| 1. |
- Andersson, Andreas, et al.
(författare)
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Public support for healthcare-mediated disclosure of hereditary cancer risk information: Results from a population-based survey in Sweden
- 2020
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Ingår i: Hereditary Cancer in Clinical Practice. - : Springer Science and Business Media LLC. - 1731-2302 .- 1897-4287. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Targeted surveillance of at-risk individuals in families with increased risk of hereditary cancer is an effective prevention strategy if relatives are identified, informed and enrolled in screening programs. Despite the potential benefits, many eligible at-risk relatives remain uninformed of their cancer risk. This study describes the general public's opinion on disclosure of hereditary colorectal cancer (CRC) risk information, as well as preferences on the source and the mode of information. Methods A random sample of the general public was assessed through a Swedish citizen web-panel. Respondents were presented with scenarios of being an at-risk relative in a family that had an estimated increased hereditary risk of CRC; either 10% (moderate) or 70% (high) lifetime risk. A colonoscopy was presented as a preventive measure. Results were analysed to identify significant differences between groups using the Pearson's chi-square (chi(2)) test. Results Of 1800 invited participants, 977 completed the survey (54%). In the moderate and high-risk scenarios, 89.2 and 90.6% respectively, would like to receive information about a potential hereditary risk of CRC (chi 2,p = .755). The desire to be informed was higher among women (91.5%) than men (87.0%, chi 2,p = .044). No significant differences were found when comparing different age groups, educational levels, place of residence and having children or not. The preferred source of risk information was a healthcare professional in both moderate and high-risk scenarios (80.1 and 75.5%). However, 18.1 and 20.1% respectively would prefer to be informed by a family member. Assuming that healthcare professionals disclosed the information, the favoured mode of information was letter and phone (38.4 and 33.2%). Conclusions In this study a majority of respondents wanted to be informed about a potential hereditary risk of CRC and preferred healthcare professionals to communicate this information. The two presented levels of CRC lifetime risk did not significantly affect the interest in being informed. Our data offer insights into the needs and preferences of the Swedish population, providing a rationale for developing complementary healthcare-assisted communication pathways to realise the full potential of targeted prevention of hereditary CRC.
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| 2. |
- Hawranek, Carolina, 1982-, et al.
(författare)
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Direct letters to relatives at risk of hereditary cancer-study protocol for a multi-center randomized controlled trial of healthcare-assisted versus family-mediated risk disclosure at Swedish cancer genetics clinics (DIRECT-study)
- 2023
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Ingår i: TRIALS. - : BioMed Central (BMC). - 1745-6215. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The results of germline genetic testing for hereditary cancer are of importance not only to the patients under investigation but also to their genetic at-risk relatives. Standard care is to encourage the proband (first family member under investigation) to pass on this risk information to the relatives. Previous research suggests that with family-mediated disclosure, only about a third of at-risk relatives contact health care to receive genetic counselling. In some studies, complementing family-mediated risk disclosure with healthcare-assisted risk disclosure almost doubles the uptake of genetic counselling in at-risk relatives. In this study, we evaluate healthcare-assisted direct letters to relatives at risk of hereditary cancer syndromes in a randomized controlled trial.MethodsProbands are recruited from Swedish outpatient cancer genetics clinics to this two-arm randomized controlled trial. The study recruits probands with either a pathogenic variant in a cancer susceptibility gene (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2) or probands with familial breast and colorectal cancer based on clinical and pedigree criteria. In both arms, probands receive standard care, i.e., are encouraged and supported to pass on information to relatives. In the intervention arm, the proband is also offered to have direct letters sent to the at-risk relatives. The primary outcome measure is the proportion of at-risk relatives contacting a Swedish cancer genetics clinic within 12 months of the proband receiving the test results.DiscussionThis paper describes the protocol of a randomized controlled clinical trial evaluating a healthcare-assisted approach to risk disclosure by offering the probands to send direct letters to their at-risk relatives. The results of this study should be informative in the future development of risk disclosure practices in cancer genetics clinics.
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| 3. |
- Anedda, Francesca, et al.
(författare)
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Multiple polymorphisms affect expression and function of the neuropeptide S receptor (NPSR1)
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:12, s. e29523-
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Tidskriftsartikel (refereegranskat)abstract
- Background: neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02). Principal Findings: we identified one promoter SNP (rs2530547 [-103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk. Significance: these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance.
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| 4. |
- Böttcher, Malin, 1969-, et al.
