated as pathogenic or likely pathogenic in ClinVar. The study found 130 rare variants (MAF <5%) reported to cause degenerative, neoplastic, and cardiac diseases with various inheritance patterns. Notably, several carriers had no clinical manifestations despite carrying variants linked to serious diseases (e.g., an APOE ε4 homozygote without Alzheimer's disease, a UBQLN2 P525S carrier without ALS). These findings suggest incomplete penetrance and reduced clinical significance for many reported disease mutations.

This study examined whether genetic variants that predict higher 25-hydroxyvitamin D (25(OH)D) levels are associated with reduced multiple sclerosis (MS) risk in 1,655 MS cases and 6,349 controls. SNPs in GC (rs2282679) were significant predictors of 25(OH)D levels but showed no association with MS risk. The CYP2R1 rs10741657 'A' allele was associated with increased 25(OH)D and reduced MS risk among HLA-DR15 negative individuals (OR=0.89, 95% CI: 0.79-1.01) but not HLA-DR15 positive individuals. CYP27B1 rs703842 'C' allele was inversely associated with MS risk, with stronger effects in HLA-DR15 negative (OR=0.79, 95% CI: 0.69-0.90) versus positive individuals (OR=0.91, 95% CI: 0.80-1.04), suggesting vitamin D's protective effect on MS may be attenuated by the HLA-DR15 risk allele.