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Genes (Basel). 2018 May 3;9(5). pii: E240. doi: 10.3390/genes9050240.

Whole Exome Sequencing Identifies New Host Genomic Susceptibility Factors in Empyema Caused by Streptococcus pneumoniae in Children: A Pilot Study.

Salas A1,2,3,4,5, Pardo-Seco J6,7,8,9,10, Barral-Arca R11,12,13,14,15, Cebey-López M16,17, Gómez-Carballa A18,19,20,21,22, Rivero-Calle I23,24, Pischedda S25,26,27,28,29, Currás-Tuala MJ30,31,32,33,34, Amigo J35,36,37,38,39, Gómez-Rial J40,41, Martinón-Torres F42,43; GENDRES Network44.

Author information

1
Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. antonio.salas@usc.es.
2
GenPoB Research Group, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain. antonio.salas@usc.es.
3
Hospital Clínico Universitario de Santiago (SERGAS), 15706 Santiago de Compostela, Spain. antonio.salas@usc.es.
4
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain. antonio.salas@usc.es.
5
GENVIP Research Group (www.genvip.org), 15706 Santiago de Compostela, Spain. antonio.salas@usc.es.
6
Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. j.pardoseco@gmail.com.
7
GenPoB Research Group, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain. j.pardoseco@gmail.com.
8
Hospital Clínico Universitario de Santiago (SERGAS), 15706 Santiago de Compostela, Spain. j.pardoseco@gmail.com.
9
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain. j.pardoseco@gmail.com.
10
GENVIP Research Group (www.genvip.org), 15706 Santiago de Compostela, Spain. j.pardoseco@gmail.com.
11
Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. barralarcaruth@gmail.com.
12
GenPoB Research Group, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain. barralarcaruth@gmail.com.
13
Hospital Clínico Universitario de Santiago (SERGAS), 15706 Santiago de Compostela, Spain. barralarcaruth@gmail.com.
14
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain. barralarcaruth@gmail.com.
15
GENVIP Research Group (www.genvip.org), 15706 Santiago de Compostela, Spain. barralarcaruth@gmail.com.
16
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain. Miriam.Cebey.Lopez@sergas.es.
17
GENVIP Research Group (www.genvip.org), 15706 Santiago de Compostela, Spain. Miriam.Cebey.Lopez@sergas.es.
18
Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. Alberto.Gomez.Carballa@sergas.es.
19
GenPoB Research Group, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain. Alberto.Gomez.Carballa@sergas.es.
20
Hospital Clínico Universitario de Santiago (SERGAS), 15706 Santiago de Compostela, Spain. Alberto.Gomez.Carballa@sergas.es.
21
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain. Alberto.Gomez.Carballa@sergas.es.
22
GENVIP Research Group (www.genvip.org), 15706 Santiago de Compostela, Spain. Alberto.Gomez.Carballa@sergas.es.
23
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain. Irene.Rivero.Calle@sergas.es.
24
GENVIP Research Group (www.genvip.org), 15706 Santiago de Compostela, Spain. Irene.Rivero.Calle@sergas.es.
25
Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. sara.pischedda91@hotmail.it.
26
GenPoB Research Group, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain. sara.pischedda91@hotmail.it.
27
Hospital Clínico Universitario de Santiago (SERGAS), 15706 Santiago de Compostela, Spain. sara.pischedda91@hotmail.it.
28
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain. sara.pischedda91@hotmail.it.
29
GENVIP Research Group (www.genvip.org), 15706 Santiago de Compostela, Spain. sara.pischedda91@hotmail.it.
30
Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. mjcurras@gmail.com.
31
GenPoB Research Group, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain. mjcurras@gmail.com.
32
Hospital Clínico Universitario de Santiago (SERGAS), 15706 Santiago de Compostela, Spain. mjcurras@gmail.com.
33
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain. mjcurras@gmail.com.
34
GENVIP Research Group (www.genvip.org), 15706 Santiago de Compostela, Spain. mjcurras@gmail.com.
35
Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. jorge.amigo@usc.es.
36
GenPoB Research Group, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain. jorge.amigo@usc.es.
37
Hospital Clínico Universitario de Santiago (SERGAS), 15706 Santiago de Compostela, Spain. jorge.amigo@usc.es.
38
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain. jorge.amigo@usc.es.
39
GENVIP Research Group (www.genvip.org), 15706 Santiago de Compostela, Spain. jorge.amigo@usc.es.
40
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain. Jose.Gomez.Rial@sergas.es.
41
GENVIP Research Group (www.genvip.org), 15706 Santiago de Compostela, Spain. Jose.Gomez.Rial@sergas.es.
42
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain. federicomartinon@gmail.com.
43
GENVIP Research Group (www.genvip.org), 15706 Santiago de Compostela, Spain. federicomartinon@gmail.com.
44
Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.

Abstract

Pneumonia is the leading cause of death amongst infectious diseases. Streptococcus pneumoniae is responsible for about 25% of pneumonia cases worldwide, and it is a major cause of childhood mortality. We carried out a whole exome sequencing (WES) study in eight patients with complicated cases of pneumococcal pneumonia (empyema). An initial assessment of statistical association of WES variation with pneumonia was carried out using data from the 1000 Genomes Project (1000G) for the Iberian Peninsula (IBS) as reference controls. Pseudo-replication statistical analyses were carried out using different European control groups. Association tests pointed to single nucleotide polymorphism (SNP) rs201967957 (gene MEIS1; chromosome 2; p-valueIBS = 3.71 × 10-13) and rs576099063 (gene TSPAN15; chromosome 10; p-valueIBS = 2.36 × 10-8) as the best candidate variants associated to pneumococcal pneumonia. A burden gene test of pathogenicity signaled four genes, namely, OR9G9, MUC6, MUC3A and APOB, which carry significantly increased pathogenic variation when compared to controls. By analyzing various transcriptomic data repositories, we found strong supportive evidence for the role of MEIS1, TSPAN15 and APOBR (encoding the receptor of the APOB protein) in pneumonia in mouse and human models. Furthermore, the association of the olfactory receptor gene OR9G9 has recently been related to some viral infectious diseases, while the role of mucin genes (MUC6 and MUC3A), encoding mucin glycoproteins, are well-known factors related to chronic obstructive airway disease. WES emerges as a promising technique to disentangle the genetic basis of host genome susceptibility to infectious respiratory diseases.

KEYWORDS:

Streptococcus pneumoniae; infectious disease; next generation sequencing; parallel sequencing; pediatrics; transcriptome; whole exome sequencing

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