Klaus Rostgaard

A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 ( REL ), 8q24.21 and 10p14 ( GATA3 )

To identify susceptibility loci for classical Hodgkins lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10−8), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10−13) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10−8). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10−50). These data provide new insight into the pathogenesis of cHL.

Duration of red blood cell storage and survival of transfused patients (CME)

BACKGROUND: Disquieting reports of increased complication and death rates after transfusions of red blood cells (RBCs) stored for more than 14 days prompted us to perform an observational retrospective cohort study of mortality in relation to storage time.

Infectious Mononucleosis, Childhood Social Environment, and Risk of Hodgkin Lymphoma

Infectious mononucleosis (IM) has been associated with an increased risk of Hodgkin lymphoma (HL), implicating a role for Epstein-Barr virus (EBV) in HL development. Although essential to the understanding of the association, it has remained uncertain if the relationship is restricted to the EBV-positive subset of HL. We collected information on mononucleosis history and childhood socioenvironmental characteristics in a population-based study of 586 patients with classic HL and 3,187 controls in Denmark and Sweden. Tumor EBV status was established for 499 cases by immunohistochemistry and in situ hybridization techniques. Odds ratios (OR) for the relationship between HL risk and mononucleosis and other risk factors were estimated by logistic regression for HL in younger (18-44 years) and older (45-74 years) adults, overall and by tumor EBV status. All analyses were adjusted for country-specific measures of maternal education and mononucleosis history. IM was associated with an increased risk of EBV-positive [OR, 3.23; 95% confidence interval (95% CI) 1.89-5.55] but not EBV-negative HL (OR, 1.35; 95% CI, 0.86-2.14). Risk of EBV-positive HL varied with time since IM and was particularly pronounced in younger adults (OR, 3.96; 95% CI, 2.19-7.18). IM-associated lymphomas occurred with a median of 2.9 years (1.8-4.9 years) after infection. The EBV specificity of the IM association was corroborated by a case-case comparison of IM history between younger adult EBV-positive and EBV-negative HL patients (OR(IM EBV+ HL versus EBV- HL), 2.68; 95% CI, 1.40-5.12). We found further evidence that IM is associated only with EBV-positive HL. This finding is compatible with the notion that EBV-positive and EBV-negative HL may have different etiologies.

Cancer risk among patients with multiple sclerosis: A population-based register study

Cancer occurrence in patients with multiple sclerosis (MS) has been little studied, but associations with brain tumours, breast cancer, Hodgkin lymphoma and nasopharyngeal carcinoma have been suggested. We took advantage of population‐based registers of MS and cancer to assess the risk of cancer following diagnosis of MS. Patients registered in the Danish Multiple Sclerosis Register were linked with the Danish Cancer Register to obtain information on cancer occurrence. The ratio of the observed to the number of expected cancers based on population‐based incidence rates, i.e., the standardised incidence ratio (SIR), served as measure of the relative cancer risk. A database comprising all Danish women born after April 1, 1935, with information on all live‐born children, was used in the analyses of breast cancer to adjust for reproductive factors. Overall 1,037 cancers were observed in 11,817 MS patients during 153,875 person‐years of follow‐up vs. an expected number of 1,098 (SIR = 0.94 [95% confidence interval CI: (0.89–1.00)]. The risk of brain tumours and Hodgkin lymphoma was not increased. A 16% overall reduced cancer risk in men with MS was explained by reduced numbers of cancers of the digestive, respiratory and genital organs. Though the overall cancer risk was not increased [SIR = 1.01(0.94–1.09), n = 676], female MS patients had an increased risk of breast cancer [SIR = 1.21 (1.05–1.39), n = 193]. Adjusting for parity and age at first child delivery did not change this risk estimate materially. In general MS patients are not at increased risk of cancer. Women with MS, however, seem to have a small excess risk of breast cancer, which cannot be attributed to reduced parity or delayed first child birth.

Autoimmune disease in patients with multiple sclerosis and their first-degree relatives: a nationwide cohort study in Denmark.

Background Multiple sclerosis (MS) and other autoimmune diseases might cluster. Our aim was to estimate the relative risk (RR) of other autoimmune diseases among MS patients and their first-degree relatives in a population-based cohort study. Methods Using the Danish Multiple Sclerosis Register, the Danish Hospital Discharge Register, and the Danish Civil Registration System, we estimated RRs for 42 different autoimmune diseases in a population-based cohort of 12 403 MS patients and 20 798 of their first-degree relatives. Ratios of observed to expected numbers of autoimmune diseases, based on national sex-, age-, and period-specific incidence rates, served as measures of the RRs. Results Compared with the general population, MS patients were at an increased risk of developing ulcerative colitis (RR = 2.0 (95% confidence interval (CI): 1.4–2.8), n = 29) and pemphigoid (RR = 15.4 (CI: 8.7–27.1), n = 12) but at reduced risk of rheumatoid arthritis (RR = 0.5 (CI: 0.4–0.8), n = 28) and temporal arteritis (RR = 0.5 (CI: 0.3–0.97), n = 11). First-degree relatives of MS patients were at increased risks of Crohn’s disease (RR = 1.4 (CI: 1.04–1.9), n = 44), ulcerative colitis (RR = 1.3 (CI: 0.99–1.7), n = 51), Addison’s disease (RR = 3.4 (CI: 1.3–9.0), n = 4), and polyarteritis nodosa (RR = 3.7 (CI: 1.4–10.0), n = 4). Conclusion Patients with MS and their first-degree relatives seem to be at an increased risk of acquiring certain other autoimmune diseases.

HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma

A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphomas association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60–2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51–0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBV-related HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74–6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL.

Autoimmune diseases in women with Turner's Syndrome

OBJECTIVE In terms of number of X chromosomes, women with Turners syndrome cytogenetically resemble men. An increased risk of autoimmune diseases has been observed among women with Turners syndrome. This study was undertaken to investigate whether the autoimmune disease profile in women with Turners syndrome is characterized by diseases with a female or male predominance. METHODS Using the Danish Cytogenetic Central Register, the Danish National Patient Register, and the Danish Civil Registration System, we estimated relative risk of 46 different autoimmune diseases in a cohort of 798 Danish women with Turners syndrome followed up for 12,461 person-years between 1980 and 2004. Standardized incidence ratios (SIRs) of first hospitalization for autoimmune disease and 95% confidence intervals (95% CIs) were used as measures of relative risk. RESULTS The overall risk of autoimmune disease among women with Turners syndrome was twice that among Danish women in general (SIR 2.1 [95% CI 1.6-2.7]). For autoimmune diseases with a female predominance, the SIR among women with Turners syndrome was 1.7 (95% CI 1.2-2.4), whereas the SIR for autoimmune diseases with a male predominance among these women was 3.9 (95% CI 2.5-5.8). Associations were strongest for Hashimoto thyroiditis (SIR 14.6 [95% CI 6.7-27.1]), a strongly female-predominant condition, and type 1 diabetes mellitus (SIR 4.1 [95% CI 2.5-6.3]). CONCLUSION Women with Turners syndrome are at excess risk of autoimmune diseases, notably autoimmune diseases characterized by male predominance.

Survival after blood transfusion

BACKGROUND: 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.

Post-transfusion mortality among recipients of ABO-compatible but non-identical plasma

Background and Objectives  The consequences of ABO‐compatible non‐identical plasma for patient outcome have not been studied in randomized clinical trials or large cohort studies and use varies widely in the absence of evidence‐based policies. We investigated if transfusion with compatible instead of identical plasma confers any short‐term survival disadvantage on the recipients.

Hepatitis C infection and risk of malignant lymphoma

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.