Individual Genetic Susceptibility Research Articles

A clinical review of recent findings in the epidemiology of inflammatory bowel disease.

Inflammatory bowel diseases (IBD), including both Crohn’s disease and ulcerative colitis, are disorders of chronic inflammation of the gastrointestinal tract marked by episodes of relapse and remission. Over the past several decades, advances have been made in understanding the epidemiology of IBD. The incidence and prevalence of both Crohn’s disease and ulcerative colitis have been increasing worldwide across pediatric and adult populations. As IBD is thought to be related to a combination of individual genetic susceptibility, environmental triggers, and alterations in the gut microbiome that stimulate an inflammatory response, understanding the potentially modifiable environmental risk factors associated with the development or the course of IBD could impact disease rates or management in the future. Current hypotheses as to the development of IBD are reviewed, as are a host of environmental cofactors that have been investigated as both protective and inciting factors for IBD onset. Such environmental factors include breast feeding, gastrointestinal infections, urban versus rural lifestyle, medication exposures, stress, smoking, and diet. The role of these factors in disease course is also reviewed. Looking forward, there is still much to be learned about the etiology of IBD and how specific environmental exposures intimately impact the development of disease and also the potential for relapse.

Longitudinal trajectory of vitamin D status from birth to early childhood in the development of food sensitization

BackgroundIncreasing evidence supports the immunomodulatory effect of vitamin D on allergic diseases. The combined role of prenatal and postnatal vitamin D status in the development of food sensitization (FS) and food allergy remains under-studied.Methods460 children in the Boston Birth Cohort had plasma 25(OH)D measured at birth and early childhood, and were genotyped for rs2243250 (C-590T) in the IL4 gene. We defined FS as specific IgE ≥0.35kUA/L to any of eight common food allergens; and persistently low vitamin D status as cord blood 25(OH)D <11ng/ml and postnatal 25(OH)D <30ng/ml.ResultsWe observed a moderate correlation between cord blood 25(OH)D at birth and venous blood 25(OH)D measured at 2–3 years (r=0.63), but a weak correlation at <1 year (r=0.28). There was no association between low vitamin D status and FS at any single time point alone. However, in combination, persistence of low vitamin D status at birth and early childhood increased the risk of FS (OR=2.03, 95%CI:1.02–4.04), particularly among children carrying the C allele of rs2243250 (OR=3.23, 95%CI:1.37–7.60).ConclusionsPrenatal and early postnatal vitamin D levels, along with individual genetic susceptibility, should be considered in assessing the role of vitamin D in the development of FS and food allergy.

Association of Rs1139971, a KAI1 polymorphism, with bone metastasis progression in prostate cancer and ganglionnary metastasis.

e16089 Background: Metastatic prostate cancer, with bones as principal location, is responsible for most of the death from this malignancy. If the molecular mecanisms of the metastasis progression are not completely solved, many involved pathways have been clarified. Association studies have proven that genetic factors could affect the risk of prostate cancer or its agressiveness. Likewise, some polymorphisms from genes involved in metastatic pathways could have a meaningfull function in the individual genetic susceptibility to metastatic prostate cancer. The KAI1 gene is known to be implicated in the metastatic process of many malignant tumors, such as breast, lung or colorectal cancer. Moreover, the protein encoded by this gene seems to act as a metastatic suppressor. In this study, we searched for an association between the risk of metastatic progression and a polymorphism from the KAI gene (rs1139971). Methods: It was a retrospective and multicentrique study, comparing 195 patients harbouring bone and/or ganglionnary metastatic prostate cancer with 386 patients affected by a non metastatic prostate cancer. All the patients were caucasians. The variant rs1139971 has been genotyped by Taqman technology. Results: The allele A from rs1139971 was found to be less frequent in metastatic patients but this result wasn’t significant. The patients were then stratified according to the metastatic location : bone or ganglionnary. In this case, the allele A was significantly associated with metastatic risk in the group of patients with bone metastasis [OR = 0,525 ; IC 95% = 0,332-0,828 ; p = 0,0056]. Conclusions: In this study, a significant association has been pointed up between bone metastatic prostate cancer and the polymorphism rs1139971 from KAI1 gene. However, these results need to be confirmed on a larger and independant population.

