Association of Common Variants in TNFRSF13B, TNFSF13, and ANXA3 with Serum Levels of Non-Albumin Protein and Immunoglobulin Isotypes in Japanese

We performed a genome-wide association study (GWAS) on levels of serum total protein (TP), albumin (ALB), and nonalbumin protein (NAP). We analyzed SNPs on autosomal chromosomes using data from 9,103 Japanese individuals, followed by a replication study of 1,600 additional individuals. We confirmed the previously-reported association of GCKR on chromosome 2p23.3 with serum ALB (rs1260326, P-meta = 3.1x10(-9)), and additionally identified the significant genome-wide association of rs4985726 in TNFRSF13B on 17p11.2 with both TP and NAP ( P-meta = 1.2x10(-14) and 7.1x10(-24), respectively). For NAP, rs3803800 and rs11552708 in TNFSF13 on 17p13.1 (P-meta = 7.2x10(-15) and 7.5x10(-10), respectively) as well as rs10007186 on 4q21.2 near ANXA3 (Pmeta = 1.3x10(-9)) also indicated significant associations. Interestingly, TNFRSF13B and TNFSF13 encode a tumor necrosis factor (TNF) receptor and its ligand, which together constitute an important receptor-ligand axis for B-cell homeostasis and immunoglobulin production. Furthermore, three SNPs, rs4985726, rs3803800, and rs11552708 in TNFRSF13B and TNFSF13, were indicated to be associated with serum levels of IgG (P<2.3x10(-3)) and IgM (P<0.018), while rs3803800 and rs11552708 were associated with IgA (P<0.013). Rs10007186 in 4q21.2 was associated with serum levels of IgA (P = 0.036), IgM (P = 0.019), and IgE (P = 4.9x10(-4)). Our results should add interesting knowledge about the regulation of major serum components.