Genetic Factors in Sepsis

September 27, 2007

Jean-Paul Mira

Medical Intensive Care Unit, Cochin University Hospital,

Cochin Institute; Paris, France

Genetic Factors in Sepsis

What is proven?

September 27, 2007

Jean-Paul Mira

Medical Intensive Care Unit, Cochin University Hospital,

Cochin Institute; Paris, France

Genetics of Sepsis: What is proven?

• All hosts are not equal!

Evidences for a Genetic Component to Sepsis

Animal Studies

- Susceptibility/resistance to certain infection in mice

Intranasal challenge, 106 cfu S. pneumoniae strain D39

Fighting S. Pneumoniae: Candidate Genes !

One phenotype may be due to different

genotypes

Despite the complexity of the immune

defense, one missing element may have

dramatic clinical consequences

Human Studies

- Clinical Evidences

- Ethnic Differences

- Twin Studies

- Adoptee Studies

Animal Studies

- Susceptibility/resistance to certain infection in mice

Evidences for a Genetic Component to Sepsis

Genetic and environmental influences

on premature death in adult adoptees

Sørensen TI, et al. NEJM 1988; 318:727-32.

Cause of Death

(Parent Dead before the age of 50)Relative risk for the adoptee

to die from the same cause

All causes

Biologic

Adoptive

1.71

0.71

Biologic

Adoptive

Infection

5.8

0.73

Vascular

Biologic

Adoptive

4.5

3.1

Genetics of Sepsis: What is proven?

• All host are not equal!

• >100 Mendelian diseases are associated with sepsis

Severe Combined Immune Deficiencies (SCID)

Pathologies

Reticular dysgenesia

ADA deficit

B(-) SCID

NK(-) SCID

NK(-) SCID

SCID

Transmission

AR

AR

AR

X

AR

AR

Cells

Myeloid cells,T B,NK

T, B, NK

T, B

T, NK

T, NK

T α/β

Gene

Unknown

ADA

RAG1/RAG2

γc

JAK-3

CD45

Genetics of Sepsis: What is proven?

• All host are not equal!

• Mendelian diseases are associated with sepsis

• Number of genetic variants is « limited »

• Genetic Polymorphisms

Mars 2003

• Haplotypes

Oct 2005

• Insertion-deletion

Juin 2006

Genetic Variants

CD14/159T & Susceptibility to Septic Shock

Le Van TD et al. J Immunol 2001;167:5838 Gibot S et al., Crit Care Med 2002: 30:969-73

% P

ati

en

ts

60

-159CC -159CT -159TT

10

20

30

40

50

0

Control

P<0.05

Septic Shock

Gibot S et al. Crit Care Med 2002; 30:969-73

CD14/159T and Mortality to Septic Shock

CD14/159TT RR= 5.1; 95%CI [3.2-7,9]

Characteristics C/C N=19

C/T N=43

T/T N=28

p

Age (meanSD) 5315 5913 5917 .18

SAPSII (meanSD) 5318 5621 6019 .21

OSF (meanSD) 31.2 2.80.9 3.11 .42

Mortality (%) 26.3 58.1 71.4 <.0001

Genetics of Sepsis: What is proven?

• All host are not equal!

• Mendelian diseases associated with sepsis susceptibility

• Number of functional variants is limited

• Complex genetics influences specific infectious diseases

(meningococcemia, malaria, tuberculosis, AIDS, pneumococcemia)

Cytokine Polymorphisms and Meningococcemia

Gene Polymorphism Csqs Pts Su Severity Outcome Ref

ACE DD (deletion) ACE 110 14% Death

[OR]= 2.8

Harding D.

2002

TNF - 308 (TNF2) TNF a 98 [OR] =2.5

[CI]: 1.1-5.7

Nadel S.

1996

IL-6 -174 (GC) IL-6 85 [OR]= 3.06 [OR] = 2.64

[CI]: 1.1- 6.2

Balding J.

2001

IL-1B

ILRN

-511 (1+)

+2018 (2+)

IL-1b

IL-RA

1106 [OR] = 0.61

[CI] 0.38-0.98

Read RC.

2003

MBL, TLR4, Complement, FcgRIIA variants are associated with susceptibility

Genetics of Sepsis: What is proven?

• All host are not equal!

• Mendelian diseases associated with sepsis susceptibility

• Number of functional variants is limited

• Complex genetics influences specific infectious diseases

• Quality criteria for genetic association studies are defined

Hattersley AT and McCarthy MI. Lancet 2005: 366;1315

- How good a candidate is the gene?

- Is the study size large enough?