Occupational Exposure to Ultraviolet Radiation and Risk of Non-Melanoma Skin Cancer in a Multinational European Study

BackgroundStudies suggest that ambient sunlight plays an important role in the pathogenesis of non-melanoma skin cancers (NMSC). However, there is ongoing controversy regarding the relevance of occupational exposure to natural and artificial ultraviolet radiation (UV) radiation.ObjectivesWe investigated potential associations between natural and artificial UV radiation exposure at work with NMSC in a case-control study conducted in Hungary, Romania, and Slovakia.MethodsOccupational exposures were classified by expert assessment for 527 controls and 618 NMSC cases (515 basal cell carcinoma, BCC). Covariate information was collected via interview and multiple logistic regression models were used to assess associations between UV exposure and NMSC.ResultsLifetime prevalence of occupational exposure in the participants was 13% for natural UV radiation and 7% for artificial UV radiation. Significant negative associations between occupational exposure to natural UV radiation and NMSC were detected for all who had ever been exposed (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.27–0.80); similar results were detected using a semi-quantitative metric of cumulative exposure. The effects were modified by skin complexion, with significantly decreased risks of BCC among participants with light skin complexion. No associations were observed in relation to occupational artificial UV radiation exposure.ConclusionsThe protective effect of occupational exposure to natural UV radiation was unexpected, but limited to light-skinned people, suggesting adequate sun-protection behaviors. Further investigations focusing on variations in the individual genetic susceptibility and potential interactions with environmental and other relevant factors are planned.

Exercise and airway injury in athletes.

Olympic level athletes present an increased risk for asthma and allergy, especially those who take part in endurance sports, such as swimming or running, and in winter sports. Classical postulated mechanisms behind EIA include the osmotic, or airway-drying, hypothesis. Hyperventilation leads to evaporation of water and the airway surface liquid becomes hyperosmolar, providing a stimulus for water to move from any cell nearby, which results in the shrinkage of cells and the consequent release of inflammatory mediators that cause airway smooth muscle contraction. But the exercise-induced asthma/bronchoconstriction explanatory model in athletes probably comprises the interaction between environmental training factors, including allergens and ambient conditions such as temperature, humidity and air quality; and athlete's personal risk factors, such as genetic and neuroimmuneendocrine determinants. After the stress of training and competitions athletes experience higher rate of upper respiratory tract infections (URTI), compared with lesser active individuals. Increasing physical activity in non-athletes is associated with a decreased risk of URTI. Heavy exercise induces marked immunodepression which is multifactorial in origin. Prolonged, high intensity exercise temporarily impairs the immune competence while moderate activity may enhance immune function. The relationship between URTI and exercise is affected by poorly known individual determinants such genetic susceptibility, neurogenic mediated immune inflammation and epithelial barrier dysfunction. Further studies should better define the aetiologic factors and mechanisms involved in the development of asthma in athletes, and propose relevant preventive and therapeutic measures.

Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk

Barrett's esophagus, with gastroesophageal reflux disease and obesity as risk factors, predisposes to esophageal adenocarcinoma (EAC). Recently a British genome wide association study identified two Barrett's esophagus susceptibility loci mapping within the major histocompatibility complex (MHC; rs9257809) and closely to the Forkhead-F1 (FOXF1; rs9936833) coding gene. An interesting issue is whether polymorphisms associated with Barrett's esophagus, are also implicated in esophageal carcinoma (EC), and more specifically EAC genesis. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from surveillance programs. Our hypothesis: Barrett associated MHC and FOXF1 variants modify EC risk in Caucasians. In a Dutch case-control study, 431 patients with EC and 605 healthy controls were included. Polymorphisms at chromosomes 6p21 (MHC) and 16q24 (FOXF1) were determined by means of real-time polymerase chain reaction (RT-PCR). Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals. The FOXF1 rs9936833 variant C allele was associated with an increased EAC susceptibility; OR, [95% CI]; 1.21, [0.99-1.47]. A sex-stratified analysis revealed a similar association in males; 1.24 [1.00-1.55]. The variant MHC rs9257809 G allele as well as the MHC heterozygous AG genotype significantly increased ESCC risk; 1.76 [1.16-2.66] and 1.74 [1.08-2.80], respectively. Sex-stratification showed that the variant G allele was especially present in female patients; 2.32 [1.04-5.20]. In conclusion, this study provides evidence that MHC rs9257809 and FOXF1 rs9936833 variants, associated with Barrett's esophagus, also increase ESCC and EAC susceptibility in Caucasians. FOX proteins are transcription factors involved in organogenesis of the GI tract, while MHC haplotypes are strongly associated with smoking behavior, a crucial risk factor for ESCC. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from (Barrett) surveillance programs.

XPD gene polymorphism and colorectal cancer risk.

TO THE EDITOR We examined Rezaei et al's paper (1) and we are interested in the subject. The study was about the functions of repair genes, their mechanisms in cancer development and associated polymorphisms which increase susceptibility to CRC. As we know Single nucleotide polymorphisms (SNPs) are the most common genetic sequence variation in human genome. SNPs are associated with population diversity, disease susceptibility and individual response to medical therapy (2, 3). In the other hand, the development of CRC is associated with environmental factors, genetic susceptibilities, and their interaction (4). Polymorphisms in DNA repair genes contribute to the variations in individual genetic susceptibility to many types of cancers, such as lung cancer, breast cancer and gastric cancer (5–9). The study population of this paper was heterogeneous in terms of colorectal cancer. The authors mentioned that of 88 colorectal cancer patients enrolled in this study, 32 patients (45%) had a positive family history for colorectal cancer in their first-degree relatives. They didn’t determine the type of familial CRC in these

What adverse events occur with disease-modifying therapy in multiple sclerosis?

Multiple sclerosis (MS) is a potentially devastating inflammatory demyelinating disease of the CNS affecting approximately one in 1000 people, mainly young adults. Relapsing-remitting MS (RRMS), characterized by an individual frequency of relapses, bears the risk of incomplete remissions and further progressive disability, then termed as secondary progressive MS. The etiology of MS remains unknown, but it is generally assumed that, based on a certain individual genetic susceptibility, as yet unidentified environmental factors trigger its autoimmune cascade in the CNS [1]. A disease-modifying therapy (DMT) describes a drug that modulates MS disease course either as an immunosuppressant or immunomodulator. However, this description appears increasingly arbitrary. The lack of an appropriate pharmacological classif ication based on specific modes of action of respective drugs causes inconsistencies and confusion. The semantic confusion (an immunosuppressant does per se also modulate the immune system and vice versa) preserves the opinion that immunosuppressive drugs are more dangerous than immunomodulators in terms of tolerability, adverse events (AEs) and risks; and the recently added term ‘selective immunosuppressant’ may intuitively be placed right in between. As a consequence, (selective) immunosuppressants for MS therapy are labeled as ‘use with caution’ in clinical practice, unnecessarily delaying a more effective treatment in patients with active disease and, thus, causing potentially devastating consequences. This confusion is topped by different drug approvals by different health authorities: the benefit–risk evaluation of the same selective immunosuppressive drug (e.g., fingolimod) led to different approved indications by the EMA [101] and the US FDA [102]. Taken together, perception of a drug’s benefit–risk is obviously not only based on clinical trial evidence. However, apart from these formal issues, it should be kept in mind that treatment decision making is an exclusively individual process, which needs to balance the individual risks and consequences Thomas Berger* Editorial

Developmental Programming: Impact of Prenatal Bisphenol-A on Estradiol Negative Feedback in Sheep.

