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

Parks C, Cooper G, Dooley M, Treadwell E, St. Clair E, Gilkeson G, Pandey J. Systemic lupus erythematosus and genetic variation in the interleukin 1 gene cluster: a population based study in the southeastern United States . Ann Rheum Dis. 2004;63:91-94.

(Additional information on study design and methods from: Cooper G, Dooley M, Treadwell E, St. Clair E, Gilkeson G. Hormonal and reproductive risk factors for development of systemic lupus erythematosus. Arthrit Rheum. 2002; 46(7):1830-1839.)

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

Differences in IL1-alpha, IL1-beta and IL1-receptor antagonist production have been seen in SLE. The purpose of this study is to examine polymorphisms at IL1-889(C-->T), IL1 +4845(C-->T), IL1ß -511(C-->T), IL1ß +3953(G-->T), and IL1R a (86 bp VNTR) in a population based study of SLE in North Carolina and South Carolina: 1) To estimate the effects of these polymorphisms on SLE individually and after adjusting for variation at all five loci. 2) To examine gene-gene interactions between these loci with SLE and proteinuria as outcomes.

Gene(s)
Identification of the following:

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

1. Gene name: IL1A (interleukin 1-alpha) , IL1ß (interleukin 1-beta) , IL1RN (interleukin 1 receptor antagonist)
2. Chromosome location: 2q13-21 (the IL1 gene cluster) IL1A : 2q14 IL1ß : 2q14 IL1RN : 2q14.2
3. Gene product/function: IL1A and IL1ß: Have similar functions; operate at different pH. They are mediators of inflammation and immunity: upregulate adhesion molecule expression, neutrophil and macrophage emigration, mimic shock, fever, upregulate hepatic acute-phase protein production, facilitate hematopoeisis. Produced by monocytes/macrophages, B cells, fibroblasts, most epithelial cells, endothelial cells; target is all cells. IL1RN: Binds to IL1-receptors, inhibiting the binding of IL1A and IL1B and thus inhibiting their biologic activity.
4. Alleles: IL1-889(C-->T), IL1 +4845(C-->T), IL1ß -511(C-->T), IL1ß +3953
   (G-->T), IL1Ra (86 bp VNTR)
5. OMIM #: IL1A: 147760   IL1B: 147720  IL1RN: 147679

Aside from race, none were considered in this analysis, although the original study did collect data on the following factors: education level, smoking history, age at menarche and menopause, pregnancy and live birth history, breast feeding history, hormonal contraceptive use, hormonal replacement therapy, infertility and use of fertility drugs, and history of other gynecological events. Medical records abstraction included presence or absence of arthritis, photosensitivity, malar rash, pleuritis, and proteinuria (symptoms/signs associated with SLE).

1. Systemic lupus erythematosus (SLE), defined by the 1997 revised American College of Rheumatology (ACR) classification criteria.
2. Proteinuria, defined as two or more urine samples containing equal to or greater than 3 mg/ml albumin reported in medical records up to six months after diagnosis.

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

1. Case-control

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: Systemic lupus erythematosus (SLE), defined by the 1997 revised American College of Rheumatology (ACR) classification criteria
2. Eligibility criteria: age equal to or greater than 18 years at study enrollment, residence within study area during at least six months of year prior to diagnosis, ability to speak and understand English
3. Exclusion criteria: none specified other than not meeting eligibility criteria
4. Gender: 90% female
5. Race/ethnicity: 60% African American
6. Age: mean age at diagnosis 39 years (range 15-81)
7. Time period: diagnosed between January 1, 1995 and July 31, 1999
8. Geographic location: 60 counties in North Carolina and South Carolina
9. Number of participants: 265

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: identified through state driver's license records for the 60 study counties
2. Matching variables: age (five-year age groups), sex, state of residence
3. Eligibility criteria: same as non-medical criteria for cases
4. Exclusion criteria: ever having been diagnosed with any kind of lupus
5. Gender: 90% female (matched)
6. Race/ethnicity: 30% African American Age: not given, besides matching method Time period:
7. Age: not given, besides matching method
8. Time period: not given
9. Geographic location: 60 counties in North Carolina and South Carolina (same as cases)
10. Number of participants: 355

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

1. Environmental factor: none
2. Exposure assessment: in-person interview
3. Exposure definition:
4. Number of participants with exposure data: see above

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

1. Gene: IL1A, IL1B
2. DNA source: blood specimens
3. Methodology: amplification by PCR, then biallelic restriction fragment length polymorphisms (digested with Fun4HI, Nco1, AvaI, a Taq respectively for the four polymorphisms in the order listed above)
4. Number of participants genotyped: 243 cases (92% of total eligible); 298 controls (84% of total eligible)

1. Gene: IL1Ra
2. DNA source: blood specimens
3. Methodology: amplification by PCR, genotyped by visual determination of size relative to known markers
4. Number of participants genotyped: 243 cases (92% of total eligible); 298 controls (84% of total eligible)

Analysis

X² computed by Fisher's exact test was used to compare genotype frequencies in cases and controls at each locus.

Odds ratios with 95% confidence intervals were obtained by unconditional logistic regression: models were run for each locus separately, comparing the genotypes with the variant allele with the homozygous wild-type genotype. A five-loci model was used to adjust for confounding by linkage disequilibrium.

Linkage disequilibrium was examined using the estimating haplotypes program: http://linkage.rockefeller.edu/ott/eh.html

Analysis did not adjust for multiple comparisons.

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

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

>> Click here to view tables

2. Gene-disease interaction (proteinuria as outcome)
None of the genotypes were independently associated with proteinuria, data not shown.

4. Gene-gene interaction (SLE as outcome)
Data not shown for all gene-gene combinations.

• In African Americans: no interaction was seen between IL1-889 and IL1ß-511 for overall risk of SLE (p = 0.938)
• In African Americans: interaction was seen between IL1-889 and IL1ß-511 for risk of proteinuria (p = 0.002) (genotypes not specified)
• Combined genotype of IL1-889 C/C, IL1ß-511T was positively associated with risk of SLE (OR = 2.4, 95% CI 1.2 to 5.1; p = 0.019) (in whites?)
• Same combined genotype was inversely associated with proteinuria (OR = 0.4, 95% CI 0.2 to 0.9; p = 0.027) (in whites?)

Haplotype estimation:
There was evidence of linkage disequilibrium between IL1 a -889 and IL1 b -511 in African American cases and controls. In contrast, there was significant linkage disequilibrium for most pairwise comparisons in whites.

A strength of the study is the use of population-based controls and stratification by race to minimize the potential role of population stratification as a confounder.

The authors had access to data on many other factors, as described above in the Environmental Factors section. Gene-environment interaction could have been assessed, and adjustment for confounding by these factors could have been done by including them in the development of the logistic regression models.

There is no description of validation of the genotyping method.

Data/results on gene-gene interaction are unclear.