Population-based Case-control Study In Denmark Research Articles

Abstract 3441: Application of a maternal comorbidity index to predict childhood cancer risk: A population-based case-control study in Denmark

Abstract Background: Maternal health has been found to be an indicator of children’s health and has also been found to affect the risk of childhood diseases. Children are especially susceptible to in-utero exposures. A mother’s health conditions before and during pregnancy could have important consequences for her child's health, including cancer development, as was observed in some prior studies. Objectives: This study aimed to identify the impact of varying maternal comorbidities on the development of childhood cancers. This study applied an Obstetric Comorbidity Index (Bateman et al, 2013) to examine maternal comorbid conditions in childhood cancer risk. Methods: Using maternal and birth records, and cancer records from the Danish Cancer Registry, we conducted a population-based case-control study with two population groups- the first population included cases (n=2578) and controls (n=64450) with ICD-10 diagnoses from 1994-2013, and the second population included cases (n=8339) and controls (n=208475) with ICD-8 and 10 diagnoses from 1977-2013. Maternal comorbidities were ascertained from the National Patient Register using the Obstetric Comorbidity Index. We estimated the risk of childhood cancer using conditional logistic regression. Results: Multiple gestation pregnancy (OR=1.17, 95% CI 1.05, 1.30), maternal pre-existing diabetes (OR=1.68, 95% CI 1.14, 2.48), congenital heart disease (OR=2.62, 95% CI 1.13, 6.09) and previous cesarean delivery (OR=1.35, 95% CI 1.03, 1.75) showed an increased risk of childhood cancers (all types combined). Children born to mothers between the ages of 35 and 39 also had a higher risk of cancer as compared to those born before. In the 1977-2013 population, there was an increased risk of acute lymphocytic leukemia (ALL; OR=1.08, 95% CI 1.04, 1.13) and rhabdomyosarcoma (OR=1.13, 95% CI 1.01, 1.27) for each unit of increase on the Obstetric Comorbidity Index. There was also an increased risk of retinoblastoma (OR=1.16, 95% CI 1.01, 1.32) for each unit of increase on the maternal comorbidities index in the 1994-2013 population. Examining mothers that had a score of one or more in the Obstetric Comorbidity Index, there was a higher risk of ALL (OR=1.43, 95% CI 1.26, 1.62), non-Hodgkin lymphoma (OR=1.50, 95% CI 1.17, 1.91), Burkitt lymphoma (OR=1.71, 95% CI 1.12, 2.61), and rhabdomyosarcoma (OR=1.58, 95% CI 1.10, 2.26) for children whose mothers with at least one maternal comorbidity. A similar trend was observed in the 1994-2013 population for ALL, non-Hodgkin lymphoma, and Burkitt lymphoma. Conclusion: The results of the study show varying effects of exposure to one or more maternal comorbidities on individual pediatric cancer types, and an overall increased risk of most cancers development in children with exposure of mothers to 1 or more maternal comorbidities. Citation Format: Tobiloba Adanma Adenekan, Julia E. Heck, Cheng Yin, Johnni Hansen. Application of a maternal comorbidity index to predict childhood cancer risk: A population-based case-control study in Denmark [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3441.

Maternal autoimmune disease and its association with childhood cancer: A population-based case-control study in Denmark