(författare)
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Effects of breast milk from allergic and non-allergic mothers on mitogen- and allergen-induced cytokine production
- 2003
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Ingår i: Pediatric Allergy and Immunology. - : Wiley. - 0905-6157 .- 1399-3038. ; 14:1, s. 27-34
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Tidskriftsartikel (refereegranskat)abstract
- Breast milk contains several components that provide specific immunity and affect the maturation of the infant's immune system. The aim of this study was to analyze the effects of breast milk, on mitogen- and allergen-induced cytokine production from cord blood mononuclear cells (CBMC), and if those effects differ between allergic and non-allergic mothers. The cells were incubated for 96 h with phytohemagglutinin (PHA), ovalbumin or cat dander in the presence of various dilutions of colostrum. Colostrum inhibited both mitogen- and cat-induced IFN-γ and mitogen-induced interleukin-4 (IL-4) production. The inhibition on IFN-γ production was to some extent caused by TGF-β, as the effect was modified when an anti-TGF-β antibody was added to the cultures. In contrast, colostrum enhanced allergen-induced production of the Th2-like cytokines IL-5 and IL-13, and this was accompanied with increased production of IL-10. No differences were found between allergic and non-allergic mothers. The inhibitory effect of breast milk on IFN-γ production, which was partly due to the high levels of TGF-β, together with the enhancing effect on IL-10 secretion, confirm that breast milk is anti-inflammatory. Although the production of IL-5 and IL-13 was enhanced by colostrum, this was accompanied with an increased production of IL-10. Together with the high levels of TGF-β in breast milk and inhibitory effect of colostrum on IL-4 production, this suggests a possible mechanism whereby breast-feeding may protect against the development of allergy. Despite differences in the composition of breast milk between allergic and non-allergic mothers, the effects of breast milk on cytokine production from CBMC were independent of the atopic status of the mothers.
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| 5. |
- Hawranek, Carolina, et al.
(författare)
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Cancer worry distribution and willingness to undergo colonoscopy at three levels of hypothetical cancer risk - a population-based survey in Sweden
- 2022
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We describe levels of cancer worry in the general population as measured with the Cancer Worry Scale (CWS) and investigate the association with colonoscopy screening intentions in three colorectal cancer risk scenarios. Methods: The data were sourced through a population-based survey. Respondents (n = 943) completed an eight-item CWS and questions on colonoscopy screening interest at three hypothetical risk levels. Results: Respondents without a personal cancer history (n = 853) scored 9.46 on the six-item CWS (mean, SD 2.72). Mean scores were significantly higher in women (9.91, SD 2.89) as compared to men (9.06, SD 2.49, p < 0.001). Linear regression showed higher cancer worry in women and those with children when controlling for education, age group, and country of birth. High cancer worry (six-item CWS mean >12) was identified in 25% of women and in 17% of men. Among those, 71% would attend a colonoscopy screening compared to 52% of those with low cancer worry (p < 0.001, 5% CRC-risk). Conclusions: The distribution of cancer worry in a general population sample showed higher mean scores in women, and levels overlapped with earlier findings in cancer-affected samples. Respondents with high cancer worry were more inclined to undergo a colonoscopy screening, and intention increased with higher levels of hypothetical risk.
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| 6. |
- Hawranek, Carolina, 1982-
(författare)
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Someone has to tell them : exploring hereditary cancer risk disclosure in Sweden
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Summary in EnglishBackground: An awareness of hereditary susceptibility for breast, ovarian and colorectal cancer in high-risk families enables targeted cancer prevention. A discovered hereditary risk in one family member (proband) may thus be important for several members of that family. Identified at-risk relatives can be offered surveillance to allow early detection or in some cases risk-reducing surgery to lower the risk of disease and premature death. Problem: The current clinical praxis with family-mediated risk disclosure leaves up to half of all at-risk relatives uninformed of their potential cancer risk. Complementary disclosure pathways have demonstrated promising results suggesting new opportunities to develop clinical management of hereditary cancer risk disclosure. However, concerns over legal liability, risk of inducing cancer worry and lack of robust outcome data from randomized trials among other factors, have hampered translation of emerging findings into clinical practice.Aim: This thesis explores perceptions and preferences on the disclosure of risk information concerning hereditary cancer syndromes in the general public and in patients. The work also estimates cancer worry levels in the Swedish population and explores willingness to participate in screening colonoscopy at different hypothetical levels of lifetime risk of colorectal cancer. Methods: Two quantitative and two qualitative studies were designed to address the aims. Data collection included focus groups, a population survey, and semi-structured patient interviews. Quantitative data was analyzed using descriptive statistics and groups were compared using tests and regression analysis. Interview data was analyzed with inductive qualitative content analysis of both manifest and latent content. Focus was placed on participants’ perceptions and preferences and patients’ management of risk disclosure as well as their interaction with genetic healthcare professionals.Results: Study I describes how lay people view