Malene L. Børresen

Classification of Hepatitis B Virus Genotype B into 2 Major Types Based on Characterization of a Novel Subgenotype in Arctic Indigenous Populations

Hepatitis B virus genotype B (HBV/B) has been classified into 5 subgenotypes. Except for Bj/B1 in Japan, the subgenotypes (Ba/B2-B5) have undergone recombination with HBV/C in the core promoter/precore/core genomic region. Phylogenetic analyses of complete sequences show that the Arctic strains belong to a novel subgenotype (HBV/B6) without the recombination, analogous to what is seen with Bj/B1. Comparison of 50 HBV/B6 carriers from the Arctic versus 50 Bj and 50 Ba age- and sex-matched carriers from Asia revealed that clinical characteristics of HBV/B6 carriers were similar to those of Bj/B1 carriers in Japan. The results suggest that HBV/B may be classified into nonrecombinant (Bj/B1 and B6) and recombinant (Ba/B2-B5) types.

Hepatitis D outbreak among children in a hepatitis B hyper‐endemic settlement in Greenland

Summary.  Hepatitis B virus (HBV) infection is endemic in Greenland with 5–10% of the population being HBsAg‐positive (chronic carriers). Surprisingly, despite of the high prevalence of HBV infection, acute and chronic hepatitis B, liver cirrhosis and primary hepatocellular carcinoma appear much less frequently than expected. The reasons for the low frequencies are unknown, but as a consequence implementation of a childhood HBV vaccination programme, though debated for years, has never been instituted. We describe an outbreak of hepatitis D (HDV) infection among children in a hepatitis B hyper‐endemic settlement of 133 inhabitants on the west coast of Greenland. In 2006 a total of 27% of the inhabitants were HBsAg‐positive (chronic carriers) and 83% were HBcAb‐positive (previously exposed). Forty‐six percent of the HBsAg‐positive persons were below 20 years of age. On follow‐up 1 year later a total of 68% of the HBsAg‐positive persons were HDV‐IgG positive. Five children, who were HBsAg‐positive in 2006, had HDV‐seroconverted from 2006 to 2007, indicating a HDV‐super‐infection. Most of the HDV‐IgG positive children had markedly elevated liver enzymes. In the multivariate analysis, among the HBV and HDV markers, presence of HDV‐IgG was most strongly associated with elevation of liver enzymes. In conclusion, the HBV‐HDV super‐infection and presumed HDV outbreak in this settlement challenges the notion that HBV infection may not be as harmless in Greenland as previously anticipated. The findings strongly suggest that HBV vaccination should be included in the child‐immunization program in Greenland.

Estimating Glomerular Filtration Rate Using the New CKD-EPI Equation and Other Equations in Patients with Autosomal Dominant Polycystic Kidney Disease

Background: No studies have compared the performance of equations for estimating glomerular filtration rate (GFR) in patients with autosomal dominant polycystic kidney disease (ADPKD), where the declining GFR typically is followed for many years or even decades. This was the purpose of the present investigation. Methods: 101 ADPKD patients with chronic kidney disease stages 1–5 were recruited and GFR was measured with the 51Cr-EDTA clearance method, and estimated with the Modification of Diet in Renal Disease Study (MDRD) equation with 4 variables, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Cockcroft-Gault equation adjusted for body surface area and the MDRD equation with cystatin C. Performance was evaluated by mean bias, precision and accuracy. Results: The MDRD equation with cystatin C had 97% of GFR estimates within 30% of measured GFR (accuracy). Both the CKD-EPI and Cockcroft-Gault equations had an accuracy of 90% whereas the MDRD equation had an accuracy of 83%. This difference of accuracy was especially marked with GFR >60 ml/min/1.73 m2. Conclusion: For estimating GFR in ADPKD patients the MDRD equation with cystatin C incorporated had the best performance. The CKD-EPI or the Cockcroft-Gault equations showed better performance compared to the 4-variable MDRD equation.

Climate change and infectious diseases in the Arctic: establishment of a circumpolar working group.

