| 1. |
- Horikoshi, Momoko, et al.
(författare)
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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:1
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Tidskriftsartikel (refereegranskat)abstract
- Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
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| 2. |
- Kamper-Jörgensen, Mads, et al.
(författare)
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Survival after blood transfusion
- 2008
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Ingår i: Transfusion. - : Wiley. - 0041-1132 .- 1537-2995. ; 48:12, s. 2577-2584
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Tidskriftsartikel (refereegranskat)abstract
- Long-term survival of transfusion recipients has rarely been studied. This study examines short- and long-term mortality among transfusion recipients and reports these as absolute rates and rates relative to the general population. Population-based cohort study of transfusion recipients in Denmark and Sweden followed for up to 20 years after their first blood transfusion. Main outcome measure was all-cause mortality. A total of 1,118,261 transfusion recipients were identified, of whom 62.0 percent were aged 65 years or older at the time of their first registered transfusion. Three months after the first transfusion, 84.3 percent of recipients were alive. One-, 5-, and 20-year posttransfusion survival was 73.7, 53.4, and 27.0 percent, respectively. Survival was slightly poorer in men than in women, decreased with increasing age, and was worst for recipients transfused at departments of internal medicine. The first 3 months after the first transfusion, the standardized mortality ratio (SMR) was 17.6 times higher in transfusion recipients than in the general population. One to 4 years after first transfusion, the SMR was 2.1 and even after 17 years the SMR remained significantly 1.3-fold increased. The survival and relative mortality patterns among blood transfusion recipients were characterized with unprecedented detail and precision. Our results are relevant to assessments of the consequences of possible transfusion-transmitted disease as well as for cost-benefit estimation of new blood safety interventions.
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| 3. |
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| 4. |
- Schöllkopf, Claudia, et al.
(författare)
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Hepatitis C infection and risk of malignant lymphoma
- 2008
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 122:8, s. 1885-1890
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Tidskriftsartikel (refereegranskat)abstract
- The association between hepatitis C virus (HCV) infection and risk of malignant lymphoma remains controversial, perhaps due to small-sized studies and low prevalence of HCV in the general population. On the basis of a large Danish-Swedish population-based case-control study, 2,819 lymphoma patients and 1,856 controls of second-generation Danish-Swedish origin were screened for HCV infection using an enzyme-linked immunosorbent assay and a confirming recombinant immunoblot assay (RIBA) test. Positive samples were tested with real-time PCR for the presence of HCV RNA. The association between HCV infection and risk of malignant lymphoma was assessed by logistic regression. When intermediate RIBA test results were interpreted as positive, anti-HCV antibody positivity was associated with a nonsignificant increased risk of non-Hodgkin lymphoma (NHL) overall (odds ratio (OR) = 2.2; 95% confidence interval (CI) 0.9-5.3; n = 20 cases), of B-cell lymphomas combined (OR = 2.4 [1.0-5.8]; n = 20) and of lymphoplasmacytic lymphoma (OR = 5.2 [1.0-26.4]; n = 2). No patients with T-cell or Hodgkin lymphoma were HCV-positive. A more conservative definition of HCV positivity (disregarding intermediate RIBA results) resulted in an OR = 1.6 (0.3-8.5; n = 5) for NHL overall. When the definition was further restricted to require HCV RNA positivity, OR was 1.7 (0.2-16.2; n = 3) for NHL overall. Our findings from a population with a low prevalence of HCV suggest a positive association between HCV and risk of NHL, in particular of B-cell origin.
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| 5. |
- Smedby, Karin Ekström, et al.
