Genetics of Infectious and Inflammatory Diseases: Overlapping Discoveries from Association and Exome-Sequencing Studies

Langlais, David; Fodil, Nassima; Gros, Philippe

doi:10.1146/annurev-immunol-051116-052442

Cited by 37 publications

(32 citation statements)

References 175 publications

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“…While no variants reached a P value < 2 × 10 −6 in our GWAS, 121 variants with a more significant P value than P1104A (<2 × 10 −3 ) and with an MAF > 2% gave ORs higher than 5, suggesting that there may be other recessive etiologies of TB in this cohort. Interestingly, GWAS performed on other, larger population samples for phenotypes other than TB have shown that homozygosity for TYK2 P1104A has a strong protective effect (ORs ranging from 0.1 to 0.3) against various autoinflammatory or autoimmune conditions (25,(48)(49)(50)(51)(52)(53)(54). In light of these results, the potential pharmacological benefits of TYK2 inhibitors for treating autoinflammatory or autoimmune conditions are currently being evaluated (55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

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

Kerner

Ramírez-Alejo

Seeleuthner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96-10.31, P = 2 × 10 −3 ]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for ∼1% of TB cases in Europeans.T uberculosis (TB) remains a major global public health problem. About a quarter of the world's population is infected with Mycobacterium tuberculosis (1, 2), resulting in ∼10 million new cases and 1.6 million deaths worldwide in 2017 (3). Nevertheless, only ∼5% of infected individuals develop active TB in their lifetime (1,4). Abundant evidence for the existence of a genetic component of TB in humans has accumulated from classic genetics studies performed from the turn of the 20th century onward, but its molecular architecture has long remained elusive (5-9). From 1996 onward, single-gene inborn errors of IFN-γ immunity have been found to underlie Mendelian susceptibility to mycobacterial disease (MSMD), which is characterized by severe disease caused by poorly virulent mycobacteria (bacillus Calmette-Guérin vaccines and environmental mycobacteria) (10-15). The clinical penetrance for MSMD depends on the genetic etiology and is inversely correlated with the levels of residual IFN-γ immunity (16). From 2001 onward, autosomal recessive interleukin-12 receptor β1 (IL-12Rβ1) and tyrosine kinase 2 (TYK2) deficiencies have also been identified in children with severe TB and without MSMD (17-23). These two deficiencies impair both the IL-12-and IL-23-dependent production of IFN-γ. They are caused by very rare (minor allele frequency, MAF <5 × 10 −5 worldwide) or private loss-of-function alleles.We recently discovered a strong enrichment in homozygosity for the common TYK2 missense variant P1104A in a genetically heterogeneous cohort of patients with TB from countries outside of Europe in which this disease is endemic, relative to ancestryadjusted controls, with an odds ratio (OR) of 89.3 (95% CI, 14.7-1,725, P = 8.37 × 10 −8 ) (24). Homozygosity for P1104A is also a genetic etiology of MSMD, albeit with much lower estimate...

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Section: Discussionmentioning

confidence: 99%

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

Kerner

Ramírez-Alejo

Seeleuthner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Genomic analysis is performed similarly to transcriptomic analysis, except that changes in the DNA sequence are identified to determine single nucleotide polymorphisms (SNPs) that may be predictive of genetic risks for disease progression [43]. Hybridization microarray assays identify common variants throughout the genome for genome-wide association studies (GWAS) [44, 45].…”

Section: System Biology Analysis Of Clinical Samples Provides Unique mentioning

confidence: 99%

“…To reduce costs and data analysis, exome sequencing (i.e., genomic sequencing of the exonic coding regions of the genome) is often performed. This method accounts for <2% of the total genome and can identify causal variants that lead to non-functional proteins or nonsynonymous amino acid substitutions that may affect protein function [43, 48]. Despite the high cost and bioinformatics infrastructure required to analyze these datasets [49], the results are very precise and offer the potential to identify causal genetic factors that increase patients risks for poor outcomes.…”

Section: System Biology Analysis Of Clinical Samples Provides Unique mentioning

confidence: 99%

Early Diagnosis of Sepsis: Is an Integrated Omics Approach the Way Forward?

Wong

2017

Mol Diagn Ther

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Sepsis remains one of the leading causes of death in the United States and it is expected to get worse as the population ages. Moreover, the standard of care, which recommends aggressive treatment with appropriate antibiotics, has led to an increase in multiple drug resistant organisms (MDROs). There is a dire need for the development of new antibiotics, improved antibiotic stewardship and therapies that treat the host response. Development of new sepsis therapeutics has been a disappointment as no drugs are currently approved to treat the various complications from sepsis. Much of the failure has been blamed on animal models that do not accurately reflect the course of the disease. However, recent improvements in metabolomic, transcriptomic, genomic and proteomic platforms have allowed for a broad spectrum look at molecular changes in the host response using clinical samples. Integration of these multi-omic data sets allows researchers to perform systems biology approaches to identify novel pathophysiology of the disease. In this review, we will highlight what is currently known about sepsis and how integrative omics has identified new diagnostic and predictive models of sepsis as well as novel mechanisms. These changes may improve patient care as well as guide future preclinical analysis of sepsis.

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“…[75,76] Even independently of diet, host genotype affects the microbiome. [82,83] Similarly, variants at key pro-inflammatory cytokines such as IFN-γ are associated with an abundance of Akkermansia muciniphila (A. muciniphila), and Ifnγ −/− mice have increased A. muciniphila populations. [77] Socalled mGWAS (microbiome-genomewide association studies) have shown that anywhere between 9 and 83 loci affect microbiome composition.…”

Section: Host Genetics Alter the Microbiomementioning

confidence: 99%

“…[81] Genetic association studies in humans reveal that up to 40 of the identified IBD risk loci affect the composition of the microbiome. [82,83] Similarly, variants at key pro-inflammatory cytokines such as IFN-γ are associated with an abundance of Akkermansia muciniphila (A. muciniphila), and Ifnγ −/− mice have increased A. muciniphila populations. [84] Finally, variants of FUT2, an IBD risk factor, have been found to impact the gut microbiome, particularly IBD-associated bacteria, Faecalibacterium and Proteobacteria.…”

Section: Host Genetics Alter the Microbiomementioning

confidence: 99%

Shifting Climates, Foods, and Diseases: The Human Microbiome through Evolution

et al. 2019

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Human evolution has been punctuated by climate anomalies, structuring environments, deadly infections, and altering landscapes. How well humans adapted to these new circumstances had direct effects on fitness and survival. Here, how the gut microbiome could have contributed to human evolutionary success through contributions to host nutritional buffering and infectious disease resistance is reviewed. How changes in human genetics, diet, disease exposure, and social environments almost certainly altered microbial community composition is also explored. Emerging research points to the microbiome as a key player in host responses to environmental change. Therefore, the reciprocal interactions between humans and their microbes are likely to have shaped human patterns of local adaptation throughout our shared evolutionary history. Recent alterations in human lifestyle, however, are altering human microbiomes in unprecedented ways. The consequences of interrupted host–microbe relationships for human adaptive potential in the future are unknown.

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Genetics of Infectious and Inflammatory Diseases: Overlapping Discoveries from Association and Exome-Sequencing Studies

Cited by 37 publications

References 175 publications

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

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

Early Diagnosis of Sepsis: Is an Integrated Omics Approach the Way Forward?

Shifting Climates, Foods, and Diseases: The Human Microbiome through Evolution

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