The Arctic, even more so than other parts of the world, has warmed substantially over the past few decades. Temperature and humidity influence the rate of development, survival and reproduction of pathogens and thus the incidence and prevalence of many infectious diseases. Higher temperatures may also allow infected host species to survive winters in larger numbers, increase the population size and expand their habitat range. The impact of these changes on human disease in the Arctic has not been fully evaluated. There is concern that climate change may shift the geographic and temporal distribution of a range of infectious diseases. Many infectious diseases are climate sensitive, where their emergence in a region is dependent on climate-related ecological changes. Most are zoonotic diseases, and can be spread between humans and animals by arthropod vectors, water, soil, wild or domestic animals. Potentially climate-sensitive zoonotic pathogens of circumpolar concern include Brucella spp., Toxoplasma gondii, Trichinella spp., Clostridium botulinum, Francisella tularensis, Borrelia burgdorferi, Bacillus anthracis, Echinococcus spp., Leptospira spp., Giardia spp., Cryptosporida spp., Coxiella burnetti, rabies virus, West Nile virus, Hantaviruses, and tick-borne encephalitis viruses.

Genetic diversity of hepatitis B virus genotypes B6, D and F among circumpolar indigenous individuals.

Summary.  Hepatitis B virus (HBV) infection is highly prevalent in circumpolar indigenous peoples. However, the clinical outcome is extremely variable, such that while hepatocellular carcinoma (HCC) is uncommon in Canadian Inuit, the incidence of HCC is slightly higher in Greenlanders than in Danes, and it is especially high in Alaskan Native people infected with HBV genotypes F (HBV/F) and C (HBV/C). These differences may be associated with the genomic variability of the predominant HBV genotype in each group. The purpose of this study was to determine the rate, nature and regional susceptibility of HBV genomic mutations among circumpolar indigenous individuals. Paired serum samples, separated by 5–6 years, were analysed from Canadian and Greenlandic Inuit infected with HBV genotype B6 (HBV/B6) and HBV/D, respectively, and from Alaskan Native people infected with HBV/F, each having subsequently developed HCC. Phylogenetic and mutational analyses were performed on full‐genome sequences, and the dynamic evolution within the quasispecies population of each patient group was determined by clonal analysis of the non‐overlapping core coding region. Mutations associated with severe outcomes predominated in HBV/F, mostly within the precore/core and PreS1 region. HBV/B6 genomes exhibited higher diversity compared to HBV/D and HBV/F, particularly within the core coding region. Thus, differing mutational profiles and genetic variability were observed among different HBV genotypes predominating in circumpolar indigenous patients. The unusual observation of persistently high genetic variability with HBV/B6 despite clinical inactivity could be due to the evolution of a host‐pathogen balance, but other possible factors also need to be explored.

Hepatocellular Carcinoma and Other Liver Disease Among Greenlanders Chronically Infected with Hepatitis B Virus: A Population-Based Study

BACKGROUND In Greenland, the prevalence of hepatitis B surface antigen carriers, reflecting chronic hepatitis B virus (HBV) infection, is 5%-10%. However, the incidence of cirrhosis and hepatocellular carcinoma in this population has been reported to be low. We investigated this discrepancy in a large population-based cohort study. METHODS In total, 8879 Greenlanders (16% of the population) were recruited for population-based surveys performed from May 5 to July 7, 1987, and from November 1 to November 21, 1998, with follow-up until March 31, 2010. HBV status was based on serological testing, supplemented by data from all available HBV registries in Greenland to determine changes in HBV status over time. Information on morbidity and mortality was obtained from the Patient Discharge Registry, the Cancer Registry, and the Central Registration System. Sex, age, ethnicity, and period-adjusted incidence rate ratios (IRRs) were estimated using Poisson regression. World standardized rates were derived from these and World Health Organization data. RESULTS The 650 chronically HBV-infected persons had higher rates of hepatocellular carcinoma (adjusted IRR = 8.70; 95% CI = 2.06 to 36.7), liver disease (adjusted IRR = 5.73, 95% CI = 3.52 to 9.34), and all-cause mortality (adjusted IRR = 1.47; 95% CI = 1.21 to 1.79) than the 5160 HBV-negative persons. However, the world standardized incidence rates of hepatocellular carcinoma (38.5 cancers per 100 000 person-years) and cirrhosis (24 cases per 100 000 person-years) among chronically HBV-infected persons were low compared with results from population-based studies from countries with low, intermediate, and high rates of endemic HBV infection. CONCLUSION The relatively low incidence of hepatocellular carcinoma and other HBV-related morbidity among chronic HBV-infected persons in Greenland suggest a more benign course of HBV among the Greenlandic Inuit than in populations in other parts of the world.

