Association of cytokine and chemokine gene polymorphisms with severe acute respiratory syndrome.
ABSTRACT 1. The IFN-gamma +874A allele and RANTES -28 G allele are risk factors for SARS susceptibility. 2. The RANTES -28 G allele plays a role in the pathogenesis of SARS. 3. The polymorphisms of IL-10, TNF-alpha, IL-12, IP-10, Mig and MCP-1 are not associated with SARS susceptibility.
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ABSTRACT: Severe acute respiratory syndrome (SARS) is caused by infection of a previously undescribed coronavirus (CoV). L-SIGN, encoded by CLEC4M (also known as CD209L), is a SARS-CoV binding receptor that has polymorphism in its extracellular neck region encoded by the tandem repeat domain in exon 4. Our genetic risk association study shows that individuals homozygous for CLEC4M tandem repeats are less susceptible to SARS infection. L-SIGN is expressed in both non-SARS and SARS-CoV-infected lung. Compared with cells heterozygous for L-SIGN, cells homozygous for L-SIGN show higher binding capacity for SARS-CoV, higher proteasome-dependent viral degradation and a lower capacity for trans infection. Thus, homozygosity for L-SIGN plays a protective role during SARS infection.Nature Genetics 02/2006; 38(1):38-46. · 35.21 Impact Factor
- New England Journal of Medicine 03/1998; 338(7):436-45. · 51.66 Impact Factor
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ABSTRACT: As yet, no one has written a comprehensive epidemiologic account of a severe acute respiratory syndrome (SARS) outbreak from an affected country. To provide a comprehensive epidemiologic account of a SARS outbreak from an affected territory. Epidemiologic analysis. The 2003 Hong Kong SARS outbreak. All 1755 cases and 302 deaths. Sociodemographic characteristics; infection clusters by time, occupation, setting, and workplace; and geospatial relationships were determined. The mean and variance in the time from infection to onset (incubation period) were estimated in a small group of patients with known exposure. The mean and variance in time from onset to admission, from admission to discharge, or from admission to death were calculated. Logistic regression was used to identify important predictors of case fatality. 49.3% of patients were infected in clinics, hospitals, or elderly or nursing homes, and the Amoy Gardens cluster accounted for 18.8% of cases. The ratio of women to men among infected individuals was 5:4. Health care workers accounted for 23.1% of all reported cases. The estimated mean incubation period was 4.6 days (95% CI, 3.8 to 5.8 days). Mean time from symptom onset to hospitalization varied between 2 and 8 days, decreasing over the course of the epidemic. Mean time from onset to death was 23.7 days (CI, 22.0 to 25.3 days), and mean time from onset to discharge was 26.5 days (CI, 25.8 to 27.2 days). Increasing age, male sex, atypical presenting symptoms, presence of comorbid conditions, and high lactate dehydrogenase level on admission were associated with a greater risk for death. Estimates of the incubation period relied on statistical assumptions because few patients had known exposure times. Temporal changes in case management as the epidemic progressed, unavailable treatment information, and several potentially important factors that could not be thoroughly analyzed because of the limited sample size complicate interpretation of factors related to case fatality. This analysis of the complete data on the 2003 SARS epidemic in Hong Kong has revealed key epidemiologic features of the epidemic as it evolved.Annals of internal medicine 12/2004; 141(9):662-73. · 13.98 Impact Factor
Final Report # 03040302
Research Fund for the Control of Infectious Diseases
Health and Health Services Research Fund
Health Services Research Fund
Health Care & Promotion Fund
Association of Cytokine and Chemokine Genes Polymorphism with
Severe Acute Respiratory Syndrome (SARS)
Submitted to the Grant Review Board (27th Feb., 2007)
Department of Paediatrics & Adolescent Medicine
(The University of Hong Kong)
Department of Microbiology
(The University of Hong Kong)
List of Research Workers 21
This project was mainly supported by the Research Fund for the Control of Infectious Diseases
(03040302) from the Health, Welfare and Food Bureau of the Hong Kong SAR Government. In
addition, this project was partially supported by the Outstanding Researcher Awards (YLL and
JSMP), Postgraduate Studentships from The University of Hong Kong, and Edward Sai Kim
Hotung Paediatric Education and Research Fund.
