FCGR2B I232T - GET-Evidence

Curation:
Currentness:

FCGR2B I232T

(FCGR2B Ile232Thr)


Short summary

A study in an Asian population associates this variant with increased susceptibility to anti-glomerular basement membrane antibody disease (anti-GBM), an autoimmune disease that causes bleeding, lung, and kidney disease. Even for carriers of this variation, anti-GBM is quite rare — this variant only increases absolute risk for the disease by 0.1-0.2%. A much weaker finding seems to correlate homozygosity for the variant with increased risk for systemic lupus erythematosus (SLE); if true, the amount of increased risk due to the variant is unclear.

Variant evidence
Computational 1

There are other variants such as FCGR2A, FCGR2B, FCGR3A, and FCGR3B that have caused the same autoimmune diseases.

Functional -
Case/Control 4

For anti-GBM association with variant was high, corrected p-value of 0.0004, 95% CI: 1.78-6.43.

See Kyogoku C et al. 2002 (12115230).

Familial

No familial data

 
Clinical importance
Severity 4

SLE and anti-GBM can be lethal. Rheumatoid arthritis is less severe.

Treatability 4

All three conditions can be treated to significantly reduce morbidity, but cannot be eliminate completely.

Penetrance

Based on Zhou et al., increased attributable risk for anti-GBM is around 0.1-0.2%. For SLE it may be in .1-1% range, but significance of the findings from Kyogoku et al. are quite weak.

See Kyogoku C et al. 2002 (12115230), Zhou XJ et al. 2010 (19640933).

 

Impact

Low clinical importance, Likely pathogenic

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

other

Summary of published research, and additional commentary

http://emedicine.medscape.com/article/1001872-overview#a0156 Estimates annual incidence at 1 per 2 million population. Elsewhere estimates are 1 per 1 million — these seem to place the lifetime risk at around 1 in 20,000 or .005%

http://www.medscape.com/viewarticle/736557 places lifetime risk of SLE at 0.9% for women and 0.2% for men.

The frequencies of the genotype vary greatly in populations worldwide, with Asians usually having a higher frequency of the FCGR2B I232T allele compared to Europeans. Anti-GBM disease is autoimmune, relatively uncommon, and causes rapid renal failure and lung bleeding and has been found to be associated with the FCGR2B I232T allele in the Chinese. SLE, also an autoimmune disorder that may affect skin, joints, kidney, brain and other organs and rheumatoid arthritis, which leads to long term inflammation of joints has found to be associated with FCGR2B I232T allele in Japanese and Thais. Additionally FCGR2B I232T found in the FCGR gene polymorphisms such as FCGR2A, FCGR2B, FCGR3A, and FCGR3B that have been reported to be associated with similar human autoimmune diseases.

show discussion

Discussion

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Allele frequency

  • C @ chr1:161643798: 13.3% (1017/7666) in EVS
  • C @ chr1:159910421: 6.2% (6/96) in GET-Evidence
  • Frequency shown in summary reports: 13.3% (1017/7666)

Publications
 

Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H, Yamaguchi A, Fukazawa T, Jansen MD, Hashimoto H, van de Winkel JG, Kallenberg CG, Tokunaga K. Fcgamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum. 2002 May;46(5):1242-54. PubMed PMID: 12115230.

Reports FCGR2B-232T/T as having OR 2.35, 95% confidence interval [95% CI] 1.4–4.0, χ2 = 9.5, P = 0.002 … But in discussion it reports “When the P values are corrected by multiplying the number of comparisons, only the association of the FCGR2B-232T/T genotype remains significant (Pcorr = 0.044).”

An odds ratio of 2.35 implies 2-3 fold incidence of disease — so increased attributable risk of 0.9-1.8% for women and 0.2-0.4% for men.

Zhou XJ, Lv JC, Yu L, Cui Z, Zhao J, Yang R, Han J, Hou P, Zhao MH, Zhang H. FCGR2B gene polymorphism rather than FCGR2A, FCGR3A and FCGR3B is associated with anti-GBM disease in Chinese. Nephrol Dial Transplant. 2010 Jan;25(1):97-101. Epub 2009 Jul 29. PubMed PMID: 19640933.

Associated with anti-GBM disease with 3.38 OR, corrected p-value 0.0004. Note that even with 3 or 4 fold risk, if one assumes the disease has a lifetime risk of 0.005% this predicts only a small increased attributable risk in the range of 0.01-0.02%.

I vs T genotype frequencies:
Cases — T/T: 0, T/I: 29, I/I: 19
Controls — T/T: 0, T/I: 70, I/I: 155

Genomes
 

GS18537 - var-GS18537-1100-36-ASM
hom C @ chr1:159910422

 

GS19129 - var-GS19129-1100-36-ASM
het C @ chr1:159910422

 

GS19649 - var-GS19649-1100-36-ASM
het C @ chr1:159910422

 

Other external references
 

    dbSNP
  • rs1050501
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.003 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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