Endocrine disruptors are hormonally active substances that impact the trajectory of the developing fetus/offspring. An NHANES study found that 99% of humans studied had measurable urinary levels of bisphenol-A (BPA), a chemical with steroidogenic potential used in the plastic industry. Developmental exposure to BPA leads to detrimental effects at several levels including the reproductive axis. In sheep, prenatal exposure to BPA dampens ovulatory LH surges and induces LH hypersecretion. This study tested the hypothesis that LH hypersecretion in prenatal BPA-treated females is the consequence of reduced sensitivity to estrogen negative feedback. A dose response study was conducted involving 4 groups: control (C; n=7), BPA 0.05 mg/kg/day (B1; n=8), 0.5 mg/kg/day (B2; n=8), and 5 mg/kg/day (B3; n=7). Pregnant sheep were treated daily with BPA (in corn oil, s.c.) from days 30 to 90 of gestation. Controls received corn oil. Sensitivity to estrogen negative feedback was tested in all female offspring at ~12 weeks of age. All animals were administered a GnRH antagonist (acycline, 10 μg/kg, s.c.) every 12 h for 72 h to arrest follicular growth and suppress endogenous estradiol production. Eighty hours after cessation of acyline treatment, animals were implanted with a 3 mm Silastic implant containing estradiol (produces prepubertal levels of estradiol). Blood samples were collected at 20 min intervals for 6 h before, at the end of, and 72 h after cessation of GnRH antagonist treatment, and 67 h after insertion of estradiol implant for measurement of LH. LH pulses were detected by cluster algorithm. To test negative feedback effects of estradiol on LH pulse dynamics (frequency, amplitude, and area under the pulse), a paired t-test was used for all LH pulse variables to compare both pre- and post- estradiol periods. To assess BPA dose response relationship, the delta change between pre- and post- estradiol periods was subjected to regression analyses. GnRH antagonist treatment ablated LH pulsatility in all females. Cessation of GnRH antagonist treatment induced high frequency LH pulses in all groups. In controls, estradiol treatment suppressed LH pulse frequency 61.7±10.3% (P<0.01) and increased LH pulse amplitude and area under the pulse 152.2±65.2% (P<0.01) and 440.0±153.8% (P<0.05), respectively. Estradiol treatment also suppressed LH pulse frequency (B1: 45.2±10.1, B2: 48.3±7.2, B3: 66.1±8.8%) and increased LH pulse amplitude (B1: 200.4±34.9, B2: 157.1±38.7, B3: 302.2±101.9%), and area under the pulse (B1: 470.3±60.1, B2: 280.4±64.9, B3: 808.9±232.7%) in all 3 BPA-treated groups (P<0.01 for all doses and variables). The high degree of variability (P<0.05, homogeneity test) found within each BPA dose group, in response parameters, resulted in lack of BPA effect on LH pulse frequency and amplitude. Regression analysis uncovered a significant, but subtle positive linear correlation between BPA dose and area under the pulse (adjusted r2=0.140, P<0.05). In summary, reduced sensitivity to estradiol negative feedback, manifested as increased LH released per pulse, may be a contributing factor to the LH hypersecretion seen in these animals. The high variability in response parameters indicate that the organizational program involved in establishing sensitivity to steroid feedback is the result of the interplay between individual genetic susceptibility and developmental insults. Supported by NIH ES016541.

Therapy‐related acute myeloid leukemia (t‐AML) with poor‐risk cytogenetics in two patients with persistent molecular complete remission of acute promyelocytic leukemia

Therapy-related acute myeloid leukemia (t-AML) is a clinical syndrome occurring as a complication after cytotoxic and/or radiation therapy. The incidence of t-AML after acute promyelocytic leukemia (APL), all-transretinoic acid (ATRA), and anthracycline-based therapy is rather low. However, because of the high remission rates and long-term overall survival achieved with current APL treatments, late complications related to antileukemic therapy should be taken into account, giving priority to efficacy agents with the lowest potential of leukemogenesis, despite individual genetic susceptibilities that are not well known. Here, we report two cases of t-AML observed in two young women who achieved a rapid, complete molecular remission (CMR) of APL and who were still in CMR when t-AML was diagnosed. These t-AMLs shared some clinical and biological features such as poor-risk cytogenetics and a rapidly progressing, unfavorable outcome. Retrospective RT-PCR WT1 expression from the onset of APL to t-AML diagnosis did not prove to be a good marker for t-AML development.

Genetic Polymorphisms Involved in Carcinogen Metabolism and DNA Repair and Lung Cancer Risk in a Japanese Population

Several components of overall lung carcinogenesis, carcinogen metabolic and DNA repair pathways may be involved in individual genetic susceptibility to lung cancer. We evaluated the role of cytochrome P450 (CYP) 1A1 rs4646903 and rs104894, glutathione S-transferase (GST) M1 and GSTT1 deletion polymorphisms, GSTP1 rs1695, x-ray repair, excision repair cross-complementing group 2 (ERCC2) rs13181, complementing defective in Chinese hamster 1 rs25487, and XRCC3 rs861539 in a case-control study comprising 462 lung cancer cases and 379 controls in a Japanese population. Unconditional logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% CI). CYP1A1 rs4646903 (OR = 1.72, 95% CI = 1.25-2.38), rs1048943 (OR = 1.40, 95% CI = 1.02-1.92), the GSTM1 deletion polymorphism (OR = 1.38, 95% CI = 1.01-1.89), GSTP1 rs1695 (OR =1.48, 95% CI = 1.04-2.11), ERCC2 rs13181 (OR = 1.89, 95% CI = 1.28-2.78), and Chinese hamster 1 rs25487 (OR = 1.54, 95% CI = 1.12-2.13) were associated with lung cancer risk whereas the GSTT1 deletion polymorphism and XRCC3 rs861539 were not. A pertinent combination of multiple "at-risk" genotypes of CYP1A1 rs4646903, the GSTM1 deletion polymorphism and ERCC2 rs13181 was at a 5.94-fold (95% CI = 2.77-12.7) increased risk of lung cancer. A pertinent combination of multiple at-risk genotypes may detect a high-risk group. Further studies are warranted to verify our findings.

Metabolic Impact of the Amount and Type of Dietary Carbohydrates on the Risk of Obesity and Diabetes

The relationship between dietary carbohydrates and the current obesity and diabetes epidemic is the subject of intense renewed interest. Since glucose is an essential source of energy, with limited body stores, maintenance of blood levels and changes in its metabolism are strongly determined by the intake of carbohydrates in the diet. Depending on the individual genetic susceptibility and the impact of other risk factors, these metabolic changes can potentially deteriorate into manifest abnormalities with an important disease risk. In this review we focus on the impact of changing the quantity and quality of dietary carbohydrates on the biochemistry of fat synthesis and storage and on the metabolic abnormalities that can lead to overweight and obesity and to complications such as the metabolic syndrome and type 2 diabetes mellitus. Using simple illustrations of the metabolic pathways involved, we summarize current research on the following issues: ∞ Does an increase in dietary carbohydrates induce changes in blood lipids and an increase in body fat? ∞ Does a diet with a high glycemic index lead to higher energy intakes, obesity and a higher risk of developing type 2 diabetes mellitus? ∞ Is sucrose more obesigenic than starch? ∞ Does excessive consumption of food and drinks sweetened with fructose explain the current epidemic of obesity and diabetes? Despite convincing experimental data explaining the metabolic outcomes of excess consumption of these carbohydrate types, the evidence from dietary intervention studies has been undermined by methodological issues. Clear nomenclature and classification are still needed before this information can be applied to explain metabolic risks in each individual as well as to set up guidelines for the public health authorities and the food industry.

