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 non-albumin 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) = 3.1×10(−9)), and additionally identified the significant genome-wide association of rs4985726 in TNFRSF13B on 17p11.2 with both TP and NAP (P (meta) = 1.2×10(−14) and 7.1×10(−24), respectively). For NAP, rs3803800 and rs11552708 in TNFSF13 on 17p13.1 (P (meta) = 7.2×10(−15) and 7.5×10(−10), respectively) as well as rs10007186 on 4q21.2 near ANXA3 (P (meta) = 1.3×10(−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<2.3×10(−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 = 4.9×10(−4)). Our results should add interesting knowledge about the regulation of major serum components.