Positive replication and linkage disequilibrium mapping of the chromosome 21q22.1 malaria susceptibility locus.
Four cytokine receptor genes are located on Chr21q22.11, encoding the alpha and beta subunits of the interferon-alpha receptor (IFNAR1 and IFNAR2), the beta subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-gamma receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained from public databases and by sequencing a 44 kb region in and around the IFNAR1 gene in 24 Gambian children (12 cases/12 controls). Within the IFNAR1 gene, a newly studied C --> G single-nucleotide polymorphism (IFNAR1 272354c-g) at position -576 relative to the transcription start was found to be more strongly associated with susceptibility to severe malaria. Association was observed in three populations: in Gambian (P=0.002), Kenyan (P=0.022) and Vietnamese (P=0.005) case-control studies. When all three studies were combined, using the Mantel-Haenszel test, the presence of IFNAR1 -576G was associated with a substantially elevated risk of severe malaria (N=2444, OR=1.38, 95% CI: 1.17-1.64; P=1.7 x 10(-4)). This study builds on previous work to further highlight the importance of the type-I interferon pathway in malaria susceptibility and illustrates the utility of typing SNPs within regions of high linkage disequilibrium in multiple populations to confirm initial positive associations.
Khor
C C
CC
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. khor_chiea_chuen@sics.a-star.edu.sg
Vannberg
F O
FO
Chapman
S J
SJ
Walley
A
A
Aucan
C
C
Loke
H
H
White
N J
NJ
Peto
T
T
Khor
L K
LK
Kwiatkowski
D
D
Day
N
N
Scott
A
A
Berkley
J A
JA
Marsh
K
K
Peshu
N
N
Maitland
K
K
Williams
T N
TN
Hill
A V S
AV
D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D005714:Gambia; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D053710:Interleukin-10 Receptor beta Subunit / Q000235:genetics; D007630:Kenya; D015810:Linkage Disequilibrium; D008288:Malaria / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D017471:Receptors, Interferon / Q000235:genetics; D014744:Vietnam; D000096743:Interferon gamma Receptor
D005819:Genetic Markers; D053710:Interleukin-10 Receptor beta Subunit; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; C081846:IL10RB protein, human
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9148-53
16757563
Nat Genet. 2007 Jan;39(1):120-5
17159978
J Infect Dis. 2000 Apr;181(4):1513-6
10762587
Bioinformatics. 2000 Feb;16(2):182-3
10842743
Science. 2000 Jun 30;288(5475):2357-60
10875919
Am J Hum Genet. 2001 Apr;68(4):978-89
11254454
Blood. 2001 Jun 15;97(12):3966-71
11389041
Adv Biochem Eng Biotechnol. 2002;77:57-74
12227737
Nature. 2005 Apr 7;434(7034):772-7
15800576
Nature. 2005 Mar 10;434(7030):214-7
15759000
Cold Spring Harb Symp Quant Biol. 1964;29:137-49
14278460
Nat Genet. 1999 Jun;22(2):145-50
10369255
J Exp Med. 1999 Apr 19;189(8):1315-28
10209048
J Infect Dis. 1999 Apr;179(4):980-8
10068595
J Infect Dis. 1999 Jan;179(1):287-90
9841857
J Infect Dis. 1999 Jan;179(1):283-6
9841856
Genome Res. 1998 Mar;8(3):195-202
9521923
Genome Res. 1998 Mar;8(3):186-94
9521922
Genome Res. 1998 Mar;8(3):175-85
9521921
J Exp Med. 1996 Apr 1;183(4):1739-46
8666931
Nature. 1995 Jul 20;376(6537):246-9
7617034
N Engl J Med. 1995 May 25;332(21):1399-404
7723795
Nature. 1991 Aug 15;352(6336):595-600
1865923
Nature. 1986 Jun 19-25;321(6072):744-50
3713863
Infect Immun. 2004 Oct;72(10):5630-7
15385460
Hum Mol Genet. 2004 Oct 1;13 Spec No 2:R187-94
15358724
Infect Immun. 2004 Sep;72(9):5135-42
15322007
J Infect Dis. 2002 Jun 1;185(11):1684-7
12023780
Nat Genet. 2007 Jan;39(1):126-30
17159981
Nat Genet. 2007 Jan;39(1):113-9
17159979
Parasite Immunol. 2004 Mar;26(3):111-7
15279621
Genes Immun. 2003 Jun;4(4):275-82
12761564
Trends Immunol. 2003 Sep;24(9):491-9
12967673
J Immunol. 2004 Apr 15;172(8):4926-33
15067072