BackgroundAutoimmune diseases have been linked to an increased risk of pregnancy-related complications. A family history of autoimmune diseases may be related to the risk of childhood cancer based on similar histocompatibility antigens. We utilized data from national registries in Denmark to examine associations between maternal autoimmune disease and cancer in their offspring. MethodsWe linked data from several national registries in Denmark to identify childhood cancer cases in children <20 years diagnosed between 1977 to 2016. Controls were selected from the Central Population Register and matched to cases by birth year and sex (25:1). Mothers with autoimmune disease diagnosed in pregnancy or prior were identified from the National Patient Register. Multivariable conditional logistic regression analyses were used to estimate associations between maternal autoimmune diseases and childhood cancer in offspring. ResultsAutoimmune diseases (all types) were positively associated with all childhood cancers combined (Odds Ratio (OR) = 1.25, 95% CI 1.06, 1.47), acute lymphoblastic leukemia (OR =1.52, 95% CI 1.09, 2.13), Burkitt lymphoma (OR = 2.69, 95% CI 1.04, 6.97), and central nervous system tumors (OR = 1.45, 95% CI 1.06, 1.99), especially astrocytoma (OR = 2.27, 95% CI 1.36, 3.77) and glioma (OR = 1.75, 95% CI 1.13, 2.73). When we examined mothers with rheumatoid arthritis, we observed an increased association for all cancers (OR = 2.15, 95% CI 1.40, 3.30), acute lymphoblastic leukemia (OR = 3.55, 95% CI 1.69, 7.47), and central nervous system tumors (OR = 2.91, 95% CI 1.46, 5.82), especially glioma (OR = 3.58, 95% CI 1.40, 9.18) in offspring. ConclusionThere is a positive association between maternal autoimmune disease and childhood cancer. This association is especially prominent in the offspring of women with rheumatoid arthritis.

Association Between Estimated Geocoded Residential Maternal Exposure to Lithium in Drinking Water and Risk for Autism Spectrum Disorder in Offspring in Denmark

Lithium is a naturally occurring and trace element that has mood-stabilizing effects. Maternal therapeutic use of lithium has been associated with adverse birth outcomes. In animal models, lithium modulates Wnt/β-catenin signaling that is important for neurodevelopment. It is unknown whether exposure to lithium in drinking water affects brain health in early life. To evaluate whether autism spectrum disorder (ASD) in offspring is associated with maternal exposure to lithium in drinking water during pregnancy. This nationwide population-based case-control study in Denmark identified 8842 children diagnosed with ASD born from 2000 through 2013 and 43 864 control participants matched by birth year and sex from the Danish Medical Birth Registry. These data were analyzed from March 2021 through November 2022. Geocoded maternal residential addresses during pregnancy were linked to lithium level (range, 0.6 to 30.7 μg/L) in drinking water estimated using kriging interpolation based on 151 waterworks measurements of lithium across all regions in Denmark. ASD diagnoses were ascertained using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes recorded in the Danish Psychiatric Central Register. The study team estimated odds ratios (ORs) and 95% CIs for ASD according to estimated geocoded maternal exposure to natural source of lithium in drinking water as a continuous (per IQR) or a categorical (quartile) variable, adjusting for sociodemographic factors and ambient air pollutants levels. The study team also conducted stratified analyses by birth years, child's sex, and urbanicity. A total of 8842 participants with ASD (male, 7009 [79.3%]) and 43 864 control participants (male, 34 749 [79.2%]) were studied. Every IQR increase in estimated geocoded maternal exposure to natural source of lithium in drinking water was associated with higher odds for ASD in offspring (OR, 1.23; 95% CI, 1.17-1.29). Elevated odds among offspring for ASD were estimated starting from the second quartile (7.36 to 12.67 μg/L) of estimated maternal exposure to drinking water with lithium and the OR for the highest quartile (more than 16.78 μg/L) compared with the reference group (less than 7.39 μg/L) was 1.46 (95% CI, 1.35-1.59). The associations were unchanged when adjusting for air pollution exposures and no differences were apparent in stratified analyses. Estimated maternal prenatal exposure to lithium from naturally occurring drinking water sources in Denmark was associated with an increased ASD risk in the offspring. This study suggests that naturally occurring lithium in drinking water may be a novel environmental risk factor for ASD development that requires further scrutiny.