P-986 - Post-traumatic stress disorder (PTSD) as a consequence of the interaction between an individual genetic and psychopathogenic susceptibility, a traumatogenic event and a social context

PTSD is an interaction between a subject, a traumatogenic factor and a social context. Gene-by-environment studies are needed to focus more on distinct endophenotypes and influences from environmental factors. According to the monoamine predominantly incriminated PTSD can take on a more hyper-vegetative clinical expression linked with noradrenergic overuse. Differently, avoidance behaviour and the depressive aspect invoke more a modification of the serotoninergic modulation whilst post-traumatic psychotic reactions question the role of dopaminergic pathways. No neurobiological study has yet found a biological marker which would apparently and inevitably destine a subject to structure a post-traumatic stress disorder in reaction to a stress. Differently, the psychopathological study finds afterwards that a particular subject has necessarily built a traumatic repetition syndrome according to the concordance of significant data relative to their history. A PTSD does not occur by chance: the conditions of possibility of the trauma are established by genetic and psychological determinants interactively integrated at the heart of a social context. PTSD is a pathology which interacts with the societal context: on the one hand the trauma is established on the brutal reconsideration of social values which seem immutable and on the other hand, the clinical and nosographical concept of PTSD is changing with the evolution of society. Whilst the confrontation with death resembled nonsense, the subject will question the psycho-traumatic determinants of his life history to reinstate this tragic event within a search for meaning.

NCRP Report 167: Potential Impact of Individual Genetic Susceptibility and Previous Radiation Exposure on Radiation Risk for Astronauts

NCRP Report 167: Potential Impact of Individual Genetic Susceptibility and Previous Radiation Exposure on Radiation Risk for Astronauts

Evaluation of genotoxicity induced by exposure to antineoplastic drugs in lymphocytes of oncology nurses and pharmacists

The hazards of handling antineoplastic drugs have been raised and discussed in several studies. Introduction of new antineoplastics together with abuse of safety standards have contributed to the exposure risk for personnel who handle these substances. Interactions of antineoplastic drugs with biological structures vary according to the drug(s) and the individual's genetic susceptibility. This study was carried out to evaluate the genome damage induced by exposure to antineoplastic drugs in nurses (n = 20) and pharmacists (n = 18) working in the Oncology Department of Tanta Cancer Center. Thirty subjects matched in age, gender and smoking habit were selected as controls. Both chromosomal aberration analysis and micronucleus assay were used to evaluate genome damage in peripheral blood lymphocytes of the study subjects. The numbers of aberrant lymphocytes, as well as chromosomal aberration and micronuclei frequencies, were significantly increased in exposed personnel in comparison to matched controls. Compared with pharmacists, nurses showed notably higher level of chromosome damage. On the other hand, no significant difference in micronuclei frequency was observed between nurses and pharmacists. Correlation analyses pointed to the influence of age and duration of occupational exposure on the level of chromosome damage among exposed subjects. The results of this study confirmed that handling antineoplastic drugs without appropriate precautions imposed a genotoxic risk for exposed healthcare workers. These results address the need for regular biomonitoring of exposed personnel. In addition, they call attention to the need for proper implementation of intervention measures aiming to eliminate or significantly reduce worker exposure and prevent untoward biological effects.