(författare)
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Ultraviolet radiation exposure and risk of malignant lymphomas
- 2005
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 97:3, s. 199-209
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The incidence of malignant lymphomas has been increasing rapidly, but the causes of these malignancies remain poorly understood. One hypothesis holds that exposure to ultraviolet (UV) radiation increases lymphoma risk. We tested this hypothesis in a population-based case-control study in Denmark and Sweden. METHODS: A total of 3740 patients diagnosed between October 1, 1999, and August 30, 2002, with incident malignant lymphomas, including non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Hodgkin lymphoma, and 3187 population controls provided detailed information on history of UV exposure and skin cancer and information on other possible risk factors for lymphomas. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by logistic regression. Statistical tests were two-sided. RESULTS: Multivariable-adjusted analyses revealed consistent, statistically significant negative associations between various measures of UV light exposure and risk of non-Hodgkin lymphoma. A high frequency of sun bathing and sunburns at age 20 years and 5-10 years before the interview and sun vacations abroad were associated with 30%-40% reduced risks of non-Hodgkin lymphoma (e.g., for sunbathing four times a week or more at age 20 versus never sunbathing, OR = 0.7, 95% CI = 0.6 to 0.9; for two or more sunburns a year at age 20 versus no sunburns, OR = 0.6, 95% CI = 0.5 to 0.8). These inverse associations increased in strength with increasing levels of exposure (all P(trend)< or =.01). Similar, albeit weaker, associations were observed for Hodgkin lymphoma. There were no clear differences among non-Hodgkin lymphoma subtypes, although associations were stronger for B-cell than for T-cell lymphomas. A history of skin cancer was associated with a doubling in risks of both non-Hodgkin and Hodgkin lymphoma. CONCLUSIONS: A history of high UV exposure was associated with reduced risk of non-Hodgkin lymphoma. The positive association between skin cancer and malignant lymphomas is, therefore, unlikely to be mediated by UV exposure.
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| 6. |
- Ullum, Henrik, et al.
(författare)
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Blood donation and blood donor mortality after adjustment for a healthy donor effect
- 2015
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Ingår i: Transfusion. - : Wiley. - 0041-1132 .- 1537-2995. ; 55:10, s. 2479-2485
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Studies have repeatedly demonstrated that blood donors experience lower mortality than the general population. While this may suggest a beneficial effect of blood donation, it may also reflect the selection of healthy persons into the donor population. To overcome this bias, we investigated the relation between blood donation frequency and mortality within a large cohort of blood donors. In addition, our analyses also took into consideration the effects of presumed health differences linked to donation behavior.STUDY DESIGN AND METHODS Using the Scandinavian Donation and Transfusion database (SCANDAT), we assessed the association between annual number of donations in 5-year windows and donor mortality by means of Poisson regression analysis. The analyses included adjustment for demographic characteristics and for an internal healthy donor effect, estimated among elderly donors exempted from continued donation because of age criteria.RESULTS Statistical analyses included 1,182,495 donors of whom 15,401 died during 9,526,627 person-years of follow-up. Analyses adjusted only for demographic characteristics showed a 18.6% reduction in mortality per additional annual donation (95% confidence interval [CI], 16.8%-20.4%). After additional adjustment for the internal healthy donor effect, each additional annual donation was associated with a 7.5% decreased mortality risk 7.5% (95% CI, 5.7%-9.4%).CONCLUSION We observed an inverse relationship between donation frequency and mortality. The magnitude of the association was reduced after adjustment for an estimate of self-selection in the donor population. Our observations indicate that repeated blood donation is not associated with premature death, but cannot be interpreted as conclusive evidence of a beneficial health effect.
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| 7. |
- Vogelezang, Suzanne, et al.
(författare)
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Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
- 2020
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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| 8. |
- Adami, Hans-Olov, et al.
(författare)
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Pregnancy and risk of non-Hodgkin´s lymphoma : a prospective study
- 1997
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Ingår i: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 70:2, s. 155-158
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Tidskriftsartikel (refereegranskat)abstract
- The etiology of non-Hodgkin's lymphomas (NHL), including chronic lymphocytic leukemia (CLL), is likely to be related to immune function. In the light of the established immunologic effects of a pregnancy, we decided to examine the risk of NHL and CLL in relationship to full-term pregnancies. Within a nationwide cohort we identified 1,546 women with NHL and 198 women with CLL, all 15 years or older, born 1925-1972. Five age-matched controls were selected for each case patient. Conditional logistic regression was used to estimate the odds ratios after mutual adjustment for number of births and age at first birth. We found a weak, negative association between parity and risk of NHL (p for trend 0.11) and a transient, 10-40% decrease in risk within 5-14 years after the last birth among women with various parity status. The risk of CLL decreased more markedly, and orderly with increasing parity, but the trend was not significant (p = 0.18). Small numbers of cases with CLL prevented more detailed analyses of temporal relationships. Age at first birth appeared unrelated to the risk of both NHL and CLL. We conclude that the immunologic alterations associated with a pregnancy have limited, if any, relevance to the etiology of NHL and CLL; changing reproductive pattern is an unlikely contributor to the marked increase in incidence of NHL seen in many populations.
