Evaluation of microsatellite markers in association studies: a search for an immune-related susceptibility gene in sarcoidosis.
Association studies using linkage disequilibrium (LD) between candidate loci and nearby markers have been proposed to identify susceptibility genes for complex diseases. We analyzed polymorphisms of microsatellites (MSs) and LD patterns of the regions in which candidate genes related to the Th1 immune response have been annotated and attempted to identify a susceptibility gene for sarcoidosis in a marker-based association study. Nineteen MSs were identified in six Th1-related genes (IFNGR1, IFNGR2, IL12RB1, IL12RB2, STAT1 and STAT4) and then eight were further characterized as useful polymorphic markers. Most of these MSs showed LD with single nucleotide polymorphisms (SNPs) on both 5' and 3' ends of these candidate genes, in which r(2) values between at least one of the MS marker alleles and the SNPs were higher than 0.1. A significant association with one MS allele near STAT4 was shown and a cluster of SNPs in LD with the MS marker was associated with sarcoidosis. These results suggest that association studies using not only SNPs but also multi-allelic MS within or near candidate loci would be useful markers to search for a disease susceptibility gene, especially in populations with unknown LD structure.
Tanaka
Goh
G
Department of Respiratory Diseases, Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan.
Matsushita
Ikumi
I
Ohashi
Jun
J
Tsuchiya
Naoyuki
N
Ikushima
Soichiro
S
Oritsu
Masaru
M
Hijikata
Minako
M
Nagata
Taiji
T
Yamamoto
Kazuhiko
K
Tokunaga
Katsushi
K
Keicho
Naoto
N
D000328:Adult; D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005802:Genes, MHC Class II; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D050797:STAT4 Transcription Factor; D012507:Sarcoidosis / Q000235:genetics* / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators