Progression of recent Mycobacterium tuberculosis exposure to active tuberculosis is a highly heritable complex trait driven by 3q23 in Peruvians

Abstract

Luo et al. genetics study of TB progression Among 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5-15% are 1 expected to develop active tuberculosis (TB). Approximately half of these will progress 2 to active TB within the first 18 months after infection, presumably because they fail to 3 mount the initial immune response that contains the local bacterial spread. The other half 4 will reactivate their latent infection later in life, likely triggered by a loss of immune 5 competence due to factors such as HIV-associated immunosuppression or ageing. This 6 natural history suggests that undiscovered host genetic factors may control early 7 progression to active TB. Here, we report results from a large genome-wide genetic study 8 of early TB progression. We genotyped a total of 4,002 active TB cases and their 9 household contacts in Peru and quantified genetic heritability ( ) of early TB 10 progression to be 21.2% under the liability scale. Compared to the reported of 11 genome-wide TB susceptibility (15.5%), this result indicates early TB progression has a 12 stronger genetic basis than population-wide TB susceptibility. We identified a novel 13 association between early TB progression and variants located in an enhancer region on 14 chromosome 3q23 (rs73226617, OR=1.19; < × ! ). We used in silico and in vitro 15 analyses to identify likely functional variants and target genes, highlighting new 16 candidate mechanisms of host response in early TB progression. 17 18 The infectious pathogen Mycobacterium tuberculosis (M.tb) infects about one quarter of the 19 world's population 1 . Approximately 5-15% of infected individuals progress to active TB while the 20 vast majority remain infected with viable latent M.tb (Figure 1a). From the approximately 10.4 21 million patients with active TB, an estimated ~1.3 million people died in 2016 2 . Active TB can 22

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

“…It is more likely to be >10, as shown by the data for the infected control simulation, corresponding to a lifetime risk of TB between 40 and 80%. This OR is higher than those reported for the few SNPs identified by genome-wide association studies (GWAS) in TB (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). These 12 GWAS did not detect the effect of P1104A, as they did not report testing a recessive model.…”

X-linked multi-ancestry meta-analysis reveals tuberculosis susceptibility variants

“…Twin studies have estimated that the narrow sense heritability of susceptibility to TB can be up to 80%, but very few modern estimates have been done and none have focused on sex-stratified heritability estimates (26,39,(59)(60)(61). In our a previous meta-analysis we estimated the polygenic heritability of TB susceptibility on the autosomal chromosomes of the ITHGC data, which ranged from 5-36% (39).…”

“…As these factors do not fully explain the sex bias, we hypothesise that X-linked genes and the process of XCI could further clarify the phenomenon. Seventeen published GWAS have investigated TB susceptibility (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), but only six of these included the X chromosome in their analysis (16,17,20,26,28,35) and only one of the studies focused specifically on the X chromosome (35). Our previous study, in a South African setting, revealed strong sex-specific effects on both the autosome and X chromosome, suggesting that sex-stratified quality control (QC) and association testing should be done when analysing the X chromosome and autosomes (35).…”

Genetics and genomics in Peru: Clinical and research perspective

“…Two‐locus genotype −2,518 macrophage chemoattractant protein CCL2 (OMIM #158105) GG and −1607 matrix metalloproteinase MMP1 (OMIM #120353) 2G/2G has been found to promote the expression of hyperinflammation in response to Mycobacterium tuberc ulosis infection, inducing extensive tissue damage and a severe TB disease (Ganachari, Guio, Zhao, & Flores‐Villanueva, ). Regarding TB progression, some variants located near the enhancer region on chromosome 3q23 also have been found (Luo et al, ). Together with the data obtained from the Peruvian Genome Project and these previous studies, it will be possible to define the origins and distribution of these new polymorphisms associated with transmissible and non‐transmissible diseases in Peru: integrating Population Genomics knowledge to Public Health.…”