Background: Cytokines and chemokines play important roles in antiviral action. We examined
whether polymorphisms of IFN-γ, IL-10, TNF-α, IL-12, RANTES, IP-10, Mig and MCP-1 affect
the susceptibility to and outcome of severe acute respiratory syndrome (SARS).
Methods: We carried out a case-control association study on the polymorphisms of IFN-γ, IL-10,
TNF-α, IL-12, RANTES, IP-10, Mig and MCP-1 for their associations with SARS in 495 SARS
patients and 578 controls.
Results: IFN-γ +874A allele was associated with susceptibility to SARS in a dose-dependent
manner (P<0.001). Individuals with IFN-γ +874 AA and AT genotype had a 5.19-fold (95%
Confidence Interval [CI], 2.78-9.68) and 2.57-fold (95% CI = 1.35-4.88) increased risk of
developing SARS respectively. RANTES -28 G allele was associated with SARS susceptibility
(P<0.0001, OR=2.80, 95% CI = 2.11-3.71). Individuals with RANTES -28 CG and GG genotypes
had a 3.28-fold (95% CI = 2.32-4.64) and 3.06-fold (95% CI = 1.47-6.39) increased risk of
developing SARS respectively (P<0.0001). This RANTES -28 G allele conferred risk of death in a
gene-dosage dependent manner (P=0.014) with CG and GG individuals having a 2.12-fold (95%
CI = 1.11-4.06) and 4.01-fold (95% CI = 1.30-12.4) increased risk. The polymorphisms of IL-10,
TNF-α, IL-12, IP-10, Mig and MCP-1 were not associated with susceptibility to and death from
Conclusions: IFN-γ +874A allele and RANTES -28 G allele were shown to be risk factors in
SARS susceptibility and the RANTES -28 G allele plays a role in the pathogenesis of SARS.
Severe acute respiratory syndrome (SARS) is an infectious disease caused by SARS
coronavirus  with >8000 cases and 774 deaths reported in 2003 . Much progress has been
made in understanding SARS coronavirus but the pathogenesis is still unclear . It was reported
that old age, diabetes mellitus and heart disease were risk factors for adverse prognosis of SARS
[4-6], however, little is known about the contribution of genetic factors. We have demonstrated
that genetic haplotypes associated with low serum mannose-binding lectin (MBL) are associated
with SARS  and our findings were recently replicated . Recently, homozygotes for
CLEC4M tandem repeats were reported to be less susceptible to SARS in Hong Kong Chinese 
and other susceptibility genes, such as OAS-1 and MxA were also identified .
Cytokines are known to be important in antiviral action. Interferon (IFN)-γ from T and
natural killer (NK) cells is important in driving the T helper cell type 1 (Th1) responses. It also
activates monocytes and macrophages, which in turn take part in antiviral responses by producing
free radicals and pro-inflammatory cytokines like tumor necrosis factor (TNF)-α.  On the
other hand, interleukin (IL)-10 counteracts the inflammatory response by inhibiting TNF-α
production and neutrophil activation . IL-12 is an important cytokine in the initial phase of
bacterial, parasitic, and viral infections for the development of the T helper type 1 (Th1) response.
In many viral infections, IL-12 promotes viral clearance and host recovery from infection .
Chemokines play important role in cells trafficking during immune responses. Acute
respiratory viruses commonly induce inflammatory chemokines in local tissue . In the case of
SARS, our previous study confirmed that SARS coronavirus induces upregulation of a number of
inflammatory chemokines, i.e. Regulated upon Activation, Normal T cell-Expressed and
Secreted (RANTES), interferon-gamma inducible protein 10 (IP-10), and Monocyte
Chemoattractant Protein-1 (MCP-1) . The upregulation of these chemokines, including
monokine induced by interferon gene (Mig) may recruit inflammatory cells and leukocytes into
the tissue .
In this study, we hypothesized that the polymorphisms of the cytokine genes, IFN-γ, IL-10,
TNF-α, IL-12, and the chemokine genes, RANTES, IP-10, Mig and MCP-1, might be associated
with SARS. These genes were chosen based on their key roles in antiviral action and
inflammation regulation and their polymorphisms based on their potential regulation on gene
expression (Table 1).