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

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 a gene variant

2) Gene-disease association

The XRCC3 polymorphism has been shown to increase risk of some cancers, including cancer of the bladder and the skin, possibly as a result of reduced DNA repair. The authors of this study sought to test the possible association between the XRCC3 polymorphism and lung carcinoma in African Americans and Mexican Americans.

Gene(s)
Identification of the following:

• Gene name
• Chromosome location
• Gene product/function
• Alleles
• OMIM #

Gene name: XRCC3 (X-Ray Repair Cross-Complementing Group 3) Chromosome location: 14q.32.3
Gene product/function: The gene product of XRCC3 plays a role in homology directed DNA repair of double stranded breaks. It has been shown to be associated with the RAD family of genes, but its specific function is still being investigated.
Alleles: Thr241Met (on exon 7, position 18067 of the XRCC3 gene, codon 241; a C to T substitution leading to a threonine-to-methionine amino acid substitution)
OMIM #: 600675

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

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

Disease case definition: Newly diagnosed patients with histologically confirmed lung carcinoma
Exclusion criteria: No prior treatment with radiation or chemotherapy Gender: 82 males, 30 females
Race/ethnicity: 78 African Americans, 34 Mexican Americans
Mexican Americans Age: Mean age=58.79 in African Americans, Mean age=65.06 in Mexican Americans (Range not specified)
Time period: 1990-1994
Geographic location: University of Texas M.D. Anderson Cancer Center ( Houston , TX ), Various county, community, and VA hospitals in Houston , Galveston , and San Antonio ( Texas )
Number of participants: 112 cases (% eligible not specified)

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

Control selection criteria: Members of community centers in Houston , Galveston , and San Antonio , Texas
Matching variables: Frequency matched on age ( ± 5 years), gender, ethnicity, and city of residence
Exclusion criteria: No previous history of cancer (except non-melanoma skin cancer)
Gender: 127 males, 63 females
Race/ethnicity: 91 African Americans, 99 Mexican Americans
Mexican Americans Age: Mean age=60.25 in African Americans, Mean age=63.91 in Mexican Americans (Range not specified)
Time period: 1990-1994
Geographic location: Houston , Galveston , and San Antonio , Texas Number of participants: 190 controls (% eligible not specified)

• Environmental factor
• Exposure assessment
• Exposure definition
• Number of participants with exposure data (% of total eligible)

Number of participants with exposure data: 100%

• Gene
• DNA source
• Methodology
• Number of participants genotyped (% of total eligible) 

Gene: XRCC3 , exon 7
DNA source: isolates from peripheral blood lymphocytes
Methodology: PCR amplification, RFLP analysis
Number of participants genotyped: 100%

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

Genotype Distribution Among Controls

CC - wild-type
T = variant allele
The genotype frequencies did not differ between African American controls and Mexican American Controls. Therefore, for all subsequent analyses, the two groups were combined.

2. Gene-Disease Association

Genotype Distribution Among Cases and Controls

CC - wild-type
T = variant allele
* Adjusted for age, gender, ethnicity, smoking status.
There was no overall association between the variant allele and lung cancer.

3. Gene-Environment Interaction

CC - wild-type
T = variant allele
* Adjusted for age, gender, and ethnicity
There appears to be an increased risk of lung cancer for heavy smokers with the variant allele genotype. The polymorphism may be modifying the effect of the association between smoking and lung cancer.

The authors concluded that there was no difference in genotype frequencies between African Americans and Mexican Americans. They also concluded that while there was no overall association between the XRCC3 polymorphism and lung cancer, there is an increased risk of lung cancer for heavy smokers with the XRCC3 T-allele polymorphism.

Strengths of the Study:

• The major strength of this study is that it the association being tested has clear biological plausibility. Studies have shown that the accumulation of unrepaired DNA damage can lead to genomic instability and the development of cancer. The XRCC3 gene is involved in homology-directed DNA repair of double stranded breaks, and a polymorphism in this gene has been observed to cause other types of cancer. Therefore, it is very plausible and worth studying the possible association of the polymorphism and lung cancer.

Limitations of the Study:

• Selection of Cases
  • The cases were selected from a hospital-based population. As with any hospital-based study, there is bias that arises due to the fact that patients seeking hospital care may have various characteristics and exposures unique to that group, and therefore may not be comparable to other populations. This is especially true for patients of VA hospitals, who may have experienced exposures not seen in the general population being studied.
    
    
• Selection of Controls
  • The controls were selected from a source that is different from the cases. Although this might have been an attempt to prevent any bias associated with a hospital-based study, it introduces the possibility that the control population is not representative of the population that gave rise to the cases.

• The controls were "community center members." The authors fail to define exactly what a community center is. This could mean a number of various community organizations, including religious, cultural, or athletic centers, that may have their own set of exposures that makes them different from the general population.

• Selection Bias
  • The participation rates for the cases and controls were not specified for this study. If these participation rates were low, it could be an indication of selection bias.

• Stratification of Smoking Status
  • Light smokers were defined as those smokers who smoke less than 30 pack-years. In the analysis, the light smokers category also included never smokers. This leads to the possibility that the estimated effects of light and heavy smoking were biased. Those who were classified as never smokers should have been in a separate category.

• Sample Size
  • Although the overall size of the sample was sufficient (112 cases and 190 controls), some of the cells had low numbers after stratification.