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

Nelson HH, et al.  The XRCC1 Arg399Gln Polymorphism, Sunburn, and Non-melanoma Skin Cancer: Evidence of Gene-Environment Interaction. Cancer Res 2002;62(1):152-5

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

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

Purpose: To investigate the relation between the XRCC1 arg399gln polymorphism and its interaction with carcinogen exposure and non-melanoma skin cancer

Gene(s)
Identification of the following:

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

1. Gene name: XRCC1
2. Chromosome location: 19q13.2
3. Gene product/function: associated with DNA repair, RBC Glycophorin A mutations, sister chromatid exchange, and length of cell cycle
4. Alleles: Arg399arg, Arg399gln, Gln399gln
5. OMIM #: 194360

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

1. Sunburn History
2. Ionizing Radiation Therapy

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

Non-Melanoma Skin Cancer:

1. Basal Cell Carcinoma (BCC)
2. Squamous Cell Carcinoma (SCC)

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. Disease case definition: persons newly diagnosed with non-melanoma skin cancer in New Hampshire , identified by incident survey.
2. Exclusion criteria: people refusing blood draw, inconclusive results for XRCC1 genotype, or non-Caucasian
3. Gender: 
• BCC cases: 281 male and 218 female
• SCC cases: 164 male and 82 female 

4. Race/ethnicity: Caucasian
5. Age: 
• BCC cases:
  • 131 aged ≤50, 
  • 100 aged 51-60, 
  • 180 aged 61-70, 
  • 88 aged > 70
• SCC cases: 
  • 15 aged ≤50, 
  • 38 aged 51-60, 
  • 121 aged 61-70, 
  • 72 aged > 70
6. Time period: diagnosed between 7/1/1993 and 6/30/1995
7. Geographic location: New Hampshire
8. Number of participants:  
   • 499 BCC cases
   • 246 SCC cases

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: persons derived from New Hampshire Department of Transportation and the Healthcare Financing Administration enrollment lists
2. Matching variables: frequency matched by gender and age
3. Exclusion criteria: people refusing blood draw, inconclusive results for XRCC1 genotype, or non-Caucasian.
4. Gender: 263 male and 168 female
5. Race/ethnicity: Caucasian
6. Age: 80 aged ≤ 50, 80 aged 51-60, 191 aged 61-70, 80 aged > 70
7. Time period: enrolled at time of study
8. Geographic location: New Hampshire
9. Number of participants: 431

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

1. Environmental factor: sunburn history
2. Exposure assessment: number of painful sunburns assessed by questionnaire
3. Exposure definition: painful sunburn was defined as sunburns that were painful for greater than two days; greater than three painful sunburns is considered ‘high exposure’
4. Number of participants with exposure data: > three painful sunburns-
   controls: 164 (38.4%)
   BCC cases: 261 (52.8%)
   SCC cases: 131 (53.7%)

1. Environmental factor: ionizing radiation therapy
2. Exposure assessment: self-report of therapeutic ionizing radiation verified through medical records
3. Exposure definition: received ionizing radiation therapy, excluding treatments for NMSC
4. Number of participants with exposure data: 
   controls: 34 (7.9%)
   BCC cases: 66 (13.2%)
   SCC cases: 31 (12.6%)

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

1. Gene: XRCC1
2. DNA source: peripheral circulating blood specimen taken at time of interview using Qaigen genomic DNA extract kit
3. Methodology :PCR-RFLP method
4. Number of participants genotyped: 1176 (81.9%)

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

Table 1: XRCC1 codon 399 genotype prevalence and association with NMSC^a

^aOdds Ratios (95% Cofidence Interval) adjusted for age, sex, and tendency to burn

Table 2. Regression model for the joint effects of XRCC1 genotype and Sunburn^a

^aORs adjusted for age, sex, and tendency to burn

Table 3. Association of SCC and Sunburn within XRCC1 genotype strata^a

Overall, the XRCC1 gln399gln homozygote variant genotype was significantly associated with a decreased risk of both BCC and SCC.  Furthermore, high sun exposure was associated with increased risk of NMSC regardless of genotype.  However, in individuals with the homozygote variant genotype there was an increased relative risk of SCC with greater than 3 painful sunburns.

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

The study was conducted in New Hampshire , where the rate of sunburn would be low compared with other areas in the U.S. closer to the equator.  Because the study found that sun exposure alone increased the risk of NMSC regardless of genotype, knowledge of one’s genotype is probably of little practical importance.  It would be helpful to conduct a similar study in a state further south, such as Florida , to see if the results are consistent in a population of individuals with higher sun exposure.

Another concern is possible recall bias.  Because the link between skin cancer and sun exposure is common knowledge, it is possible that case subjects may have over-reported sun exposure.  This would cause estimated OR values to be artificially inflated.