Variation in antiviral 2',5'-oligoadenylate synthetase (2'5'AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene.
It is likely that human genetic differences mediate susceptibility to viral infection and virus-triggered disorders. OAS genes encoding the antiviral enzyme 2',5'-oligoadenylate synthetase (2'5'AS) are critical components of the innate immune response to viruses. This enzyme uses adenosine triphosphate in 2'-specific nucleotidyl transfer reactions to synthesize 2',5'-oligoadenylates, which activate latent ribonuclease, resulting in degradation of viral RNA and inhibition of virus replication. We showed elsewhere that constitutive (basal) activity of 2'5'AS is correlated with virus-stimulated activity. In the present study, we asked whether constitutive activity is genetically determined and, if so, by which variants. Analysis of 83 families containing two parents and two children demonstrated significant correlations between basal activity in parent-child pairs (P<.0001) and sibling pairs (P=.0044), but not spousal pairs, suggesting strong genetic control of basal activity. We next analyzed association between basal activity and 15 markers across the OAS gene cluster. Significant association was detected at multiple markers, the strongest being at an A/G single-nucleotide polymorphism at the exon 7 splice-acceptor site (AG or AA) of the OAS1 gene. At this unusual polymorphism, allele G had a higher gene frequency in persons with high enzyme activity than in those with low enzyme activity (0.44 vs. 0.20; P=3 x 10(-11)). Enzyme activity varied in a dose-dependent manner across the GG, GA, and AA genotypes (tested by analysis of variance; P=1 x 10(-14)). Allele G generates the previously described p46 enzyme isoform, whereas allele A ablates the splice site and generates a dual-function antiviral/proapoptotic p48 isoform and a novel p52 isoform. This genetic polymorphism makes OAS1 an excellent candidate for a human gene that influences host susceptibility to viral infection.
Bonnevie-Nielsen
Vagn
V
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Field
L Leigh
LL
Lu
Shao
S
Zheng
Dong-Jun
DJ
Li
Min
M
Martensen
Pia M
PM
Nielsen
Thomas B
TB
Beck-Nielsen
Henning
H
Lau
Yu-Lung
YL
Pociot
Flemming
F
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites / Q000235:genetics*
D022821:RNA Splice Sites; D015088:2',5'-Oligoadenylate Synthetase
Clin Immunol. 2000 Jul;96(1):11-8
10873423
Diabetes. 2005 May;54(5):1588-91
15855350
Eur J Immunogenet. 2000 Jun;27(3):111-7
10940077
Cell Mol Life Sci. 2000 Oct;57(11):1593-612
11092454
Cytokine Growth Factor Rev. 2001 Jun-Sep;12(2-3):143-56
11325598
J Biol Chem. 2001 Jul 6;276(27):25447-55
11323417
Annu Rev Microbiol. 2001;55:255-81
11544356
Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9322-7
12080145
Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11311-6
12186974
Nat Genet. 2002 Dec;32(4):581-3
12415269
Scand J Immunol. 2002 Dec;56(6):630-41
12472676
Biochemistry. 2003 Feb 25;42(7):1805-12
12590567
J Mol Biol. 2003 Mar 7;326(5):1449-61
12595257
Immunol Cell Biol. 2003 Jun;81(3):230-6
12752688
Genes Immun. 2003 Sep;4(6):411-9
12944978
Cancer Res. 2003 Oct 15;63(20):6795-801
14583476
Mol Cell. 2003 Nov;12(5):1173-85
14636576
Diabetes. 1989 Dec;38(12):1636-42
2573556
Diabetes. 1995 Jun;44(6):652-7
7789630
Lancet. 1997 Jan 25;349(9047):236-40
9014910
J Infect Dis. 1997 Mar;175(3):554-60
9041325
J Biol Chem. 1997 Dec 26;272(52):33220-6
9407111
J Med Virol. 1998 Sep;56(1):74-8
9700636
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15623-8
9861020
Hepatology. 1999 Apr;29(4):1248-51
10094971
Diabetes. 2000 Aug;49(8):1314-8
10923631