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

Ghaderi M, Zake LN, Wallin KL, Wiklund F, Hallmans G, Lenner P, Dillner J, Sanjeevi C. Tumor necrosis factor A and MHC class I chain related gene A (MIC-A) polymorphisms in Swedish patients with cervical cancer. Human Immunology 2001;62:1153-58.

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 variant
2. Gene-disease association
3. Gene-environment association

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

Purpose: The aim was to study two distinct non-HLA class II genes in relation to cervical cancer:
(1) to determine if a susceptibility or protective gene is located in the class III or class I of the human MHC;
(2) to determine whether MICA or TNFA polymorphisms are associated with invasive cervical cancer;
and
(3) to see if TNFA or MICA gene associations with cervical cancer are the same as CIN.

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

1. Gene name: MHC class 1 chain-related gene A (MICA).
2. Chromosome location: 6p21.3
3. Gene product/function: Antigen presentation/T cell recognition
4. Alleles: A4, A5, A5.1, A6, A9
5. OMIM#: 600169

1. Gene name: tumor necrosis factor A (TNF-A)
2. Chromosome location: 6p21.3
3. Gene product/function: proinflammatory cytokine
4. Alleles: a2, a4, a5, a6, a10, a11
5. OMIM#: 191160

1. Gene name: major histocompatibility complex class II (HLA DQA1)
2. Chromosome location: 6p21.3
3. Gene product/function: cell-membrane alloantigens that are expressed mainly on B cells
4. Alleles: DQ6- DR15
5. OMIM#: 146880

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

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

1. invasive cervical cancer
2. cervical intraepithelial neoplasia (CIN)

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

Case definition
For study designs 2, 3, and 6, the following are defined, where available:

1. Case selection criteria
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Case selection criteria: invasive cervical cancer (histologic diagnosis conducted as part of Swedish Cancer Registry)
2. Exclusion criteria: prior operative treatment of the cervix
3. Gender: women
4. Race/ethnicity: Swedish
5. Age: 18 and above
6. Time period: 1969-1995
7. Geographic location: Vasterbotten (county) resident, Sweden
8. Number of participants: 85

Control definition  
For study design 1, the following are defined, 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

1. Control selection criteria: healthy controls who did not develop cervical cancer before the time of diagnosis of a corresponding case.
2. Matching variables: age, time of sampling of a normal smear compared with the prediagnostic normal smear of the case subject and time of sampling of a normal smear taken after diagnosis of cancer in the corresponding case subject.
3. Exclusion criteria: prior operative treatment of the cervix
4. Gender: women
5. Race/ethnicity: Swedish
6. Age: 18 and above
7. Time period: 1969-1995
8. Geographic location: Vasterbotten (county) resident, Sweden
9. Number of participants: 120

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (%
   of total eligible)

1. Environmental factor: HPV 16 and 18; HLA class II
2. Exposure assessment: DNA typing by PCR via MY09, MY11 and GP5+, GP6+ primers (for HPV 16 and 18); HLA class II genotyping by PCR for DQA1, DQB1, DRB1
3. Exposure definition: Presence or absence
4. Number of participants with exposure data: assumed typing for all on basis of presented data. 

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

1. Gene: MICA and TNFA
2. DNA source: genomic DNA extracted from archival smears and biopsies
3. Methodology: PCR, Applied Biosystems Genotyper 2.0
4. Number or participants: assumed typing for all based on presented data

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

Table 1. Prevalence of Gene Variants (from Table 1 in article)

Table 2. Gene-disease Association (from Table 2 in article)

Table 3. Gene-environment Interaction

"... the HLA class II DQ6-DR15 haplotype was the most attributable HLA locus for development of cervical cancer."

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

The main focus of this report was to ascertain allele-disease association between TNFA and MICA polymorphisms. Although no associations were observed, the investigators indicate that TNFa-11 is in linkage disequilibrium with DQ6, and that the HLA DQ6-TNFa-11 extended haplotype increases the risk three-fold. The authors indicate that their findings in conjunction with previous findings based on the same population further support the HLA class II DQ6-DR15 haplotype association with increased risk for cervical cancer.

It is curious that while DQ6 is independently associated with cervical cancer, TNFa-11 is not. Methods used for typing the DQ6-TNFa-11 extended haplotype might have been beneficial to the reader; it is unclear whether the haplotype definition was presumed or actually typed. If it was presumed, then calculating the correlation coefficient between the two alleles would have been helpful to establish their close relationship. If the two alleles are in linkage disequilibrium, then we can assume a haplotype-disease association, but if not, it may then be considered gene-gene interaction. The methods as reported do not provide sufficient information to make this distinction.

Analyses stratified by HPV16 and HPV18 DNA positivity resulted in zero controls. To truly ascertain a gene-disease association, the investigators might have conducted analyses with a baseline case-control definition of HPV-positivity. Although this does not necessarily affect their main finding between DQ6 and TNFa-11, it does make the rest of the results with HPV16 and 18 difficult to interpret. Undoubtedly, the enormous odds ratios are mostly due to HPV infection, with only a small contribution made by the gene.