the roles and responsibilities involved in risk disclosure. Respondents assumed genetic healthcare professionals (HCPs) would have a clear mandate in leading the risk disclosure process and wanted to be actively involved in shaping this process. They expected healthcare services to provide easy-to-understand, personalized information suitable for themselves and potential relatives. Findings from Study II show a strong public preference to share and receive risk information about hereditary cancer (90% and 89% respectively in a 10% cancer risk scenario). A majority wanted to receive information about a potential hereditary cancer risk from a healthcare professional (80%) and also preferred healthcare services to inform their at-risk relatives (58%). Preferred options for contact were by letter or telephone, followed by digital options. Study III presents novel data on cancer worry levels in a Swedish population-based sample (mean 9.46 of a total 24 on the 6-item cancer worry scale). Female respondents and those with children had higher cancer worry scores, and those with higher worry levels were also more inclined to participate in a screening colonoscopy. For each increasing risk level presented (5, 10 or 70% lifetime risk of colorectal cancer) more respondents reported interest to undergo colonoscopy. Study IV describes patient experiences of family disclosure, which is seen as difficult yet important, and often performed for the sake of others. Patients also describe the feeling unqualified in the role as proband, while others consider it a straightforward task which needs to be done. The patient data also illustrates the difficulties in communicating complex health information and patients’ struggles to navigate benefits and drawbacks of interacting with relatives. Patients also envisioned solutions to perceived barriers and outlined alternatives for healthcare services to better facilitate the risk disclosure process.Conclusion: Findings in this thesis indicate a missing link in the communication between proband, relative and healthcare regarding hereditary cancer risk information. The combined results suggest that risk disclosure would benefit from being more:Standardized – by increasing transparency about the risk disclosure process and harmonize disclosure options to guide probands and healthcare professional in the clinical setting.Systematic – by establishing follow up of risk disclosure as routine care and clearly define communication duties of healthcare professionals and probands early in the process.Situational – by tailoring professional support for risk disclosure and adapting the content and approach to the coping style, behavioral type and need of each family.Clinical implications: This thesis highlights the challenges of risk disclosure in families with increased risk of hereditary cancer and strengthens the argument for shifting towards more healthcare involvement in the process of informing at-risk relatives. The findings complement existing evidence on how hereditary cancer risk disclosure could develop further to better support proactive management of cancer risk in families affected by hereditary cancer.
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| 7. |
- Hellquist, Anna
(författare)
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Susceptibility genes in systemic lupus erythematosus
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) is a complex autoimmune disease for which the incidence and prevalence vary between populations and also between males and females. SLE is characterized by production of pathogenic autoantibodies against nuclear antigens due to a breakdown in self-tolerance and the pathogenesis is associated with the formation of immune complexes, followed by tissue inflammation in multiple organs, such as the skin, joints, heart and kidneys. SLE is an unusually heterogeneous disease and its clinical classification is based on criteria set by the American College of Rheumatology (ACR). Although the underlying pathogenic mechanisms of SLE remain imperfectly understood, both environmental influences and genetic factors have been found to play an important role in disease initiation and progression. Both familial aggregation studies and twin studies support a strong genetic component in SLE and today over 30 convincingly associated SLE susceptibility genes have been identified. Many of these SLE-predisposing genes appear to be involved in similar and/or related biological pathways, including the processing of immune complexes, type I interferon production, and immune signal transduction. Other genes, on the contrary, have no assigned function or obvious role in the immune system, and thus represent ideal candidate to reveal novel disease mechanisms. The aim of this thesis was to study susceptibility genes in SLE, using a number of different approaches. In Paper I we performed a functional candidate gene association study of the GIMAP5 gene, which had been shown to be essential for the survival of leukocytes, and identified association between this gene and SLE in two independent family cohorts from Finland and the UK. In Paper II we performed a positional mapping study within our previously identified susceptibility loci on chromosomes 14q21-q23 and identified association to the novel SLE candidate gene MAMDC1 in four independent cohorts. This gene appears to encode for a novel member of the immunoglobulin cell adhesion molecules superfamily, which is involved in cell adhesion, migration, and recruitment to inflammatory sites. In Papers III-V we performed three different replication studies of previously identified SLE susceptibility in a Finnish case-control cohort and identified association to several genes, including STAT4, IRF5-TNPO3, TYK2, ITGAM-ITGAX, TNFAIP3, FAM167A-BLK, BANK1 and KIAA1542. We furthermore showed evidence ofgene-gene interaction (epistasis) between SNPs in IRF5 and TYK2. In conclusion we have identified two novel SLE candidate genes contributing to SLE susceptibility in several populations as well as shown that a number of previously identified SLE susceptibility genes also contribute to risk in the Finnish population.
