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HLA Class I Alleles May Affect Susceptibility and Severity of SARS

October 16, 2003

Abstraction Template
     
Key variables & Description Article

Reference
Complete the bibliographic reference for the article according to AJE format.

 

Lin M, Tseng H-K, Trejaut JA, et al. Association of HLA class I with severe acute respiratory syndrome coronavirus infection. BMC Med Genet. 2003 Sept 12; 4(9):1-9 [Epub ahead of print].

 

Category of HuGE information
Specify the types of information (from the list below) available in the article:

  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction
  4. Gene-gene interaction
  5. Genetic test evaluation/monitoring

 

  1. Prevalence of gene variants (for all cases and select variants for controls)
  2. Gene-disease association

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study

 

The authors wished to establish a screening program for high risk hospital personnel by examining the distribution of human leukocyte antigen (HLA) class I and II alleles in relation to susceptibility to SARS.

Gene(s)
Identification of the following:

  1. Gene name
  2. Chromosome location
  3. Gene product/function
  4. Alleles
  5. OMIM #
  1. Gene name: HLA-A
  2. Chromosome location: 6p21.3
  3. Gene product/function: HLA class I molecules (comprised of HLA-A, HLA-B, and HLA-C) present antigens on the surfaces of infected cells, thereby allowing cytotoxic T cells to bind and initiate the adaptive immune response [1]. HLA alleles and genotypes have a marked degree of polymorphism at the population level and are implicated in the susceptibility, severity, and transmission of various infectious diseases [3].
  4. Alleles: 282 total [2]
  5. OMIM #: 142800
  1. Gene name: HLA-B
  2. Chromosome location: 6p21.3
  3. Gene product/function: see HLA-A
  4. Alleles: 540 total [3]
  5. OMIM #: 142830 
  1. Gene name: HLA-DRB1
  2. Chromosome location: 6p21.3
  3. Gene product/function: HLA class II molecules (comprised of HLA-DR, HLA-DQ, and HLA-DP) present antigen on the surfaces of specific antigen-presenting cells to stimulate helper T cell activity for the cytotoxic T cell response and for the humoral immune response [1].
  4. Alleles: 342 total [3]
  5. OMIM #: 142857

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

 

N/A

 

Health outcome(s)
Identification of the major health outcome(s) studied

 

  1. SARS (probable case definition)
  2. Severe SARS (needed intubation or died from SARS)
Study design
Specification of the type of study design(s)
  1. Case-control
  2. Cohort 
  3. Cross-sectional
  4. Descriptive or case series
  5. Clinical trial
  6. Population screening

 

  1. Case-control, hospital based.
Case definition
For study designs 1, 4, and 5, define the following if available:
  1. Disease case definition
  2. Exclusion criteria
  3. Gender
  4. Race/ethnicity
  5. Age
  6. Time period
  7. Geographic location
  8. Number of participants (% of total eligible)
  1. Disease case definition: WHO case defintions for SARS [4]

    Suspect case:
    1) A person presenting after 11/1/02 with history of high fever (> 38°C), cough or breathing difficultly, and one or more of the following exposures 10 days prior to onset of symptoms: close contact with a person who is a suspect or probable case, history of travel to an area with recent local transmission of SARS, or residing in an area with recent local transmission of SARS.

    2) A person with an unexplained acute respiratory illness resulting in death after 11/1/02 but on whom no autopsy has been performed and one or more of the following exposures 10 days prior to onset of symptoms: close contact with a person who is a suspect or probable case, history of travel to an area with recent local transmission of SARS, or residing in an area with recent local transmission of SARS.

    Probable case:
    1) A suspect case with radiographic evidence of infiltrates consistent with pneumonia or respiratory distress syndrome on chest x-ray.

    2) A suspect case of SARS that is positive for SARS coronavirus by one or more assays [5]:

         a) Confirmed positive PCR for SARS virus.

         b) Seroconversion by ELISA or IFA.

         c) Virus isolation and PCR confirmation.

    3) A suspect case with autopsy findings consistent with the pathology of respiratory distress syndrome without an identifiable cause.


  2. Exclusion criteria: Cases are excluded if an alternative diagnosis can fully explain their illness.
  3. Gender: Not specified.
  4. Race/ethnicity: Taiwanese
  5. Age: Not specified.
  6. Time period: March 19, 2003 to May 22, 2003
  7. Geographic location: Taiwan
  8. Number of participants: 37 probable cases presumably from community and infected health care workers, though exact source unknown. Only 33 (89%) of unrelated individuals used in analysis.

 

Control definition
For study design 1, define the following if available:
  1. Control selection criteria
  2. Matching variables
  3. Exclusion criteria
  4. Gender
  5. Race/ethnicity
  6. Age
  7. Time period
  8. Geographic location
  9. Number of participants (% of total eligible)
  1. Control selection criteria: Hospital patients reported but not positive by WHO case definition for SARS (“excluded fever patients”).
  2. Matching variables: None.
  3. Exclusion criteria: None.
  4. Gender: Not specified.
  5. Race/ethnicity: Taiwanese
  6. Age: Not specified.
  7. Time period: March 19, 2003 to May 22, 2003
  8. Geographic location: Taiwan
  9. Number of participants: 28

 