Maternal anemia and childhood cancer: a population-based case-control study in Denmark

BackgroundChildhood cancer risk is associated with maternal health during pregnancy. Anemia in pregnancy is a common condition, especially in low-income countries, but a possible association between maternal anemia and childhood cancer has not been widely studied. MethodsWe examined the relation in a population-based study in Denmark (N = 6420 cancer cases, 160,485 controls). Cases were taken from the Danish Cancer Registry, and controls were selected from national records. We obtained maternal anemia diagnoses from the National Patient and Medical Births registries. In a separate analysis within the years available (births 1995–2014), we examined cancer risks among mothers taking prescribed vitamin supplements, using data from the National Prescription Register. We estimated the risks of childhood cancer using conditional logistic regression. ResultsThe risks of neuroblastoma [odds ratio (OR= 1.83, 95% confidence interval (CI): 1.04, 3.22] and acute lymphoblastic leukemia (OR= 1.46, 95% CI 1.09, 1.97) were increased in children born to mothers with anemia in pregnancy. There was a two-fold increased risk for bone tumors (OR= 2.59, 95% CI: 1.42, 4.72), particularly osteosarcoma (OR= 3.54, 95% CI 1.60, 7.82). With regards to prescribed supplement use, mothers prescribed supplements for B12 and folate deficiency anemia (OR= 4.03, 95% CI 1.91, 8.50) had an increased risk for cancer in offspring. ConclusionOur results suggest that screening for anemia in pregnancy and vitamin supplementation may be an actionable strategy to prevent some cases of childhood cancer.

Long-term PM2.5 exposure and diagnosis of amyotrophic lateral sclerosis: a population-based case-control study in Denmark

BACKGROUND AND AIM: Evidence for an association between fine particle (PM2.5) exposure and neurodegenerative diseases is increasing. Whether PM2.5 exposure is relevant in amyotrophic lateral sclerosis (ALS) pathogenesis is still unknown. Only two epidemiological studies have evaluated long-term PM2.5 exposure effects in ALS. We aim to assess long-term PM2.5 exposure and ALS incidence and identify potential critical windows of exposure. METHODS: We leveraged data from the Danish National Patient Registry (NPR) on prospectively collected ALS cases (1989-2013). One-to-five controls per case were selected through the Danish Civil Registry, matched on sex, and year of birth. We estimated 1-, 5-, and 10-year PM2.5 average exposures at residential address, lagged one-year pre-diagnosis. We also estimated 1-year exposure averages from the date of diagnosis to 10 years pre-diagnosis. All exposures were estimated using predictions from a validated spatio-temporal model. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the 1-, 5-, and 10- years exposures, adjusting for individual socioeconomic status, place of birth, civil status, and residence area. This analysis will be followed by a distributed lag analysis using the estimated 1-year exposure averages dating back to 10-years pre-diagnosis. RESULTS:Our analysis included data from 2,195 cases and 6,690 controls. In the preliminary analysis of the 1-, 5-, and 10-years exposure windows, we found no association between ALS diagnosis and PM2.5. The estimated ORs per 1 µg/m3 increase in PM2.5 were 1.00 (95%CI: 0.96–1.04), 0.99 (95%CI: 0.96–1.03), and 0.99 (95%CI: 0.95–1.02) for 1-, 5-, and 10-year averaged PM2.5 exposure respectively. CONCLUSIONS:Our preliminary results suggest no association between PM2.5 and ALS diagnosis. However, averaging long-term exposure decreases temporal exposure contrasts. Our lagged analysis will be important to more precisely analyze windows of exposure dating back to 10 years pre-diagnosis and crucial to verify our preliminary findings. KEYWORDS: ALS, air pollution, particle matter, windows of exposure

Cancers Preceding Parkinson’s Disease after Adjustment for Bias in a Danish Population-Based Case-Control Study

Cancer patients are at lower risk of developing Parkinson’s disease (PD) compared with the general population. One explanation is the negative association between smoking and PD, but PD risk is also lower for cancers not related to smoking. Another explanation is survival bias where death from cancer may act as a competing risk. We conducted a large population-based case-control study in Denmark and investigated whether cancer diagnosis reduced the risk of developing PD even after adjusting for important risk factors including smoking, physical activity, and lifetime oestrogen status. Using probabilistic bias analysis we quantified the influence of survival bias. We estimated negative point estimates (ORs) between cancers and PD for all cancers except skin, female breast, and ill-defined and unspecified 0.85 (95% CI 0.59–1.21); smoking-related cancers 0.75 (95% CI 0.45–1.23); and cancers not related to smoking 0.82 (95% CI 0.49–1.38) that are very similar to those previously reported for a much larger Danish register only based study, even though our confidence intervals include the null. These effect estimates shifted towards the null after accounting for survival bias but most bias-adjusted ORs remained below 1 within the range of priors considered in simulations. Overall, cancer patients have a lower risk of developing PD even after controlling for cancer-related lifestyles factors and correcting for survival bias.

Survival of glioma patients in relation to mobile phone use in Denmark, Finland and Sweden.

Gliomas are the most common cancer of the brain, with a poor prognosis in particular for glioblastoma. In 2014, a study suggested reduced survival in relation to latency of mobile phone use among glioblastoma patients. A joint epidemiological/experimental project to study effects of RF-EMF on tumor development and progression was established. The current analysis relates to the epidemiological part and addresses whether pre-diagnostic mobile phone use was associated with survival among glioma patients. Glioma cases (n = 806) previously enrolled in a collaborative population-based case-control study in Denmark, Finland and Sweden were followed up for survival. Vital status, date of death, date of emigration, or date last known to be alive was obtained based on registry linkages with a unique personal ID in each country. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) stratified by country. Covariates investigated were sex, age, education, histology, treatment, anatomic location and marital status. No indication of reduced survival among glioblastoma patients was observed for various measures of mobile phone use (ever regular use, time since start of regular use, cumulative call time overall or in the last 12months) relative to no or non-regular use. All significant associations suggested better survival for mobile phone users. Results were similar for high-grade and low-grade gliomas. We found no evidence of reduced survival among glioma patients in relation to previous mobile phone use.

Use of beta-blockers and risk of serious upper gastrointestinal bleeding: a population-based case-control study.

Background:Some studies indicate a reduced risk of serious upper gastrointestinal bleeding (UGIB) for users of beta-blockers, but the association remains to be confirmed in larger studies and characterized with respect to differences among beta-blockers. We aimed to assess whether beta-blocker use decreases the risk of UGIB.Methods:We conducted a register-based, population-based case-control study in Denmark. We identified cases with a first validated discharge diagnosis of UGIB during the period 1995–2006. Controls were selected by risk-set sampling in a ratio of 10:1. We estimated crude and adjusted odds ratios (ORs) of the association between current beta-blocker use and the risk of UGIB by using conditional logistic regression and further stratified by selective and non-selective beta-blockers, respectively.Results:We identified 3571 UGIB cases and 35,582 controls. Use of beta-blockers was not found to be associated with a decreased risk of UGIB (adjusted OR 1.10; 95% CI: 1.00–1.21). The association remained neutral after stratification by selective and non-selective beta-blockers, and by single beta-blocker substances. Similarly, we found no association between current beta-blocker use and the risk of UGIB within different subgroups.Conclusions:We found no association between beta-blocker use and UGIB.

Occupational and recreational physical activity and Parkinson’s disease in Denmark

Objectives This study aimed to examine whether occupational and physical activity (PA) at different ages contribute to Parkinson's disease (PD) risk in a large population-based case-control study in Denmark. Methods We identified 1828 PD patients from the Danish National Hospital Register and recruited 1909 gender and year of birth matched controls from the Danish Central Population Register. Occupational and leisure-time PA were determined from a job exposure matrix based on occupational history and self-reported leisure-time information. Results No association was found for occupational PA alone in men, but higher leisure-time PA (≥5 hours/week of strenuous activities) in young adulthood (15-25 years) was associated with a lower PD risk (adjusted odds ratio (OR adj) 0.75, 95% confidence interval (95% CI) 0.62-0.90); men who engaged in high occupational and high leisure-time PA in young adulthood had the lowest PD risk (OR adj0.58, 95% CI 0.41-0.81). Among women, inverse associations were found for occupation PA before age 50 (highest vs lowest, OR adj0.75, 95% CI 0.55-1.06) and strenuous leisure-time PA after age 50 (OR adj0.65, 95% CI 0.87-0.99); no clear pattern was seen for leisure and occupational PA combined. Conclusions We observed gender-specific inverse associations between occupational and leisure-time PA and PD risk; however, we cannot preclude reverse causation especially in older ages since PD has a long prodromal stage that might lead to a reduction of PA years before motor symptom onset and PD diagnosis.

Amyotrophic Lateral Sclerosis and the Military: A Population-based Study in the Danish Registries.

Prior studies have suggested that military service may be associated with the development of amyotrophic lateral sclerosis (ALS). We conducted a population-based case-control study in Denmark to assess whether occupation in the Danish military is associated with an increased risk of developing ALS. There were 3,650 incident cases of ALS recorded in the Danish National Patient Registry between 1982 and 2009. Each case was matched to 100 age- and sex-matched population controls alive and free of ALS on the date of the case diagnosis. Comprehensive occupational history was obtained from the Danish Pension Fund database, which began in 1964. 2.4% (n = 8,922) of controls had a history of employment in the military before the index date. Military employees overall had an elevated rate of ALS (odds ratio [OR] = 1.3; 95% confidence interval [CI]: 1.1, 1.6). A 10-year increase in years employed by the military was associated with an OR of 1.2 (95% CI: 1.0, 1.4), and all quartiles of time employed were elevated. There was little suggestion of a pattern across calendar year of first employment, but there was some evidence that increasing age at first employment was associated with increased ALS rates. Rates were highest in the decade immediately following the end of employment (OR = 1.6; 95% CI: 1.2, 2.2). In this large population-based case-control study, employment by the military is associated with increased rates of ALS. These findings are consistent with earlier findings that military service or employment may entail exposure to risk factors for ALS.

Pelvic inflammatory disease and risk of invasive ovarian cancer and ovarian borderline tumors

The aim of the study was to examine the potential association between a history of pelvic inflammatory disease (PID) and risk of epithelial ovarian cancer or ovarian borderline tumors. In a population-based case-control study in Denmark, we included 554 women with invasive ovarian cancer, 202 with ovarian borderline tumors, and 1,564 controls aged 35-79 years. The analyses were performed in multiple logistic regression models. We found a significantly increased risk of ovarian borderline tumors among women with a history of PID (OR = 1.50; 95% CI 1.08-2.08) but no apparent association between PID and risk of invasive ovarian cancer (OR = 0.83; 95% CI 0.65-1.05). We found no effect of age at time of first PID or time since first PID on the risk for either condition. Our results suggest that a history of PID is associated with an increased risk of ovarian borderline tumors, which may support the hypothesis that inflammation is an etiological factor. The lack of an association between previous PID and invasive ovarian cancer may indicate an etiological difference between ovarian borderline tumors and invasive ovarian cancer. However, an important limitation of the study is the use of self-reported PID.

Heart Disease May Be a Risk Factor for Pulmonary Embolism Without Peripheral Deep Venous Thrombosis

Heart diseases increase the risk of arterial embolism; whether they increase the risk of pulmonary embolism without peripheral venous thrombosis is less certain. We conducted a nationwide, population-based case-control study in Denmark using patients diagnosed with pulmonary embolism and/or deep venous thrombosis between 1980 and 2007. We computed odds ratios to estimate relative risks associating preceding heart disease with pulmonary embolism, pulmonary embolism and deep venous thrombosis, or deep venous thrombosis alone. In this study, 45,282 patients had pulmonary embolism alone, 4680 had pulmonary embolism and deep venous thrombosis, and 59,790 had deep venous thrombosis alone; 541,561 were population controls. Myocardial infarction and heart failure in the preceding 3 months conferred high risks of apparently isolated pulmonary embolism (odds ratio, 43.5 [95% confidence interval (CI), 39.6-47.8] and 32.4 [95% CI, 29.8-35.2], respectively), whereas the risks of combined pulmonary embolism and deep venous thrombosis (19.7 [95% CI, 16.0-24.2] and 22.1 [95% CI, 18.7-26.0], respectively) and deep venous thrombosis alone (9.6 [95% CI, 8.6-10.7] and 12.7 [95% CI, 11.6-13.9], respectively) were lower. Left-sided valvular disease was associated with an odds ratio of 13.5 (95% CI, 11.3-16.1), whereas the odds ratio was 74.6 (95% CI, 28.4-195.8) for right-sided valvular disease. Restricting the analysis to cases diagnosed after 2000 led to lower risk estimates but the same overall pattern. Heart diseases increase the near-term risk for pulmonary embolism not associated with diagnosed peripheral vein thrombosis.

Sex-specific impact of socio-economic factors on suicide risk: a population-based case-control study in Denmark

Although many authors have investigated the impact of sex on the association between socio-economic status (SES) and suicide, a definite consensus has not yet emerged. Using Danish population registration data including 15 648 suicide deaths of individuals aged 18-65 year during 1981-97 and matched population controls, we investigate the associations of multiple SES factors with suicide risk and explore the sex-specific aspects of these associations. We use conditional logistic regression models to estimate the statistical relationship between SES, sex and suicide. SES, proxied by low income, unskilled blue-collar work, non-specific wage work and unemployment, increases suicide risk more prominently for men than for women. Marital status has a comparable influence on suicide risk in both sexes; parenthood is protective against suicide, and the effect is larger for women. Living in a large city raises suicide risk for women but reduces it for men; residents with a foreign citizenship in Denmark have a lower risk of suicide compared with Danish citizens, but this protection is confined to male immigrants. Our results demonstrate that suicide risk is associated with a range of SES proxies but the strength and/or direction of the association can differ by sex. Risk assessment and, therefore, prevention approaches should take this into consideration.

Risk Factors for Squamous Cell Carcinoma of the Penis—Population-Based Case-Control Study in Denmark

Few etiologic studies of squamous cell carcinoma (SCC) of the penis have been carried out in populations where childhood circumcision is rare. A total of 71 patients with invasive (n=53) or in situ (n=18) penile SCC, 86 prostate cancer controls, and 103 population controls were interviewed in a population-based case-control study in Denmark. For 37 penile SCC patients, tissue samples were PCR examined for human papillomavirus (HPV) DNA. Overall, 65% of PCR-examined penile SCCs were high-risk HPV-positive, most of which (22 of 24; 92%) were due to HPV16. Penile SCC risk was positively associated with measures of early and high sexual activity, including lifetime number of female sex partners, number of female sex partners before age 20, age at first intercourse, penile-oral sex, a history of anogenital warts, and never having used condoms. Histories of phimosis and priapism at least 5 years before diagnosis were also significant risk factors, whereas alcohol abstinence was associated with reduced risk. Our study confirms sexually transmitted HPV16 infection and phimosis as major risk factors for penile SCC and suggests that penile-oral sex may be an important means of viral transmission. The association with priapism was unexpected and needs replication.

Risk factors for invasive squamous cell carcinoma of the vulva and vagina—Population‐based case–control study in Denmark

The etiology of vulvar and vaginal squamous cell carcinoma (VV-SCC) has received little attention. A total of 182 women with invasive VV-SCC (116 with VV-SCC(vulva), 66 with VV-SCC(vagina)), 164 uterine corpus cancer controls and 518 population controls were interviewed in a population-based case-control study in Denmark, and 87 (48%) of the VV-SCC cases had tissue samples examined for human papillomavirus (HPV) DNA using the GP5+/6+ PCR-EIA assay and subsequent reverse line blotting for HPV typing. Logistic regression-derived odds ratios with 95% confidence intervals served as relative risks. Cervical cancer-associated high-risk HPVs (hrHPVs) were detectable in most (89%) examined cases of VV-SCC(vagina) and in half (50%) of cases of VV-SCC(vulva) (p < 0.001). In site-specific multivariate logistic regression analyses, statistically significant risk factors for both VV-SCC(vulva) and VV-SCC(vagina) included measures of hrHPV exposure (anogenital warts for VV-SCC(vulva); cervical neoplasia and poor genital hygiene for VV-SCC(vagina)), tobacco smoking and alcohol consumption. Furthermore, socioeconomic variables (marital status and years at school) were associated with risk of VV-SCC(vulva). Comparing hrHPV-positive and hrHPV-negative VV-SCCs in polytomous logistic regression analysis revealed that tobacco smoking and cervical neoplasia were significant risk factors only for hrHPV-positive VV-SCCs. Our study shows that VV-SCC(vulva) and VV-SCC(vagina) share measures of prior hrHPV exposure, tobacco smoking and alcohol consumption as statistically significant risk factors. HPV vaccination programs aimed at reducing the burden of cervical cancers are likely to also provide considerable protection against VV-SCCs.

Variation in DNA Repair GenesERCC2, XRCC1, andXRCC3and Risk of Follicular Lymphoma

The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.

Autoimmune and Chronic Inflammatory Disorders and Risk of Non-Hodgkin Lymphoma by Subtype

Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin lymphoma (NHL). Because different NHL subtypes develop at different stages of lymphocyte differentiation, associations of autoimmune and inflammatory disorders with specific NHL subtypes could lead to a better understanding of lymphomagenic mechanisms. In a population-based case-control study in Denmark and Sweden, 3055 NHL patients and 3187 matched control subjects were asked about their history of autoimmune and chronic inflammatory disorders, markers of severity, and treatment. Logistic regression with adjustment for study matching factors was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for NHL overall and for NHL subtypes. Risks of all NHL were increased in association with rheumatoid arthritis (OR = 1.5, 95% CI = 1.1 to 1.9), primary Sjögren syndrome (OR = 6.1, 95% CI = 1.4 to 27), systemic lupus erythematosus (OR = 4.6, 95% CI = 1.0 to 22), and celiac disease (OR = 2.1, 95% CI = 1.0 to 4.8). All of these conditions were also associated with diffuse large B-cell lymphoma, and some were associated with marginal zone, lymphoplasmacytic, or T-cell lymphoma. Ever use of nonsteroidal anti-inflammatory drugs, systemic corticosteroids, and selected immunosuppressants was associated with risk of NHL in rheumatoid arthritis patients but not in subjects without rheumatoid arthritis. Also, multivariable adjustment for treatment had little impact on risk estimates. Psoriasis, sarcoidosis, and inflammatory bowel disorders were not associated with increased risk of NHL overall or of any NHL subtype. Our results confirm the associations between certain autoimmune disorders and risk of NHL and suggest that the associations may not be general but rather mediated through specific NHL subtypes. These NHL subtypes develop during postantigen exposure stages of lymphocyte differentiation, consistent with a role of antigenic drive in autoimmunity-related lymphomagenesis.

Medication Use and Risk of Non-Hodgkin's Lymphoma

Conflicting results from previous epidemiologic studies shed little light on whether medication use is associated with risk of non-Hodgkin's lymphoma (NHL). To investigate this question, the authors conducted a population-based case-control study in Denmark and Sweden from 1999 to 2002, including 3,055 incident NHL cases and 3,187 controls. Participants reported their past use of medications and history of particular medical conditions. Unconditional logistic regression was used to estimate multivariate odds ratios and 95% confidence intervals for the associations between medication use and risk of NHL; all statistical tests were two sided. Use of antibiotics more than 10 times during adulthood was positively associated with risk of NHL and most major NHL subtypes; when users were compared with nonusers, the odds ratio for NHL was 1.8 (95% confidence interval: 1.4, 2.3); p(trend) for total antibiotic use <0.001. In addition, high cumulative use of nonsteroidal anti-inflammatory drugs was marginally associated with elevated NHL risk. Other medications evaluated were not associated with risk of NHL or its most common subtypes. Findings suggest that inflammation, infections, susceptibility to infections, and/or use of antibiotics or nonsteroidal anti-inflammatory drugs to treat these conditions may increase the risk of NHL. However, most of the medications examined were not associated with NHL risk.

Ultraviolet Radiation Exposure and Risk of Malignant Lymphomas

The incidence of malignant lymphomas has been increasing rapidly, but the causes of these malignancies remain poorly understood. One hypothesis holds that exposure to ultraviolet (UV) radiation increases lymphoma risk. We tested this hypothesis in a population-based case-control study in Denmark and Sweden. A total of 3740 patients diagnosed between October 1, 1999, and August 30, 2002, with incident malignant lymphomas, including non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Hodgkin lymphoma, and 3187 population controls provided detailed information on history of UV exposure and skin cancer and information on other possible risk factors for lymphomas. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by logistic regression. Statistical tests were two-sided. Multivariable-adjusted analyses revealed consistent, statistically significant negative associations between various measures of UV light exposure and risk of non-Hodgkin lymphoma. A high frequency of sun bathing and sunburns at age 20 years and 5-10 years before the interview and sun vacations abroad were associated with 30%-40% reduced risks of non-Hodgkin lymphoma (e.g., for sunbathing four times a week or more at age 20 versus never sunbathing, OR = 0.7, 95% CI = 0.6 to 0.9; for two or more sunburns a year at age 20 versus no sunburns, OR = 0.6, 95% CI = 0.5 to 0.8). These inverse associations increased in strength with increasing levels of exposure (all P(trend)< or =.01). Similar, albeit weaker, associations were observed for Hodgkin lymphoma. There were no clear differences among non-Hodgkin lymphoma subtypes, although associations were stronger for B-cell than for T-cell lymphomas. A history of skin cancer was associated with a doubling in risks of both non-Hodgkin and Hodgkin lymphoma. A history of high UV exposure was associated with reduced risk of non-Hodgkin lymphoma. The positive association between skin cancer and malignant lymphomas is, therefore, unlikely to be mediated by UV exposure.

Hormone Therapy and the Impact of Estrogen Intake on the Risk of Ovarian Cancer

The association between menopausal hormone therapy (HT) and risk of ovarian cancer is as yet equivocal, and the effect of estrogen and estrogen-progestogen therapy, specifically the effect of the cumulative hormone intake, is unclear. We conducted a nationwide population-based case-control study in Denmark. Cases were women aged 35 to 79 years with incident ovarian cancer diagnosed between January 1, 1995, and May 30, 1999. Controls were frequency age-matched women from the Danish Central Population Register. The analyses included data on 376 cases who have not undergone hysterectomy and 1111 controls. The risk of ovarian cancer in relation to oral HT increased with the cumulative intake of the estrogen component of HT but not with the duration or the cumulative intake of the progestogen component when the 3 variables were mutually adjusted. A simple trend was found such that each additional gram of estrogen was associated with the same relative increase. The odds ratio was constant throughout the range of cumulative intake. After adjustment for established risk factors, the estimated odds ratio per each additional gram of cumulative estrogen was 1.056 (95% confidence interval, 1.003-1.112), corresponding to an odds ratio of 1.31 (95% confidence interval, 1.01-1.70) per 5 g of estrogen. Oral HT is associated with risk of ovarian cancer in women who have not undergone hysterectomy. Our results imply that the risk increases with cumulative oral estrogen intake but not with duration of HT, indicating that the increased ovarian cancer risk associated with oral HT may be diminished substantially by minimizing the daily dose of estrogen from oral HT.