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| 9. |
- Adami, Johanna, et al.
(författare)
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Evidence of an association between non-Hodgkin´s lymphoma and skin cancer
- 1995
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Ingår i: BMJ (Clinical research ed.). - : BMJ. - 0959-8138 .- 1468-5833. ; 310:6993, s. 1491-1495
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE--To investigate a possible link between exposure to ultraviolet light and the almost epidemic increase in non-Hodgkin's lymphoma worldwide. Because ultraviolet light is known to cause skin cancers, the association between non-Hodgkin's lymphoma and skin cancer was studied. DESIGN--Secondary occurrence of either malignant melanoma or squamous cell skin cancer in cohorts of patients with a first diagnosis of either non-Hodgkin's lymphoma or chronic lymphocytic leukaemia, and vice versa, were studied. Expected numbers of subsequent cancers were calculated by sex, age, and period specific national incidence rates multiplied by the person years under observation in the cohorts. SETTING--Denmark (1943-89) and Sweden (1958-89). SUBJECTS--Four population based cohorts identified in the nationwide cancer registries (34,641 people with non-Hodgkin's lymphoma, 17,400 with chronic lymphocytic leukaemia, 34,989 with malignant melanoma, 25,980 with squamous cell skin cancer). A total of 562,085 person years were accrued for the analysis. MAIN OUTCOME MEASURES--The ratios of observed to expected cancers (the standardised incidence ratio) served as a measure of the relative risk. RESULTS--The relative risk for developing squamous cell skin cancer was 5.5 (95% confidence interval 4.6 to 6.6) among patients with non-Hodgkin's lymphoma and 8.6 (7.2 to 10.3) among patients with chronic lymphocytic leukaemia. The relative risks remained high over more than 15 years of follow up. Relative risks for malignant melanoma were 2.4 (1.8 to 3.2) for patients with non-Hodgkin's lymphoma and 3.1 (2.1 to 4.4) for patients with chronic lymphocytic leukaemia. After squamous cell skin cancer had been diagnosed there was a twofold excess risk for non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. By contrast, in each of the cohorts the general cancer risks excluding skin and lymphoproliferative malignancies were close to the expected. CONCLUSIONS--The occurrence of non-Hodgkin's lymphoma and skin cancer are strongly associated; this supports the hypothesis that the secular increase in exposure to ultraviolet light may have contributed to the increasing incidence of non-Hodgkin's lymphoma in recent decades.
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| 10. |
- Akre, Olof, et al.
(författare)
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Epstein-Barr virus and cytomegalovirus in relation to testicular-cancer risk : a nested case-control study
- 1999
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Ingår i: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 82:1, s. 1-5
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Tidskriftsartikel (refereegranskat)abstract
- An infectious etiology of testicular cancer has been suggested. We have evaluated seroreactivity against cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in relation to testicular-cancer risk in a case-control study, nested within a cohort of prospectively collected serum specimens from 293,692 individuals. For each of 81 cases of testicular cancer identified, 3 controls were randomly selected from the cohort. Serum IgG antibody titers against CMV and EBV were determined using enzyme-linked immunosorbent assays (ELISAs) and immunofluorescence methods. Odds ratios (OR) were obtained from conditional logistic-regression models. No association was found between CMV positivity and testicular cancer overall (OR = 1.08; 95% confidence interval 0.60-1.94); risk for testicular seminoma was increased among CMV seropositive [OR = 1.70 (0.80-3.59)], whereas seropositivity was associated with decreased risk for testicular non-seminoma [OR = 0.54 (0.19-1.56)] (p for heterogeneity, 0.09). For EBV, the risk for testicular cancer was increased among individuals seropositive for viral capsid antigen (VCA) [OR = 2.74 (0.62-12.12)]. The results lend some support to the hypothesis of an infectious etiology, and we propose that future studies should take into account age at infection.
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| 11. |
- Akre, Olof, et al.
