Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians

Abstract

Of the 1.8 billion people worldwide infected with Mycobacterium tuberculosis , 5–15% will develop active tuberculosis (TB). Approximately half will progress to active TB within the first 18 months after infection, presumably because they fail to mount an effective initial immune response. Here, in a genome-wide genetic study of early TB progression, we genotype 4002 active TB cases and their household contacts in Peru. We quantify genetic heritability ( ) of early TB progression to be 21.2% (standard error 0.08). This suggests TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases. We identify a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR = 1.18; P = 3.93 × 10 −8 ). With in silico and in vitro analyses we identify rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function.

Blood RNA Signatures Predict Recent Tuberculosis Exposure in Mice, Macaques and Humans

“…A recent genetic study of early progression to TB disease (within 18 months) demonstrated that the genetic architecture of early progression and later reactivation disease are different (47).…”

Using population-specific add-on polymorphisms to improve genotype imputation in underrepresented populations

“…Under Setting 1, regions spanning 5000 base pairs upstream and downstream of genes or SNPs associated with TB outcomes (reported by GWAS catalog [31], Open Targets[32], and other GWAS studies[33, 34, 35]) were considered. The killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) gene regions were also considered.…”

Higher Native Peruvian ancestry proportion is associated with tuberculosis progression risk

“…Here we investigate this hypothesis in a prospective cohort of 3,980 Peruvains 9 . The genome of contemporary Peruvians is shaped by extensive admixture between Native Peruvians and the Europeans, Africans, and Asians that arrived in Peru following colonization 12–14 .…”

“…We observed nominal evidence of association at 3q23 (Wald test Wald test p-value = 2.8×10 −5 ), 2p24.3 (Wald test p-value = 5.9×10 −5 ), and 5p23.2 (Wald test p-value = 7.2×10 −5 , Figure S3 ). In a previous genome-wide association study (GWAS) our group showed that 3q23 locus is significantly associated with TB progression risk in Peruvians (p-value < 5×10 −8 ) 9 . In our GWAS, the top risk variant (rs73226617, OR = 1.18; p-value = 3.9×10 −8 ) at 3q23 has a higher frequency in Europeans compared to Peruvians (MAF = 0.05 vs. 0.03) and is unlikely to explain the admixture mapping signal we observe at this locus.…”