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| 8. |
- Hellquist, Anna, et al.
(författare)
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Variation in STAT4 is associated with systemic lupus erythematosus in a Finnish family cohort
- 2010
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 69:5, s. 883-886
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES:To investigate if 10 single nucleotide polymorphisms (SNPs) and haplotypes in the STAT4 gene, previously associated with SLE in a Swedish case-control cohort, also are associated with SLE risk in a Finnish SLE family cohort.METHOD: Genotyping was performed in 192 Finnish families, with 237 affected individuals and their healthy relatives, using the SNPstream genotyping system.RESULTS:TDT analysis provided the strongest signal of association for two linked SNPs; rs7582694 (P-value = 0.002, OR = 2.57) and rs10181656 (P-value = 0.001, OR = 2.53). We further performed haplotype association analysis using a sliding window approach which showed that the strongest association signal originates from SNPs in intron 3 of STAT4.CONCLUSION:Our results provide evidence that the main association signal for STAT4 with SLE previously reported in Caucasians is the same in the Finnish population. This is the first study that confirms the association of STAT4 with SLE in a family cohort.
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| 9. |
- Järvinen, Tiina M., et al.
(författare)
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Polymorphisms of the ITGAM Gene Confer Higher Risk of Discoid Cutaneous Than of Systemic Lupus Erythematosus
- 2010
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:11, s. e14212-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear. Principal Findings: To specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus. SLE patients were further subdivided by the presence or absence of discoid rash and renal involvement. In addition, 235 Finnish and Swedish patients positive for Ro/SSA-autoantibodies were included in a subphenotype analysis. Analysis of the ITGAM coding variant rs1143679 showed highly significant association to DLE in patients without signs of systemic disease (P-value = 4.73x10(-11), OR = 3.20, 95% CI = 2.23-4.57). Significant association was also detected to SLE patients (P-value = 8.29x10(-6), OR = 2.14, 95% CI = 1.52-3.00), and even stronger association was found when stratifying SLE patients by presence of discoid rash (P-value = 3.59x10(-8), OR = 3.76, 95% CI = 2.29-6.18). Significance: We propose ITGAM as a novel susceptibility gene for cutaneous DLE. The risk effect is independent of systemic involvement and has an even stronger genetic influence on the risk of DLE than of SLE.
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| 10. |
- Numan Hellquist, Barbro, et al.
(författare)
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Effectiveness of population-based service screening with mammography for women ages 40 to 49 years with a high or low risk of breast cancer : socioeconomic status, parity, and age at birth of first child
- 2015
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 121:2, s. 251-258
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Invitation to mammography screening of women aged 40 to 49 years is a matter of debate in many countries and a cost-effective alternative in countries without screening among women aged 40 to 49 years could be inviting those at higher risk. The relative effectiveness of mammography screening was estimated for subgroups based on the breast cancer risk factors parity, age at time of birth of first child, and socioeconomic status (SES).METHODS: The SCReening of Young Women (SCRY) database consists of all women aged 40 to 49 years in Sweden between 1986 and 2005 and was split into a study and control group. The study group consisted of women residing in areas in which women aged 40 to 49 years were invited to screening and the control group of women in areas in which women aged 40 to 49 years were not invited to screening. Rate ratio (RR) estimates were calculated for 2 exposures: invitation and attendance.RESULTS: There were striking similarities noted in the RR pattern for women invited to and attending screening and no statistically significant difference or trend in the RR was noted by risk group. The RR estimates increased by increasing parity for parity of 0 to 2 and ranged from 0.55 (95% confidence interval [95% CI], 0.38-0.79) to 0.79 (95% CI, 0.65-0.95) for attending women. The RR for women with high SES was lower than that for women with low SES (RR, 0.72 [95% CI, 0.60-0.86] and RR, 0.79 [95% CI, 0.63-0.99], respectively). For women aged 20 to 24 years at the time of the birth of their first child, the RR was 0.73 (95% CI, 0.58-0.91) and estimates for other ages were similar.CONCLUSIONS: There was no statistically significant difference noted in the relative effectiveness of mammography screening by parity, age at the time of birth of the first child, or SES. Cancer 2014.
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