Risiken oraler Kontrazeptiva

Oral contraceptives (OC) are either composed of a combination of an estrogen derivative (usually ethinly estradiol) and a progestogen, or they contain a progestogen only. OC are characterized by a high effectiveness and have a low failure rate if taken correctly. Most women tolerate OC relatively well, but adverse effects do occur which are driven by the estrogen dose as well as by the type of progestogen. The most frequently reported adverse effects are nausea or vomiting, breast tenderness, headache or inbalanced mood, but these unwanted side effects are often transient. The fear of weight gain of many OC users is not necessarily supported by data from studies which report relatively little differences in body mass index on average during OC use. Nevertheless, substantial weight gain can occur in individual women. The widely discussed fear of breast cancer is also not justified, and the risk of developing ovarian or endometrial cancer is reduced for women who use OC on a regular basis. Venous thromboembolism (VTE) is the adverse effect with the greatest potential for serious harm if pulmonary embolism develops. This rare, but potentially dangerous adverse effect of OC has been discussed emotionally for many years and keeps attracting a lot of public interest. VTE is rare in young women, but the VTE risk is increased two- to sixfold for OC users as compared to non-users. The VTE risk increases with increasing estrogen dose, is highest in the first year of use, and is higher for OC from the third generation (containing desogestrel, gestodene or norgestimate) than for OC from the second generation (containing levonorgestrel) or than for the progestogen-only pill. According to most studies, OC containing the progestogens drospirenone or cyproterone acetate are similar with regard to VTE risks than OC from the third generation. Individual genetic susceptibility affecting the clotting system plays a major role in the risk of developing VTE in combination with OC, and smoking is also an important contributing factor to an increased VTE risk for women using OC. It is important that doctors and pharmacists inform new users of OC about potential health risks of OC use, and that the personal and family history of previous health risks is assessed thoroughly in order to rule out that important and relevant contraindications are present when a women starts taking OC.

A study protocol for the evaluation of occupational mutagenic/carcinogenic risks in subjects exposed to antineoplastic drugs: a multicentric project

BackgroundSome industrial hygiene studies have assessed occupational exposure to antineoplastic drugs; other epidemiological investigations have detected various toxicological effects in exposure groups labeled with the job title. In no research has the same population been studied both environmentally and epidemiologically. The protocol of the epidemiological study presented here uses an integrated environmental and biological monitoring approach. The aim is to assess in hospital nurses preparing and/or administering therapy to cancer patients the current level of occupational exposure to antineoplastic drugs, DNA and chromosome damage as cancer predictive effects, and the association between the two.Methods/DesignAbout 80 healthy non-smoking female nurses, who job it is to prepare or handle antineoplastic drugs, and a reference group of about 80 healthy non-smoking female nurses not occupationally exposed to chemicals will be examined simultaneously in a cross-sectional study. All the workers will be recruited from five hospitals in northern and central Italy after their informed consent has been obtained.Evaluation of surface contamination and dermal exposure to antineoplastic drugs will be assessed by determining cyclophosphamide on selected surfaces (wipes) and on the exposed nurses' clothes (pads). The concentration of unmetabolized cyclophosphamide as a biomarker of internal dose will be measured in end-shift urine samples from exposed nurses.Biomarkers of effect and susceptibility will be assessed in exposed and unexposed nurses: urinary concentration of 8-hydroxy-2-deoxyguanosine; DNA damage detected using the single-cell microgel electrophoresis (comet) assay in peripheral white blood cells; micronuclei and chromosome aberrations in peripheral blood lymphocytes. Genetic polymorphisms for enzymes involved in metabolic detoxification (i.e. glutathione S-transferases) will also be analysed.Using standardized questionnaires, occupational exposure will be determined in exposed nurses only, whereas potential confounders (medicine consumption, lifestyle habits, diet and other non-occupational exposures) will be assessed in both groups of hospital workers.Statistical analysis will be performed to ascertain the association between occupational exposure to antineoplastic drugs and biomarkers of DNA and chromosome damage, after taking into account the effects of individual genetic susceptibility, and the presence of confounding exposures.DiscussionThe findings of the study will be useful in updating prevention procedures for handling antineoplastic drugs.

Gene–Environment Interactions in Parkinson's Disease: The Importance of Animal Modeling

Parkinson's disease (PD), a late-onset neurodegenerative disorder, occurs most commonly in a "sporadic" (idiopathic) form, without a clearly defined genetic basis and only a vaguely delineated pathogenesis. Together, the various monogenic forms of PD (i.e., those arising from mutations in single genes) account for a minority of PD cases but have provided crucial insights into disease mechanisms. Although it is commonly believed that sporadic PD is caused by a lifetime of environmental exposures that are superimposed on an individual's composite genetic susceptibility, this hypothesis has not been tested adequately. This article reviews genetic and environmental factors that have been associated with PD and attempts to put these into a pathogenic framework. We argue that animal modeling will become increasingly important in attempting to elucidate gene-environment interactions, to define pathogenic mechanisms, and to provide a platform for testing of targeted therapeutic interventions.

