NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans.
Tuberculosis (TB) has substantial mortality worldwide with 5-10% of those exposed progressing to active TB disease. Studies in mice and humans indicate that the inducible nitric oxide synthase (iNOS) molecule plays an important role in immune response to TB. A mixed case-control association study of individuals with TB, relatives, or close contact controls was performed in 726 individuals (279 case and 166 control African-Americans; 198 case and 123 control Caucasians). Thirty-nine single nucleotide polymorphisms (SNPs) were selected from the NOS2A gene for single SNP, haplotype, and multilocus interaction analyses with other typed candidate genes using generalized estimating equations. In African-Americans, ten NOS2A SNPs were associated with TB. The strongest associations were observed at rs2274894 (odds ratio (OR) = 1.84, 95% confidence interval (CI) [1.23-2.77], p = 0.003) and rs7215373 (OR = 1.67, 95% CI [1.17-2.37], p = 0.004), both of which passed a false discovery rate correction for multiple comparisons (q* = 0.20). The strongest gene-gene interactions were observed between NOS2A rs2248814 and IFNGR1 rs1327474 (p = 0.0004) and NOS2A rs944722 and IFNGR1 rs1327474 (p = 0.0006). Three other SNPs in NOS2A interacted with TLR4 rs5030729 and five other NOS2A SNPs interacted with IFNGR1 rs1327474. No significant associations were observed in Caucasians. These results suggest that NOS2A variants may contribute to TB susceptibility, particularly in individuals of African descent, and may act synergistically with SNPs in TLR4 and IFNGR1.
Velez
Digna Rosa
DR
Dr. John T. Macdonald Foundation Department of Human Genetics, Miami Institute of Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. dvelez@med.miami.edu
Hulme
William F
WF
Myers
Jamie L
JL
Weinberg
J Brice
JB
Levesque
Marc C
MC
Stryjewski
Martin E
ME
Abbate
Eduardo
E
Estevan
Rosa
R
Patillo
Sara G
SG
Gilbert
John R
JR
Hamilton
Carol D
CD
Scott
William K
WK
D000293:Adolescent; D000328:Adult; D044383:Black People / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002874:Chromosome Mapping; D005091:Exons / Q000235:genetics; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns; D008297:Male; D008957:Models, Genetic; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017471:Receptors, Interferon / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014397:Tuberculosis, Pulmonary / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics; D000096743:Interferon gamma Receptor; D001741:Black or African American
D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D051197:Toll-Like Receptor 4; D000096743:Interferon gamma Receptor; C495345:TLR4 protein, human; C496319:NOS2 protein, human