(författare)
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Maternal and gestational risk factors for hypospadias
- 2008
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 116:8, s. 1071-1076
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: An increase in the prevalence of hypospadias has been reported, but the environmental causes remain virtually unknown. OBJECTIVES: Our goal was to assess the association between risk of hypospadias and indicators of placental function and endogenous hormone levels, exposure to exogenous hormones, maternal diet during pregnancy, and other environmental factors. METHODS: We conducted a case-control study in Sweden and Denmark from 2000 through 2005 using self-administered questionnaires completed by mothers of hypospadias cases and matched controls. The response rate was 88% and 81% among mothers of cases and controls, respectively. The analyses included 292 cases and 427 controls. RESULTS: A diet during pregnancy lacking both fish and meat was associated with a more than 4-fold increased risk of hypospadias [odds ratio (OR) 4.6, 95% confidence interval (CI), 1.6-13.3]. Boys born to obese [body mass index (BMI) > ;= 30] women had a more than 2-fold increased risk of hypospadias (OR = 2.6, 95% CI, 1.2-5.7) compared with boys born to mothers with a normal weight (BMI = 20-24). Maternal hypertension during pregnancy and absence of maternal nausea increased a boy's risk of hypospadias 2.0-fold (95% CI, 1.1-3.7) and 1.8-fold (95% CI, 1.2-2.8), respectively. Nausea in late pregnancy also appeared to be positively associated with hypospadias risk (OR = 7.6, 95% CI, 1.1-53). CONCLUSIONS: A pregnancy diet lacking meat and fish appears to increase the risk of hypospadias in the offspring. Other risk associations were compatible with a role for placental insufficiency in the etiology of hypospadias.
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| 12. |
- Baecklund, Fredrik, et al.
(författare)
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A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival
- 2014
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 15, s. 113-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed. Methods: We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of similar to 300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999-2002 and in the United States 2001-2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model. Results: In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0x10(-8)). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom = 3.17, 95% CI 2.09-4.79, prandom = 5.24x10(-8)). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR = 0.73, 95% CI 0.58-0.91, p = 0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR = 0.78, 95% CI 0.62-0.97, p = 0.02; rs2227307 HR = 0.75, 95% CI 0.60-0.94, p = 0.01) previously associated with overall survival. Conclusions: The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS.
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| 13. |
- Beaumont, Robin N, et al.
(författare)
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Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
- 2018
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 1460-2083 .- 0964-6906. ; 27:4, s. 742-756
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5x10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
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| 14. |
- Beaumont, Robin N, et al.
(författare)
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Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.
- 2023
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Ingår i: Nature genetics. - 1546-1718 .- 1061-4036. ; 55:11, s. 1807-19
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Tidskriftsartikel (refereegranskat)abstract
- A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n=65,405), maternal (n=61,228) and paternal (n=52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.
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| 15. |
- Bernatsky, Sasha, et al.
(författare)
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Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma
- 2017
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Ingår i: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE.
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| 16. |
- Berndt, Sonja, I, et al.
(författare)
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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
- 2022
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Ingår i: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36:12, s. 2835-2844
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Tidskriftsartikel (refereegranskat)abstract
- Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
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| 17. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:8, s. 868-U202
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 x 10(-14)), 18q21.33 (BCL2, P = 7.76 x 10(-11)), 11p15.5 (C11orf21, P = 2.15 x 10(-10)), 4q25 (LEF1, P = 4.24 x 10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 x 10(-9)), 9p21.3 (CDKN2B-AS1, P = 1.27 x 10(-8)), 18q21.32 (PMAIP1, P = 2.51 x 10(-8)), 15q15.1 (BMF, P = 2.71 x 10(-10)) and 2p22.2 (QPCT, P = 1.68 x 10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 x 10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 x 10(-8)) and 5p15.33 (TERT, P = 1.92 x 10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
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| 18. |
- Berndt, Sonja I., et al.
(författare)
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Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P = 2.55 x 10(-11)), 6p25.2 (rs73718779, SERPINB6, P = 1.97 x 10(-8)) and 3q28 (rs9815073, LPP, P = 3.62 x 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P = 1.00 x 10(-11)) in the combined analysis. We find suggestive evidence (P<5 x 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P = 7.19 x 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P = 2.12 x 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.
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| 19. |
- Biggar, Robert J, et al.