Incidence of Breast Cancer and Its Subtypes in Relation to Individual and Multiple Low-Penetrance Genetic Susceptibility Loci

There is limited evidence on how the risk of breast cancer and its subtypes depend on low-penetrance susceptibility loci, individually or in combination. To analyze breast cancer risk, overall and by tumor subtype, in relation to 14 individual single-nucleotide polymorphisms (SNPs) previously linked to the disease, and in relation to a polygenic risk score. Study of 10,306 women with breast cancer (mean age at diagnosis, 58 years) and 10,393 women without breast cancer who in 2005-2008 provided blood samples for genotyping in a large prospective study of UK women; and meta-analysis of these results and of other published results. Estimated per-allele odds ratio (OR) for individual SNPs, and cumulative incidence of breast cancer to age 70 years in relation to a polygenic risk score based on the 4, 7, or 10 SNPs most strongly associated with risk. Odds ratios for breast cancer were greatest for FGFR2-rs2981582 and TNRC9-rs3803662 and, for these 2 SNPs, were significantly greater for estrogen receptor (ER)-positive than for ER-negative disease, both in our data and in meta-analyses of all published data (pooled per-allele ORs [95% confidence intervals] for ER-positive vs ER-negative disease: 1.30 [1.26-1.33] vs 1.05 [1.01-1.10] for FGFR2; interaction P < .001; and 1.24 [1.21-1.28] vs 1.12 [1.07-1.17] for TNRC9; interaction P < .001). The next strongest association was for 2q-rs13387042, for which the per-allele OR was significantly greater for bilateral than unilateral disease (1.39 [1.21-1.60] vs 1.15 [1.11-1.20]; interaction P = .008) and for lobular than ductal tumors (1.35 [1.23-1.49] vs 1.10 [1.05-1.15]; interaction P < .001). The estimated cumulative incidence (95% confidence interval) of breast cancer to age 70 years among women in the top and bottom fifths of a polygenic risk score based on 7 SNPs was 8.8% (8.3%-9.4%) and 4.4% (4.2%-4.8%), respectively. For ER-positive disease the corresponding risks were 7.4% (6.9%-8.0%) and 3.4% (3.1%-3.8%), respectively; while for ER-negative disease they were 1.4% (1.2%-1.6%) and 1.0% (0.8%-1.2%). The findings did not differ materially according to the number of SNPs included in the polygenic risk model. The polygenic risk score was substantially more predictive of ER-positive than of ER-negative breast cancer, particularly for absolute risk.

Review: Dupuytren's disease in Asia and the migration theory of Dupuytren's disease

The presentation of a Chinese patient with unilateral Dupuytren's disease (DD) prompted a literature search and a review of the epidemiology of DD in the Asian population as it has never been cumulatively reported. The purpose of this paper is to review all the reported cases of DD in the literature and aetiological links to DD elsewhere. The literature was searched with a wide variety of terms, and subsequent references were analysed and further references investigated for other reported cases of DD in the Asian population. This review found 595 cases and has shown that DD is present to a variable extent in China (96 cases), Thailand (19 cases), Vietnam (one case), India (15 cases) and Japan (474 cases). A total of 54% had bilateral disease. Risk factors (diabetes, trauma, epilepsy, alcoholism, manual labour) were reportedly present in 65% of the patients, and a positive family history was reported in 9%. The average patient age was 67 years. This review shows that there is a low but significant incidence of DD across Asia, which supports the hypothesis of a widespread genetic susceptibility to the disease. Therefore, the prevalence of DD in this community is not likely due to sporadic genetic mutation as previously presumed but rather individual genetic susceptibility and that risk factors play a major role in the expression of DD in this population.