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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.

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