(författare)
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Digoxin use and the risk of breast cancer in women
- 2011
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 29:16, s. 2165-2170
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Digoxin resembles estrogen chemically and may have estrogenic effect. We hypothesized that digoxin use might increase breast cancer incidence and examined if use might be associated with risk of breast cancer, categorized by estrogen receptor (ER) status. To determine if being under care for heart disease biased the findings, rate ratios in users of angina drugs were similarly evaluated as a control exposure group. PATIENTS AND METHODS Women using digoxin and angina drugs were identified in the nationwide Danish Prescription Database, available between 1995 and 2008. Incident breast cancers were identified in the Danish Cancer Registry and further classifying by ER status. Relative risks (RR) were compared to nonusers using age- and period-adjusted incidence rate ratios. RESULTS Two thousand one hundred forty-four of 104,648 women using digoxin developed breast cancer. Current digoxin users were at increased risk of breast cancer (RR, 1.39; 95% CI, 1.32 to 1.46), but risk was not increased in former users (RR, 0.91; 95% CI, 0.83 to 1.00). The increased risks in digoxin users were marginally higher for ER-positive breast cancers (RR, 1.35; 95% CI, 1.26 to 1.45) and ER unknown breast cancers (RR, 1.51; 95% CI, 1.38 to 1.64) than for ER-negative breast cancers (RR, 1.20; 95% CI, 1.03 to 1.40). Among 137,493 women exposed to angina drugs only (a comparison group with cardiovascular disease; n = 2,658 breast cancers), incidence was not increased in current or former users. CONCLUSION Women currently using digoxin had a significantly increased risk of breast cancer. Risk normalized when digoxin was stopped. No risk increases were observed in women using angina drugs only. The higher risk of developing ER-positive breast cancers supports an estrogen-mimicking mechanism.
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| 20. |
- Biggar, Robert J., et al.
(författare)
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Immunoglobulin subclass levels in patients with non-Hodgkin lymphoma
- 2009
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124:11, s. 2616-20
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Tidskriftsartikel (refereegranskat)abstract
- Allergy/atopy has been suggested to protect against non-Hodgkin lymphoma (NHL) and specific IgE levels are decreased in patients with NHL. We speculated that all immunoglobulin subclass levels might be downregulated in NHL and examined levels of IgM, IgD, IgA, IgE, IgG and IgG(4) in 200 NHL patients and 200 age- and sex-matched controls. Patients with B-cell NHL of many types had consistently lower median immunoglobulin subclass levels than controls. In every subclass except IgD, about 10-15% of B-cell NHL patients had absolute levels below the 2.5 percentile of controls. Subclass levels correlated with each other and many patients had more than one significantly low level. Levels were lowest for IgG(4) and IgE. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma had especially low total IgE levels. In other B-cell NHL types, total IgE levels were decreased to a similar extent as other immunoglobulin subclasses. In conclusion, low IgE levels are only part of a more generalized loss of immunoglobulins of all subtypes in a wide variety of B-cell NHL types. Low immunoglobulin levels appear to be a consequence of B-cell NHL presence, and we speculate about molecular mechanisms that could reduce all immunoglobulin subclasses in B-cell NHL.
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| 21. |
- Biggar, Robert J., et al.
(författare)
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Serum YKL-40 and interleukin 6 levels in Hodgkin lymphoma
- 2008
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 14:21, s. 6974-8
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Serum levels of the inflammatory markers YKL-40 and interleukin 6 (IL-6) are increased in many conditions, including cancers. We examined serum YKL-40 and IL-6 levels in patients with Hodgkin lymphoma, a tumor with strong immunologic reaction to relatively few tumor cells, especially in nodular sclerosis Hodgkin lymphoma. EXPERIMENTAL DESIGN: We analyzed Danish and Swedish patients with incident Hodgkin lymphoma (N=470) and population controls from Denmark (n=245 for YKL-40; n=348 for IL-6). Serum YKL-40 and IL-6 levels were determined by ELISA, and log-transformed data were analyzed by linear regression, adjusting for age and sex. RESULTS: Serum levels of YKL-40 and IL-6 increased in Hodgkin lymphoma patients compared with controls (YKL-40, 3.6-fold; IL-6, 8.3-fold; both, P<0.0001). In pretreatment samples from pretreatment Hodgkin lymphoma patients (n=176), levels were correlated with more advanced stages (P(trend), 0.0001 for YKL-40 and 0.013 for IL-6) and in those with B symptoms; however, levels were similar in nodular sclerosis and mixed cellularity subtypes, by EBV status, and in younger (<45 years old) and older patients. Patients tested soon after treatment onset had significantly lower levels than pretreatment patients; however, even >or=6 months after treatment onset, serum YKL-40 and IL-6 levels remained significantly increased compared with controls. In patients who died (n=12), pretreatment levels for YKL-40 and IL-6 were higher than in survivors, although not statistically significantly. CONCLUSIONS: Serum YKL-40 and IL-6 levels were increased in untreated Hodgkin lymphoma patients and those with more advanced stages but did not differ significantly by Hodgkin lymphoma histology. Following treatment, serum levels were significantly lower.