  1. Control selection criteria: Exposed but uninfected health care workers (“Control A”). 62 (61%) workers from a hospital that followed infection control measures. 39 (39%) workers from another hosptial who did not have adequate protection from infection; ~10% of workers from these same wards developed probable SARS.
  2. Matching variables: None
  3. Exclusion criteria: None
  4. Gender: Not specified
  5. Race/ethnicity: Taiwanese
  6. Age: Not specified
  7. Time period: Blood samples obtained at end of May
  8. Geographic location: Taiwan
  9. Number of participants: 101
  1. Control selection criteria: Normal, healthy unrelated individuals from general population.
  2. Matching variables: None
  3. Exclusion criteria: None
  4. Gender: Not specified
  5. Race/ethnicity: Taiwanese
  6. Age: Not specified
  7. Time period: Not specified, lab databank information used.
  8. Geographic location: Taiwan
  9. Number of participants: 190

 

Assessment of environment factors
For studies that include gene-environment interactions, define the following, if available:
  1. Environmental factor
  2. Exposure assessment
  3. Exposure definition
  4. Number of participants with exposure data (% of total eligible)

 

N/A

 

 

Genotyping
Specify the following:
  1. Gene
  2. DNA source
  3. Methodology
  4. Number of participants genotyped (% of total eligible) 

 

  1. Gene: HLA-A, HLA-B, HLA-DRB1
  2. DNA source: EDTA blood
  3. Methodology: Medium resolution HLA typing by PCR followed by sequence-specific oligonucleotide probing (PCR-SSOP). Serologic methods were used to type HLA-A and HLA-B for Control B (general population databank).
  4. Number of participants genotyped: 356 (100%)

 

Results
Describe the major results under each of the following HuGE categories. Include tables when data are provided:
  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction
  4. Gene-gene interaction
  5. Genetic test evaluation/monitoring

 

  1. See Tables 1-2 for HLA allele frequencies among 33 probable cases used in subsequent analyses.
  2. See Table 3 for HLA-B*4601 genotype association. (Also refer to Lin M et al., Tables 2 and 4 for allele associations.)
Conclusion
State the author's overall conclusions from the study

The authors conclude that HLA-B*4601 is associated with both SARS infection and subsequent severity of disease, and that HLA-B*1301 may confer resistance to SARS. They further speculate that the prevalence of HLA-B*4601 in Southeast Asians may have contributed to the rapid expansion of the SARS epidemic in China and neighboring countries. The authors state that these findings justify the mass screening of health care workers to identify those at risk for infection.

 

Comments
Provide additional insight, including methodologic issues and/or concerns about the study

Methodology:

  1. The use of two HLA typing methods (sequencing vs. serology) raises a concern regarding the potential misclassification of HLA alleles. Alleles were discriminated to a medium resolution of 4 digits, but there were still individuals for whom the true alleles could not be determined (i.e., HLA-A*1101/02 is either HLA-A*1101 or HLA-A*1102).
  2. Misclassification of cases may also have occurred since only 24 (65%) of probable cases had positive RT-PCR lab tests for SARS. Moreover, Taiwan recently revised its number of cases and deaths due to SARS, reducing previous estimates by more than 50% to a total of 346 cases and 37 deaths [6].
  3. Little information was provided for the presumably healthy individuals of the general population that were obtained from the hospital’s laboratory databank.
  4. Data on other important risk factors such as age, sex, or co-infection were not provided or considered in the analyses. Such information is vital for assessing the relative comparability of all the groups.

Analysis:

  1. Select allele frequencies were provided for the controls, making it difficult to evaluate the correction factors used to adjust for multiple testing. Correction for multiple comparisons has been a contentious topic but the authors did provide more conservative estimates by applying a Bonferroni-like correction to their P-values.
  2. Non-significant associations for HLA alleles and risk of infection may be due to lack of statistical power. These findings seem to provide primary evidence that can guide larger HLA studies.
  3. The association of HLA-B*4601 and severity of SARS is novel and surprising given the small numbers of cases examined (OR: 10.62, CI: 2.80-40.26). It would have been helpful if the authors had provided analyses for all HLA-B alleles examined.

Despite incomplete information about cases and controls and concerns regarding potential misclassification of both case status and genotype, these provisional findings may guide further studies in larger, better defined study populations. The authors’ final statement that the findings justify the mass screening of health care workers seems premature and cannot be substantiated without additional research.

 

  References
  1. Marsh SGE, Parham P, Barber LD. The HLA FactsBook. London, UK: Academic Press, 1999.
  2. Hill AV. Immunogenetics and genomics. Lancet. 2001 Jun 23;357(9273):2037-41.
  3. HLA Informatics Group. Anthony Nolan Research Institute (London), 2003. (http://www.anthonynolan.org.uk/HIG/index.html).
  4. Case definition for surveillance of severe acute respiratory syndrome (SARS). World Health Organization (Geneva), 2003. (http://www.who.int/csr/sars/casedefinition/en/print.html).
  5. Use of laboratory methods for SARS diagnosis. World Health Organization (Geneva), 2003. (http://www.who.int/csr/sars/labmethods/en/print.html).
  6. Taiwan revises data on SARS; total toll drops. (Editorial). New York Times Oct 5, 2003; (http://www.nytimes.com/2003/10/05/international/asia/05SARS.html).

Supplementary Tables

  • Table 1 HLA Class I allele fequencies of 33 unrelated, probable cases of SARS.
  • Table 2 HLA Class II allele fequencies of 33 unrelated, probable cases of SARS.
  • Table 3 Association of HLA-B*4601 genotypes with susceptibility to SARS1.

 

Last Updated August 25, 2004