Effectiveness of the Targeted Hepatitis B Vaccination Program in Greenland

OBJECTIVES To evaluate the effectiveness of the hepatitis B virus (HBV) vaccination program in Greenland, which targets children born to mothers who are positive for HBV surface antigen (HBsAg), we determined vaccination coverage, levels of postvaccination antibodies, and frequency of breakthrough infections in at-risk children. METHODS We conducted a population-based retrospective cohort study with data from nationwide registries. We identified all children born to HBsAg-positive mothers from 1992 to 2007 and collected data on their HBV vaccination status. In 2008 to 2010, we tested the children for HBV core antibody, HBsAg, and anti-HBsAg antibody (HBsAb). RESULTS Of 4050 pregnant women, 3.2% were HBsAg positive. Of 207 children born to these women, 20% received no vaccinations, and only 58% received at least 3 vaccinations. At follow-up, HBsAb levels in vaccinated children were much lower than expected, and 8 (6%) of 140 at-risk children had breakthrough infections, with 4 chronically infected (persistently HBsAg positive). CONCLUSIONS The prevention program targeting children at risk for HBV in Greenland is ineffective. HBV vaccination should be included in the universal childhood vaccination program, and postvaccination HBsAb levels should be monitored.

Cytokine responses in relation to age, gender, body mass index, Mycobacterium tuberculosis infection, and otitis media among Inuit in Greenland

To evaluate the cytokine response pattern in Inuit in Greenland in relation to age, gender, body mass index (BMI), Mycobacterium tuberculosis infection (MTI), and otitis media (OM) to assess whether Inuit may have signs of impaired immune responsiveness to infection.

Nasopharyngeal bacterial carriage in young children in Greenland: a population at high risk of respiratory infections

The incidence of childhood respiratory infections in Greenland is among the highest globally. We performed a population-based study of 352 Greenlandic children aged 0-6 years aiming to describe rates and risk factors for carriage of four key bacteria associated with respiratory infections, their antimicrobial susceptibility and inter-bacterial associations. Nasopharyngeal swabs were tested for Streptococcus pneumoniae grouped by serotypes included (VT) or not included (NVT) in the 13-valent pneumococcal conjugate vaccine, non-typable Haemophilus influenzae (NTHi), Staphylococcus aureus and Moraxella catarrhalis. S. pneumoniae was detected from age 2 weeks with a peak carriage rate of 60% in 2-year-olds. Young age and having siblings attending a daycare institution were associated with pneumococcal carriage. Overall co-colonization with ⩾2 of the studied bacteria was 52%. NTHi showed a positive association with NVT pneumococci and M. catarrhalis, respectively, M. catarrhalis was positively associated with S. pneumoniae, particular VT pneumococci, whereas S. aureus were negatively associated with NTHi and M. catarrhalis. Nasopharyngeal bacterial carriage was present unusually early in life and with frequent co-colonization. Domestic crowding increased odds of carriage. Due to important bacterial associations we suggest future surveillance of pneumococcal conjugate vaccines impact on carriage in Greenland to also include other pathogens.

CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders

Background— Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders. Methods and Results— Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in CPT1A, was strongly associated with markers of n-3 fatty acid metabolism, including degree of unsaturation (P=1.16×10−34), levels of polyunsaturated fatty acids, n-3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels (P=2.35×10−15, P=4.02×10−19, and P=7.92×10−27). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm (P=1.04×10−9). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779. Conclusion— Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations.