Lifestyle factors related to prevalent chronic disease multimorbidity: A population-based cross-sectional study.

BACKGROUND: Multimorbidity is associated with poor quality of life, polypharmacy, health care costs and mortality, with those affected potentially benefitting from a healthy lifestyle. We assessed a comprehensive set of lifestyle factors in relation to multimorbidity with major chronic diseases. METHODS: This cross-sectional study utilised baseline data for adults from the prospective Lifelines Cohort in the north of the Netherlands (N = 79,345). We defined multimorbidity as the co-existence of two or more chronic diseases (i.e. cardiovascular disease, cancer, respiratory disease, type 2 diabetes) and evaluated factors in six lifestyle domains (nutrition, physical (in)activity, substance abuse, sleep, stress, relationships) among groups by the number of chronic diseases (≥2, 1, 0). Multinomial logistic regression models were created, adjusted for appropriate confounders, and odds ratios (OR) with 95% confidence intervals (95%CI) were reported. RESULTS: 3,712 participants had multimorbidity (4.7%, age 53.5 ± 12.5 years), and this group tended to have less healthy lifestyles. Compared to those without chronic diseases, those with multimorbidity reported physical inactivity more often (OR, 1.15; 95%CI, 1.06-1.25; not significant for one condition), chronic stress (OR, 2.14; 95%CI, 1.92-2.38) and inadequate sleep (OR, 1.70; 95%CI, 1.41-2.06); as expected, they more often watched television (OR, 1.70; 95%CI, 1.42-2.04) and currently smoked (OR, 1.91; 95%CI, 1.73-2.11), but they also had lower alcohol intakes (OR, 0.66; 95%CI, 0.59-0.74). CONCLUSIONS: Chronic stress and poor sleep, in addition to physical inactivity and smoking, are lifestyle factors of great concern in patients with multimorbidity.

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene.

While many disease-associated single nucleotide polymorphisms (SNPs) are associated with gene expression (expression quantitative trait loci, eQTLs), a large proportion of complex disease genome-wide association study (GWAS) variants are of unknown function. Some of these SNPs may contribute to disease by regulating gene splicing. Here, we investigate whether SNPs that are associated with alternative splicing (splice QTL or sQTL) can identify novel functions for existing GWAS variants or suggest new associated variants in chronic obstructive pulmonary disease (COPD). RNA sequencing was performed on whole blood from 376 subjects from the COPDGene Study. Using linear models, we identified 561,060 unique sQTL SNPs associated with 30,333 splice sites corresponding to 6,419 unique genes. Similarly, 708,928 unique eQTL SNPs involving 15,913 genes were detected at 10% FDR. While there is overlap between sQTLs and eQTLs, 55.3% of sQTLs are not eQTLs. Co-localization analysis revealed that 7 out of 21 loci associated with COPD (p<1x10-6) in a published GWAS have at least one shared causal variant between the GWAS and sQTL studies. Among the genes identified to have splice sites associated with top GWAS SNPs was FBXO38, in which a novel exon was discovered to be protective against COPD. Importantly, the sQTL in this locus was validated by qPCR in both blood and lung tissue, demonstrating that splice variants relevant to lung tissue can be identified in blood. Other identified genes included CDK11A and SULT1A2. Overall, these data indicate that analysis of alternative splicing can provide novel insights into disease mechanisms. In particular, we demonstrated that SNPs in a known COPD GWAS locus on chromosome 5q32 influence alternative splicing in the gene FBXO38.

Prevalence and factors associated with asthma among adolescents and adults in Uganda: a general population based survey.

BACKGROUND: Recent large-scale population data on the prevalence of asthma and its risk factors are lacking in Uganda. This survey was conducted to address this data gap. METHODS: A general population based survey was conducted among people ≥12 years. A questionnaire was used to collect participants socio-demographics, respiratory symptoms, medical history, and known asthma risk factors. Participants who reported wheeze in the past 12 months, a physician diagnosis of asthma or current use of asthma medications were classified as having asthma. Asthmatics who were ≥ 35 years underwent spirometry to determine how many had fixed airflow obstruction (i.e. post bronchodilator forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio < lower limit of normal (LLN). Descriptive statistics were used to summarize participants' characteristics. Prevalence of asthma was calculated as a proportion of asthmatics over total survey population. To obtain factors independently associated with asthma, a random-effects model was fitted to the data. RESULTS: Of the 3416 participants surveyed, 61.2% (2088) were female, median age was 30 years (IQR, 20-45) and 323 were found to have asthma. Sixteen people with asthma ≥35 years had fixed airflow obstruction. The prevalence of asthma was 11.0% (95% CI:8.9-13.2; males 10.3%, females 11.4%, urban 13.0% and rural 8.9%. Significantly more people with asthma smoked than non-asthmatics: 14.2% vs. 6.3%, p < 0.001, were exposed to biomass smoke: 28.0% vs. 20.0%, p < 0.001, had family history of asthma: 26.9% vs. 9.4%, p, < 0.001, had history of TB: 3.1% vs. 1.30%, p = 0.01, and had hypertension: 17.9% vs. 12.0%, p = 0. 003. In multivariate analysis smoking, (adjusted odds ratio (AOR), 3.26 (1.96-5.41, p < 0.001) family history of asthma, AOR 2.90 (98-4.22 p- < 0.001), nasal congestion, AOR 3.56 (2.51-5.06, p < 0.001), biomass smoke exposure, AOR 2.04 (1.29-3.21, p = 0.002) and urban residence, AOR 2.01(1.23-3.27, p = 0.005) were independently associated with asthma. CONCLUSION: Asthma is common in Uganda and is associated with smoking, biomass smoke exposure, urbanization, and allergic diseases. Health care systems should be strengthened to provide asthma care. Measures to reduce exposure to the identified associated factors are needed.

The impact of HIV on the prevalence of asthma in Uganda: a general population survey.

BACKGROUND: HIV and asthma are highly prevalent diseases in Africa but few studies have assessed the impact of HIV on asthma prevalence in high HIV burden settings. The objective of this analysis was to compare the prevalence of asthma among persons living with HIV (PLHIV) and those without HIV participating in the Uganda National Asthma Survey (UNAS). METHODS: UNAS was a population-based survey of persons aged ≥12 years. Asthma was diagnosed based on either self-reported current wheeze concurrently or within the prior 12 months; physician diagnosis; or use of asthma medication. HIV was defined based on confidential self-report. We used Poisson regression with robust standard errors to estimate asthma prevalence and the prevalence ratio (PR) for HIV and asthma. RESULTS: Of 3416 participants, 2067 (60.5%) knew their HIV status and 103 (5.0%) were PLHIV. Asthma prevalence was 15.5% among PLHIV and 9.1% among those without HIV, PR 1.72, (95%CI 1.07-2.75, p = 0.025). HIV modified the association of asthma with the following factors, PLHIV vs. not PLHIV: tobacco smoking (12% vs. 8%, p = < 0.001), biomass use (11% vs. 7%, p = < 0.001), allergy (17% vs. 11%, p = < 0.001), family history of asthma (17% vs. 11%, p = < 0.001), and prior TB treatment (15% vs. 10%, p = < 0.001). CONCLUSION: In Uganda the prevalence of asthma is higher in PLHIV than in those without HIV, and HIV interacts synergistically with other known asthma risk factors. Additional studies should explore the mechanisms underlying these associations. Clinicians should consider asthma as a possible diagnosis in PLHIV presenting with respiratory symptoms.

Aging-related trajectories of lung function in the general population-The Doetinchem Cohort Study.

The objective of this study was to explore trajectories of lung function decline with age in the general population, and to study the effect of sociodemographic and life style related risk factors, in particular smoking and BMI. For this purpose, we used data from the Doetinchem Cohort Study (DCS) of men and women, selected randomly from the general population and aged 20-59 years at inclusion in 1987-1991, and followed until the present. Participants in the DCS are assessed every five years. Spirometry has been performed as part of this assessment from 1994 onwards. Participants were included in this study if spirometric measurement of FEV1, which in this study was the main parameter of interest, was acceptable and reproducible on at least one measurement round, leading to the inclusion of 5727 individuals (3008 females). Statistical analysis revealed three typical trajectories. The majority of participants followed a trajectory that closely adhered to the Global Lung Initiative Reference values (94.9% of men and 96.4% of women). Two other trajectories showed a more pronounced decline. Smoking and the presence of respiratory complaints were the best predictors of a trajectory with stronger decline. A greater BMI over the follow-up period was associated with a more unfavorable FEV1 course both in men (ß = -0.027 (SD = 0.002); P < 0.001) and in women (ß = -0.008 (SD = 0.001); P < 0.001). Smokers at baseline who quit the habit during follow-up, showed smaller decline in FEV1 in comparison to persistent smokers, independent of BMI change (In men ß = -0.074 (SD = 0.020); P < 0.001. In women ß = -0.277 (SD = 0.068); P < 0.001). In conclusion, three typical trajectories of age-related FEV1 decline could be distinguished. Change in the lifestyle related risk factors, BMI and smoking, significantly impact aging-related decline of lung function. Identifying deviant trajectories may help in early recognition of those at risk of a diagnosis of lung disease later in life.

In-utero cigarette smoke exposure and the risk of earlier menopause.

OBJECTIVE: Cigarette smoking is a risk factor for earlier menopause. Animal studies show that in-utero smoke exposure is toxic to developing ovaries. Our aim was to evaluate whether in-utero smoke exposed women reach menopause earlier compared with nonexposed women. METHODS: This is a cohort study within the Avon Longitudinal Study of Parents and Children. Participants included in this study were followed from 1991/1992 until 2010. Participant characteristics for the current analysis were obtained from obstetric records and from annual follow-up questionnaires. When not available, age at natural menopause was estimated by age at filling in the questionnaire minus 1 year. Cox proportional hazards modeling was used to estimate hazard ratios of menopause for in-utero exposed and nonexposed women. RESULTS: There were 695/2,852 postmenopausal women, of whom 466 had natural menopause, 117 had hormonal therapy, and 112 had surgical menopause. Age at natural menopause was 50.6 ±â€Š3.7 years. Of all participants, 20.2% (577/2,852) were exposed to smoke in-utero. Participants who were in-utero exposed but were not smokers did not have higher hazards of menopause (adjusted hazard ratio [HR] 0.92, 95% CI 0.72-1.18), whereas participants who were ever smokers (current or previous) and were in-utero exposed (adjusted HR 1.41, 95% CI 1.01-1.95) or were ever smokers but not exposed (adjusted HR 1.24, 95% CI 1.00-1.53) did have higher hazards of earlier menopause. CONCLUSIONS: In-utero smoke exposure was not associated with earlier menopause, but the effect of in-utero smoke exposure was modified by the smoking habits of the participants themselves increasing the risk for smokers who were in-utero exposed.

Surfactant protein D is a causal risk factor for COPD: results of Mendelian randomisation.

Surfactant protein D (SP-D) is produced primarily in the lung and is involved in regulating pulmonary surfactants, lipid homeostasis and innate immunity. Circulating SP-D levels in blood are associated with chronic obstructive pulmonary disease (COPD), although causality remains elusive.In 4061 subjects with COPD, we identified genetic variants associated with serum SP-D levels. We then determined whether these variants affected lung tissue gene expression in 1037 individuals. A Mendelian randomisation framework was then applied, whereby serum SP-D-associated variants were tested for association with COPD risk in 11 157 cases and 36 699 controls and with 11 years decline of lung function in the 4061 individuals.Three regions on chromosomes 6 (human leukocyte antigen region), 10 (SFTPD gene) and 16 (ATP2C2 gene) were associated with serum SP-D levels at genome-wide significance. In Mendelian randomisation analyses, variants associated with increased serum SP-D levels decreased the risk of COPD (estimate -0.19, p=6.46×10-03) and slowed the lung function decline (estimate=0.0038, p=7.68×10-3).Leveraging genetic variation effect on protein, lung gene expression and disease phenotypes provided novel insights into SP-D biology and established a causal link between increased SP-D levels and protection against COPD risk and progression. SP-D represents a very promising biomarker and therapeutic target for COPD.

Co-morbidities are the key nominators of the health related quality of life in mild and moderate COPD.

BACKGROUND: Co-morbidities are common in chronic obstructive pulmonary disease (COPD). We assessed the contribution of common co-morbidities on health related quality of life (HRQoL) among COPD patients. METHODS: Using both generic (15D) and respiratory-specific (AQ20) instruments, HRQoL was assessed in a hospital based COPD population (N = 739, 64% males, mean age 64 years, SD 7 years) in this observational study with inferential analysis. The prevalence of their co-morbidities was compared with those of 5000 population controls. The patients represented all severity stages of COPD and the patterns of common concomitant disorders differed between patients. RESULTS: Co-morbidities such as psychiatric conditions, alcohol abuse, cardiovascular diseases, and diabetes were more common among COPD patients than in age and gender matched controls. Psychiatric conditions and alcohol abuse were the strongest determinants of HRQoL in COPD and could be detected by both 15D (Odds Ratio 4.7 and 2.3 respectively) and AQ20 (OR 2.0 and 3.0) instruments. Compared to respiratory specific AQ20, generic 15D was more sensitive to the effects of comorbidities while AQ20 was slightly more sensitive for the low FEV1. FEV1 was a strong determinant of HRQoL only at more severe stages of disease (FEV1 < 40% of predicted). Poor HRQoL also predicted death during the next five years. CONCLUSIONS: The results suggest that co-morbidities may impair HRQoL at an early stage of the disease, while bronchial obstruction becomes a significant determinant of HRQoL only in severe COPD.

Nicotinic acetylcholine receptor variants are related to smoking habits, but not directly to COPD.

Genome-wide association studies identified single nucleotide polymorphisms (SNPs) in the nicotinic acetylcholine receptors (nAChRs) cluster as a risk factor for nicotine dependency and COPD. We investigated whether SNPs in the nAChR cluster are associated with smoking habits and lung function decline, and if these potential associations are independent of each other. The SNPs rs569207, rs1051730 and rs8034191 in the nAChR cluster were analyzed in the Vlagtwedde-Vlaardingen cohort (n = 1,390) that was followed for 25 years. We used GEE and LME models to analyze the associations of the SNPs with quitting or restarting smoking and with the annual FEV(1) decline respectively. Individuals homozygote (CC) for rs569207 were more likely to quit smoking (OR (95%CI) = 1.58 (1.05-2.38)) compared to wild-type (TT) individuals. Individuals homozygote (TT) for rs1051730 were less likely to quit smoking (0.64 (0.42; 0.97)) compared to wild-type (CC) individuals. None of the SNPs was significantly associated with the annual FEV(1) decline in smokers and ex-smokers. We show that SNPs in the nAChR region are associated with smoking habits such as quitting smoking, but have no significant effect on the annual FEV(1) decline in smokers and ex-smokers, suggesting a potential role of these SNPs in COPD development via smoking habits rather than via direct effects on lung function.

Common and different genetic background for rheumatoid arthritis and coeliac disease.

Recent genome-wide association studies (GWAS) have revealed genetic risk factors in autoimmune and inflammatory disorders. Several of the associated genes and underlying pathways are shared by various autoimmune diseases. Rheumatoid arthritis (RA) and coeliac disease (CD) are two autoimmune disorders which have commonalities in their pathogenesis. We aimed to replicate known RA loci in a Dutch RA population, and to investigate whether the effect of known RA and CD risk factors generalize across the two diseases. We selected all loci associated to either RA or CD in a GWAS and confirmed in an independent cohort, with a combined P-value cut-off P < 5 x 10(-6). We genotyped 11 RA and 11 CD loci in 1368 RA patients, 795 CD patients and 1683 Dutch controls. We combined our results in a meta-analysis with UK GWAS on RA (1860 cases; 2938 controls) and CD (767 cases; 1422 controls). In the Dutch RA cohort, the PTPN22 and IL2/IL21 variants showed convincing association (P = 3.4 x 10(-12) and P = 2.8 x 10(-4), respectively). Association of RA with the known CD risk variant in the SH2B3 was also observed, predominantly in the subgroup of rheumatoid factor-positive RA patients (P = 0.0055). In a meta-analysis of Dutch and UK data sets, shared association with six loci (TNFAIP3, IL2/IL21, SH2B3, LPP, MMEL1/TNFRSF14 and PFKFB3/PRKCQ) was observed in both RA and CD cohorts. We confirmed two known loci and identified four novel ones for shared CD-RA genetic risk. Most of the shared loci further emphasize a role for adaptive and innate immunity in these diseases.

Development of a questionnaire for the assessment of bronchial hyperresponsiveness.

INTRODUCTION: Bronchial hyperresponsiveness (BHR) is a hallmark of asthma. Treatment approaches based on BHR severity have been shown to be effective. However, challenge tests are expensive, inconvenient to patients, time consuming, and not easily accessible to general practitioners. Assessment of BHR by a questionnaire would be advantageous in the diagnosis and management of asthma. AIM: To select a set of respiratory symptoms and provoking stimuli related to BHR to compose a reliable Bronchial Hyperresponsiveness Questionnaire (BHQ). METHOD: A list of 33 symptoms and 68 stimuli were selected by in-depth interviews, focus group discussions with asthma patients, and literature review. After a histamine challenge test patients (n=302) were asked to score each question on a 7-point scale (0=no; 6=severe complaints). Factor analysis was performed to identify clusters of interrelated symptoms associated with PC20-histamine. The sensitivity to detect the presence of BHR was analysed by Receiver Operating Curves (ROC). The correlation between the PC20-score and the scores on the questions was analysed. RESULTS: 15 symptoms and 19 provoking stimuli were ultimately selected for the BHQ. CONCLUSION: The BHQ was developed according to FDA-approved standards and is a condition-specific questionnaire able to assess the presence of BHR.

Expression of estrogen receptor-alpha and -beta and progesterone receptor-A and -B in a large cohort of patients with endometrioid endometrial cancer.

OBJECTIVE: The estrogen receptor (ER)-alpha and -beta and progesterone receptor (PR)-A and -B were determined in endometrioid endometrial cancer, and their prognostic values were assessed. METHODS: Tissue microarrays were constructed from 315 endometrioid endometrial cancer patients. Receptor expression was assessed by immunostaining, and their semi-quantitatively determined expression levels were correlated to classical clinico-histopathological parameters in addition to disease free and disease specific survival. RESULTS: Patients were classified as FIGO stage I (59.0%), stage II (17.1%), stage III (19.4%) and stage IV (4.1%). Sixty-five patients (20.6%) developed recurrent disease and 38 (12.1%) died due to endometrial cancer. In univariate analysis, expression of ER-alpha was related to early stage endometrial cancer (p=0.020), while expression of ER-alpha, PR-A and PR-B was associated with lower grade tumours (p<0.0001, p<0.001 and p=0.001 respectively). A ratio of ER-alpha/ER-beta <1 was related to a shorter disease free survival (p=0.027), while the ratio of PR-A/PR-B <1 both was associated with a shorter disease free survival as well as a shorter overall survival (p=0.044 and p=0.005, respectively). In early stage disease, using multivariate analysis, absence of ER-alpha was independently related to death of disease (p=0.017, OR 7.28, 95% CI 1.42-37.25), while absence of PR-A (p=0.015, OR 4.2, 95% CI 1.32-13.33) appeared to be an independent prognostic factor for relapse of disease. CONCLUSION: We conclude that in early stage endometrioid endometrial cancer absence of PR-A is an independent prognostic factor for disease-free survival, while patients with ER-alpha positive tumours have a better overall survival.

Expression of multidrug resistance-associated proteins predicts prognosis in childhood and adult acute lymphoblastic leukemia.

PURPOSE: Patients with acute lymphoblastic leukemia (ALL) are treated with a variety of chemotherapeutic drugs, which can be transported by six multidrug resistance-associated proteins (MRP). These MRPs have strongly overlapping functional activities. The aim of this study was to investigate the expression levels of MRP1 to MRP6 and study their effect on prognosis. EXPERIMENTAL DESIGN: The mRNA expression levels of MRP1 to MRP6 were analyzed by quantitative real-time PCR in leukemic blasts of 105 de novo ALL patients (adults, n=49; children, n=56) including 70% B-lineage and 30% T-lineage ALL patients. RESULTS: Adults showed a higher expressions of MRP1 (P=0.008), MRP2 (P=0.026), and MRP3 (P=0.039) than children. Interestingly, this difference disappeared when patients were categorized based on clinical outcome. Relapsed patients showed a higher expression of all MRP genes, except MRP4. For the total group of ALL patients, the expressions of MRP1, MRP2, MRP3, MRP5, and MRP6 predicted relapse. Moreover, high expression of all MRP genes, except MRP4, was associated with a reduced relapse-free survival in children and adults (MRP1, P=0.005; MRP2, P=0.008; MRP3, P=0.001; MRP5, P=0.016; MRP6, P=0.037). CONCLUSIONS: The present study shows that a subset of ALL patients with high MRP expression has an unfavorable prognosis independently of age.

Influence of functional polymorphisms of the MDR1 gene on vincristine pharmacokinetics in childhood acute lymphoblastic leukemia.

OBJECTIVE: Our objective was to investigate the effect of single nucleotide polymorphisms (SNPs) in the P-glycoprotein MDR1 gene on vincristine pharmacokinetics and side effects in childhood acute lymphoblastic leukemia. METHODS: From 52 of 70 children who participated in a previous study on vincristine pharmacokinetics, patient material was available for investigation of the MDR1 genetic variants. The SNPs C3435T and G2677T were determined by use of polymerase chain reaction-restriction fragment length polymorphism. Vincristine side effects were scored retrospectively from patient records. RESULTS: No association was observed between C3435T or G2677T and vincristine pharmacokinetic variables. When haplotypes were assigned, haplotype 1/1 carriers (3435C/2677G) showed a longer elimination half-life than noncarriers (1156 versus 805 minutes, P =.038). In contrast, haplotype 1/2 carriers (3435T/2677G) had a shorter elimination half-life than noncarriers (805 versus 1180 minutes, P =.044). However, this significance was lost after Bonferroni correction for multiple testing. The haplotypes did not affect the other pharmacokinetic parameters, such as clearance and area under the concentration-time curve, suggesting that the observed effect on elimination half-life is of very limited relevance. Moreover, SNPs in the MDR1 gene did not identify patients with an increased risk for vincristine-induced constipation. CONCLUSION: The genetic variants in the MDR1 gene alone cannot explain the large variability in vincristine pharmacokinetics.

Bronchoalveolar lavage fluid characteristics in acute and chronic lung transplant rejection.

BACKGROUND: The detection of graft rejection by bronchoalveolar lavage remains controversial. METHODS: To assess the value of bronchoalveolar lavage fluid in acute and chronic rejection after lung transplantation we analyzed bronchoalveolar lavage fluid cellular differential characteristics, lymphocyte sub-types and interleukin-6 (IL-6) and interleukin-8 (IL-8) cytokine levels in patients with exclusively either acute rejection (n = 37) or bronchiolitis obliterans (BO; n = 48). Both groups were compared with a control group of lung transplantation patients without rejection or infection, matched for the time the lavage was performed after lung transplantation. RESULTS: The bronchiolitis obliterans group showed marked neutrophilia, high IL-8 and higher CD4(+)CD25(+) and CD8(+)CD45(+) bronchoalveolar lavage fluid levels when compared with their stable controls. When using a cut-off point of >3% neutrophils in the lavage, the sensitivity for BO is 87.0%, the specificity 77.6%. The sensitivity of IL-8 for BO when using a cut-off point of >71.4 pg/ml is 74.5%, the specificity 83.3%. Bronchoalveolar lavage fluid in acute rejection was characterized by marked lymphocytosis, but showed no difference when compared with stable controls in any of the lymphocyte sub-types studied. When using a cut-off point of <==1% lymphocytes in the lavage, the sensitivity for acute rejection (AR) is 40.4%, the specificity 95.6%. The marked neutrophilia, high IL-8 cytokine level and more activated lymphocyte population in bronchiolitis obliterans may indicate ongoing local allograft rejection. CONCLUSIONS: In the present study we were not able to show any difference in lymphocyte sub-types when comparing acute rejection and control subjects. Cellular and soluble parameters in bronchoalveolar lavage fluid appear useful for diagnosing bronchiolitis obliterans.

Vulvar carcinoma. The price of less radical surgery.

BACKGROUND: The objective of this study was to determine whether modifications in the treatment of patients with vulvar carcinoma influence the rates of recurrence and survival. METHODS: Between 1982 and 1997, 253 patients with T1 and T2 invasive squamous cell carcinoma of the vulva were treated by essentially the same team of gynecologic oncologists, and 168 patients (Group I) underwent radical vulvectomy with en bloc inguinofemoral lymphadenectomy. Standard therapy was changed in 1993, and 85 patients (Group II) underwent wide local excision with inguinofemoral lymphadenectomy through separate incisions. The rates of recurrence and survival were compared between both groups. RESULTS: In Group II, the overall recurrence rate (33.3%) within 4 years was increased compared with Group I (19.9%; P = 0.03). In Group II, 5 of 79 patients (6.3%) developed fatal groin or skin bridge recurrences compared with 2 of 159 patients (1.3%) in Group I (P = 0.029); this did not result in a difference in overall survival. In Group II, 40 of 79 patients had tumor free margins measuring 8 mm, resulting in no local recurrences (P = 0.002). CONCLUSIONS: The current study showed that fatal recurrences in either the groin or the skin bridge were more frequent after wide local excision and inguinofemoral lymphadenectomy through separate incisions; however, probably due to lack of power, this did not result in shorter survival. In 40 of 79 patients, the histologic margins measured

A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk.

Excessive estrogen stimulation unopposed by progesterone strongly predisposes to endometrial cancer. Because the antiproliferative effect of progesterone requires the progesterone receptor (PR), which exists in two isoforms, PR-A and -B, we reasoned that variants in the PR gene may predispose to endometrial cancer. We found six variable sites, including four polymorphisms in the hPR gene and five common haplotypes. One promoter region polymorphism, +331G/A, creates a unique transcription start site. Biochemical assays showed that the +331G/A polymorphism increases transcription of the PR gene, favoring production of hPR-B in an endometrial cancer cell line. Using a case-control study nested within the Nurses' Health Study cohort, we observed a statistically significant association between the +331G/A polymorphism and the risk of endometrial cancer, which was even greater in overweight women carriers. After including a second population of controls, these associations remained intact. Our findings suggest that the +331G/A hPR gene polymorphism may contribute to endometrial cancer risk by increasing expression of the hPR-B isoform.