Genome-wide association study identifies common variants at TNFRSF13B associated with IgG level in a healthy Chinese male population

Abstract

IgG has a crucial role in humoral immune response. Serum IgG level is mainly determined under genetic control. To explore the genetic influence on serum IgG levels, a two-stage genome-wide association study (GWAS) was performed in a healthy Chinese population of 3495 men, including 1999 unrelated subjects in the first stage and 1496 independent individuals in the second stage. Three single-nucleotide polymorphisms (SNPs) located in TNFRSF13B on 17p11.2 or nearby were significantly associated with IgG level: rs4792800 in the intron (combined P-value ¼ 1.45 Â 10 À 12 ), rs12603708 in the intron (combined P-value ¼ 1.82 Â 10 À 8 ) and rs3751987 at B65 kb downstream of the 5 0 -UTR region of TNFRSF13B (combined P-value ¼ 3.67 Â 10 À 9 ). Additionally, smoking was identified to be associated with IgG level in both stages (Po0.001), but there was no significant interaction between smoking and the identified SNPs (P40.05). The strong association between variants at TNFRSF13B and IgG level may be helpful to further explore the biological mechanism by which the serum IgG is affected by transmembrane activator, calcium modulator and cyclophilin ligand interactor encoded by TNFRSF13B.Genes and Immunity (2012) 13, 509-513; doi:10.1038/gene.2012.26; published online 7 June 2012Keywords: IgG; genome-wide association studies; TNFRSF13B; TACI; smoking INTRODUCTION IgG, constituting some 80% of total serum immunoglobulin, is the most abundant class of antibodies (Ab) in serum and extracellular fluid. It has an important role in the defense against various pathogens, toxins and even cancers. 1 As the only isotype that can pass through the human placenta, IgG is able to protect the fetus in utero. 2 Meanwhile, IgG gets involved in chronic inflammatory processes contributed to the destruction of healthy tissues in autoimmune diseases, such as arthritis and systemic lupus erythematosus. 3 Serum IgG level varies considerably from one person to another, 4 but little when testing the same person repeatedly. 5 This variation in the serum IgG concentration reflects the balance among the rates of synthesis and catabolism. 6 Multitudinous environmental factors including infections, smoking and chemical compounds can contribute to this variation. 7-9 Reports of pedigree studies or twin studies 10,11 have shown that genetic factors are more important than environmental exposures in determining serum immunoglobulin level in human. 12,13 The values of genetic heritability was h 2 ¼ 0.617 þ 0.020 for IgG. 6 Besides, several studies in a population of common variable immunodeficiency patients or IgA deficiency patients implied that there might be an association between some gene loci and serum IgG level. 14,15 However, to the best of our knowledge, no study has ever been conducted to identify the immune loci directly involved in the regulation of the IgG level.Genome-wide association study (GWAS) is a powerful and unbiased tool for the identification of common genetic variants associated with complex traits. 16 This hypothesis-free approach base...

Genetic factors and age are the strongest predictors of humoral immune responses to common pathogens and vaccines

“…Using a significance threshold of Pthreshold < 1.3 x 10 -8 , we found no SNPs associated with total IgG, IgM, IgE and IgA levels. However, we observed nominal significance and the same direction of the effect for 3 out of 11 loci previously published for total IgA [12,30,31,32,33], 1 out of 6 loci for total IgG [12,30,34] and 4 out of 11 loci for total IgM [12,35] (Table S8). Finally, we also report a suggestive association (genome-wide significant, P < 5.0 x 10 -8 , but not significant when correcting for the number of immunoglobulin classes tested in the study) of a SNP rs11186609 on chromosome 10 with total IgA levels (P = 2.0 x 10 -8 , beta = -0.07 for the C allele).…”

Genes associated with common variable immunodeficiency: one diagnosis to rule them all?

“…Intraexonic duplications in ORC4L were found to be most highly associated with CVID 116. GWAS in healthy Chinese men (n=3495) showed an association between serum IgG and the locus containing TNFRSF13B (encoding TACI) 124. However, the 2011 GWAS did not detect associations with the TNFRSF13B locus 116…”

Inherited genetic susceptibility to monoclonal gammopathy of unknown significance

“…13 rs877529 is intronic to the gene CBX7, which acts through Ink4a/Arf cooperating with Myc to promote aggressive B-cell lymphomagenesis.…”