Human chitotriosidase polymorphisms G354R and A442V associated with reduced enzyme activity.
A common polymorphism in the chitotriosidase gene (CHIT1) exists in which a 24 bp duplication in exon 10 results in aberrant splicing and deletion of 87 nucleotides. In this study, the gene frequency was found to be 0.56 (n=2054) in subjects of Asian ancestry, 0.17 (n=984) in subjects of European ancestry and 0.07 (n=536) in subjects of African ancestry. Notably, the median enzyme activity in wild-type subjects (TT) was much higher in subjects of European ancestry (2.69 mU/ml, n=202 subjects), than subjects of African (2.57 mU/ml, n=230 subjects) (P<0.0001) and Asian ancestry (0.86 mU/ml, n=114 subjects) (P<0.0001). The question of why chitotriosidase deficiency exists at such a high frequency is a challenging one. We postulated that if there was a selective advantage for chitotriosidase deficiency then there would be polymorphisms that would be associated with reduced enzyme activity independent of the 24 bp duplication. We found that the G102S and the A442G polymorphisms found occurring in subjects of all ancestries were not significantly associated with a reduction of enzyme activity. In contrast, the G354R (P<0.0001) and the A442V (P=0.0013) polymorphisms occurring predominantly in subjects of African ancestry were significantly associated with reduced chitotriosidase activity. We also investigated the possibility that chitotriosidase deficiency was associated with tuberculosis or with atopy, including allergic rhinitis, contact dermatitis, food or drug allergies and asthma.
Lee
Pauline
P
The Scripps Research Institute, Department of Molecular and Experimental Medicine, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. plee@scripps.edu
Waalen
Jill
J
Crain
Karen
K
Smargon
Aaron
A
Beutler
Ernest
E
D000483:Alleles; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006596:Hexosaminidases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology / Q000235:genetics; D011110:Polymorphism, Genetic; D014376:Tuberculosis / Q000201:enzymology / Q000235:genetics; D044465:White People / Q000235:genetics
D006596:Hexosaminidases; C086400:chitotriosidase
J Clin Invest. 1994 Mar;93(3):1288-92
8132768
Science. 1992 May 8;256(5058):794-9
1589760
J Biol Chem. 1998 Oct 2;273(40):25680-5
9748235
J Immunol. 1998 Oct 15;161(8):4283-8
9780204
Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):687-94
10073974
Blood Cells Mol Dis. 1999 Feb;25(1):1-8
10349508
Clin Chim Acta. 2005 Mar;353(1-2):215; author reply 217
15698611
J Clin Lab Anal. 2005;19(3):128-32
15900564
Med Mycol. 2005 Jun;43(4):349-53
16110781
Leukemia. 2005 Oct;19(10):1745-50
16107886
Int Immunol. 2005 Nov;17(11):1505-12
16214810
Am J Respir Crit Care Med. 2005 Dec 15;172(12):1505-9
16179638
Int J Immunogenet. 2006 Jun;33(3):201-4
16712652
J Hum Genet. 2007;52(2):110-6
17106626
Parasitol Res. 2007 Apr;100(5):1033-9
17136386
Nature. 2007 May 3;447(7140):92-6
17450126
J Immunol. 2000 Feb 1;164(3):1314-21
10640745
J Biol Chem. 2001 Mar 2;276(9):6770-8
11085997
Genes Immun. 2001 Aug;2(5):248-53
11528516
Infect Immun. 2001 Oct;69(10):6123-30
11553551
Lancet. 2002 Jan 19;359(9302):211-8
11812557
Blood Cells Mol Dis. 2002 Jul-Aug;29(1):116-8
12482412
Blood Cells Mol Dis. 2002 Nov-Dec;29(3):418-32
12678056
Clin Chim Acta. 2003 May;331(1-2):79-85
12691867
Genes Immun. 2003 Oct;4(7):524-7
14551607
Genes Immun. 2003 Dec;4(8):570-4
14647197
Immunol Lett. 2004 Jun 15;94(1-2):57-63
15234536
Genet Med. 2004 May-Jun;6(3):145-52
15354333
Int Arch Allergy Appl Immunol. 1982;68(4):377-81
6980193
Int J Biochem. 1988;20(7):713-9
3181601
Genomics. 1991 May;10(1):229-35
1710599
J Inherit Metab Dis. 1995;18(6):717-22
8750610