- Quality of the phenotypes

- Quality of the genotyping

- Quality of the analysis and interpretation

Candidate Genes and Severe Sepsis

Meningococcemia; Severe sepsis

Meningococcemia; Severe sepsis

Severe Sepsis

PAI-1

Factor V Leiden

Protein C; Fibrinogen

Meningococcemia; Septic Shock

Severe Sepsis

Severe Sepsis, Meningococcemia

Severe sepsis

TNF locus

IL-18

IL-10

IL-6

Meningococcemia; PneumococcemiaFCgRII Receptor

Meningococcemia, Pneumococcemia

Severe sepsis

Mannose Binding Lectin

Susceptibility and/or OutcomeGene

Septic Shock, Legionnaire’s Disease

Septic Shock

Septic shock, Pneumococcemia

Toll-Like Receptors

CD14

IRAK-1; Mal; IkBa

Severe Sepsis

Viral Pneumonia

Severe Sepsis

IL-1 locus

IL-4

Caspase 12

TNF2 Polymorphism and Importance of Phenotypes

TNF-a LT-aLT-b

Nco.I

TNFB1 TNFB2

-308

-376

TNF1

TNF2

TNF2 Polymorphism and MortalityAUTHOR YEAR POPULATIONS NUMBER OF PATIENTS

N = 2713

SEPTIC SHOCK

N=405

MORTALITY

Watanabe 2005 SIRS + SOFA>5 113 41 +

Watanabe 2005 ICU PATIENTS 150 NA +

Nakada 2005 ICU PATIENTS 197 NA +

Gong 2005 ARDS 212 115 +

Gordon 2004 SS OR S SHOCK 213 NA -

Barber 2004 BURN PTS 159 NA +

Hedberg 2004 VLBW INFANTS 163 NA +

Jaber 2004 ARF ICU PTS 67 NA +

Calvano 2004 SIRS 44 NA -

Zhang 2003 PANCREATITIS 208 32 +

Gallagher 2003 CAP PTS 93 NA -

Balding 2003 MENINGO D. 183 20 -

O'keefe 2002 TRAUMA 152 NA +

Reid 2002 MOF 88 4 -

Waterer 2001 CAP 280 31 -

Appoloni 2001 SEPTIC SHOCK 37 31 +

Tang 2000 ICU PTS 112 42 +

Mira 1999 SEPTIC SHOCK 89 89 +

Nadel 1996 MENINGO D. 93 NA +

Stuber 1995 SS OR S SHOCK 80 NA -

TNF2 Polymorphism and SDRA Mortality

Gong MN Eur Respir J 2005;26:382

TNFA adjusted OR: 3.5; 95% CI: 1.4-8.6; p=0.007

<67 years adjusted OR: 14.9; 95% CI: 3.0-74; p<0.001

>67 years p=0.3

The TNF-308 GA Promoter Polymorphism

- Genetic Determinant of Sepsis Outcome ? -

• 591 adult caucasians with septic shock

• 584 age- & sex-matched control patients– ICU patients– No sepsis– No vasopressors / inotropes– No comorbidities

• Phenotyping– Septic shock with or without comorbidities– Comorbidities

• Heart failure (NYHA class III/IV) n=113• Liver cirrhosis n=63• Cancer n=119• Treatment with immunosuppressive agents n=104

• Genotyping (blind, two technics, repeated)

Prevalence of TNF2 in Patients with Septic Shock

Total Septic Shock (SS) SS + Co

61±16 60±15

52±18 55±20

57±16 59±15

51±18 54±19

63±16 62±15

53±19 57±20

Age

SAPS2

401 190 191 109 210 81n

P <0.001

P <0.001

NS

Genetics of Sepsis: What is proven?

• All host are not equal!

• Mendelian diseases associated with sepsis susceptibility

• Number of functional variants is limited

• Complex genetics influences specific infectious diseases

• Quality criteria for genetic association studies are defined

• Replication studies are essential

Genetics of Sepsis: What is proven?

• All host are not equal!

• Mendelian diseases associated with sepsis susceptibility

• Number of functional variants is limited

• Complex genetics influences specific infectious diseases

• Quality criteria for genetic association studies are defined

• Replication studies are essential

• Future is coming soon

• Large cohorts of ICU patients

• Homogeneous populations (ethnies, age, gender, infections)

• Well-defined phenotypes:

• severe sepsis septic shock, ALI ARDS, …

• « one » microorganism + one site

• importance of comorbidities

• importance of age

Conclusions: What we need?

GenoSept Pneumagene

GenIMS Gen Sep groupImpact