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| 22. |
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| 23. |
- Cerhan, James R., et al.
(författare)
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Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:11, s. 1233-1238
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Tidskriftsartikel (refereegranskat)abstract
- Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 x 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 x 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 x 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 x 10(-13) and 3.63 x 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
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| 24. |
- Chang, Ellen T., et al.
(författare)
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Alcohol intake and risk of non-Hodgkin lymphoma in men and women
- 2004
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Ingår i: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 0957-5243 .- 1573-7225. ; 15:10, s. 1067-1076
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- OBJECTIVE: The effect of alcohol intake on risk of NHL is unclear. We therefore conducted a population-based case-control study to examine the association between alcohol and NHL risk. METHODS: 613 NHL cases and 480 population controls in Sweden reported their average consumption of beer, wine, and liquor 2 years before the study. Unconditional logistic regression was used to estimate the odds ratios (OR) and corresponding 95% confidence intervals (CI) for associations between alcohol intake and NHL risk. RESULTS: Intake of total alcohol, beer, wine, or liquor was not associated with risk of overall NHL. There was no difference in risk of NHL among those who habitually consumed above 19.1 g of ethanol per day, compared to those who consumed on average 0-2.2 g of ethanol per day (OR = 1.2 (95% CI: 0.8, 1.7); Ptrend = 0.29). However, the association was significantly positive among males (OR = 1.8 (95% CI: 1.1, 2.9); Ptrend = 0.06). Total alcohol, beer, wine, or liquor intake was not associated with any major histopathologic subtype of NHL examined, apart from an association between high wine consumption and increased risk of chronic lymphocytic leukemia. CONCLUSIONS: Alcohol does not appear to be a major etiologic factor for overall NHL, nor its common subtypes.
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| 25. |
- Chang, Ellen T., et al.
(författare)
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Body mass index and risk of malignant lymphoma in Scandinavian men and women
- 2005
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 97:3, s. 210-218
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The incidence of non-Hodgkin lymphoma and prevalence of obesity are increasing globally. A suggested positive association between obesity and risk of non-Hodgkin lymphoma has prompted us to investigate the relationship between body mass index (BMI) and risk of malignant lymphoma subtypes in a population-based case-control study. METHODS: Telephone interviews were conducted with 3055 case patients with non-Hodgkin lymphoma and 618 case patients with Hodgkin lymphoma diagnosed between October 1, 1999, and August 30, 2002, and 3187 population-based control subjects. The interviews assessed current height, normal adult weight, and other possible risk factors. Multivariable odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for risk of lymphoma were estimated by unconditional logistic regression. All statistical tests were two-sided. RESULTS: BMI was not associated with risk of overall non-Hodgkin lymphoma or of Hodgkin lymphoma (for example, comparing the highly obese group [BMI > or =35.0 kg/m2] with the normal-weight group [BMI = 18.5-24.9 kg/m2], OR for risk of non-Hodgkin lymphoma = 0.9, 95% CI = 0.6 to 1.3; P(trend) across all categories of BMI = .27). BMI was also not associated with risk of any non-Hodgkin lymphoma subtype evaluated, although there was some evidence of a positive association with risk of diffuse large B-cell lymphoma (for example, comparing the highly obese group with the normal-weight group, OR for diffuse large B-cell lymphoma = 1.5, 95% CI = 0.9 to 2.4; P(trend) =.05). CONCLUSIONS: Excess weight does not appear to be associated with an increased risk of malignant lymphoma in general, or with a risk of most major lymphoma subtypes. Hence, the growing incidence of obesity is unlikely to be an important contributor to the increasing incidence of non-Hodgkin lymphoma worldwide.
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