Caroline Dickens

APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans

APOL1 variants are associated with HIV-associated nephropathy and FSGS in African Americans. The prevalence of these variants in African populations with CKD in HIV-1 infection has not been investigated. We determined the role of APOL1 variants in 120 patients with HIV-associated nephropathy and CKD and 108 controls from a South-African black population. Patients with CKD were selected on the basis of histology. Genotypes were successfully determined for APOL1 G1 and G2 variants and 42 single nucleotide polymorphisms, including 18 ancestry informative markers, for 116 patients with CKD (96.7%; 38 patients with HIV-associated nephropathy, 39 patients with HIV-positive CKD, and 39 patients with HIV-negative CKD), and 108 controls (100%). Overall, 79% of patients with HIV-associated nephropathy and 2% of population controls carried two risk alleles. In a recessive model, individuals carrying any combination of two APOL1 risk alleles had 89-fold higher odds (95% confidence interval, 18 to 912; P<0.001) of developing HIV-associated nephropathy compared with HIV-positive controls. Population allele frequencies were 7.3% for G1 and 11.1% for G2. APOL1 risk alleles were not significantly associated with other forms of CKD. These results indicate HIV-positive, antiretroviral therapy-naïve South-African blacks with two APOL1 risk alleles are at very high risk for developing HIV-associated nephropathy. Further studies are required to determine the effect of APOL1 risk variants on kidney diseases in other regions of sub-Saharan Africa.

Hepatitis B virus transmission by blood transfusion during 4 years of individual-donation nucleic acid testing in South Africa: estimated and observed window period risk

BACKGROUND: Since October 2005, a total of 2,921,561 blood donations have been screened by the South African National Blood Service for hepatitis B virus (HBV) by individual‐donation nucleic acid testing (ID‐NAT). Over 4 years, 149 hepatitis B surface antigen–negative acute‐phase HBV NAT–positive donations were identified (1:19,608). The lookback program identified one probable HBV transmission.

Stage at breast cancer diagnosis and distance from diagnostic hospital in a periurban setting: a South African public hospital case series of over 1,000 women.

Advanced stage at diagnosis contributes to low breast cancer survival rates in sub‐Saharan Africa. Living far from health services is known to delay presentation, but the effect of residential distance to hospital, the radius at which this effect sets in and the women most affected have not been quantified. In a periurban South African setting, we examined the effect of a geographic information system (GIS)‐measured straight‐line distance, from a patients residence to diagnostic hospital, on stage at diagnosis in 1,071 public‐sector breast cancer patients diagnosed during 2006–2012. Generalized linear models were used to estimate risk ratios for late stage (stage III/IV vs. stage I/II) associated with distance, adjusting for year of diagnosis, age, race and socioeconomic indicators. Mean age of patients was 55 years, 90% were black African and diagnoses were at stages I (5%), II (41%), III (46%) and IV (8%). Sixty‐two percent of patients with distances >20 km (n = 338) had a late stage at diagnosis compared to 50% with distances <20 km (n = 713, p = 0.02). Risk of late stage at diagnosis was 1.25‐fold higher (95% CI: 1.09, 1.42) per 30 km. Effects were pronounced in an underrepresented group of patients over age 70. This positive stage–distance association held to 40 km, and plateaued or slightly reversed in patients (9%) living beyond this distance. Studies of woman and the societal and healthcare‐level influences on these delays and on the late stage at diagnosis distribution are needed to inform interventions to improve diagnostic stage and breast cancer survival in this and similar settings.

Calcium ions and osteoclastogenesis initiate the induction of bone formation by coral-derived macroporous constructs.

Coral‐derived calcium carbonate/hydroxyapatite macroporous constructs of the genus Goniopora with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) initiate the induction of bone formation. Which are the molecular signals that initiate pattern formation and the induction of bone formation? To evaluate the role of released calcium ions and osteoclastogenesis, 7% HA/CC was pre‐loaded with either 500 μg of the calcium channel blocker, verapamil hydrochloride, or 240 μg of the osteoclast inhibitor, biphosphonate zoledronate, and implanted in the rectus abdominis muscle of six adult Chacma baboons Papio ursinus. Generated tissues on days 15, 60 and 90 were analysed by histomorphometry and qRT‐PCR. On day 15, up‐regulation of type IV collagen characterized all the implanted constructs correlating with vascular invasion. Zoledronate‐treated specimens showed an important delay in tissue patterning and morphogenesis with limited bone formation. Osteoclastic inhibition yielded minimal, if any, bone formation by induction. 7% HA/CC pre‐loaded with the Ca++ channel blocker verapamil hydrochloride strongly inhibited the induction of bone formation. Down‐regulation of bone morphogenetic protein‐2 (BMP‐2) together with up‐regulation of Noggin genes correlated with limited bone formation in 7% HA/CC pre‐loaded with either verapamil or zoledronate, indicating that the induction of bone formation by coral‐derived macroporous constructs is via the BMPs pathway. The spontaneous induction of bone formation is initiated by a local peak of Ca++ activating stem cell differentiation and the induction of bone formation.

Racial Comparison of Receptor-Defined Breast Cancer in Southern African Women: Subtype Prevalence and Age–Incidence Analysis of Nationwide Cancer Registry Data

Background: Receptor-defined breast cancer proportions vary across Africa. They have important implications for survival prospects and research priorities. Methods: We studied estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor statuses in two multiracial Southern African countries with routine diagnostic immunohistochemistry. A total of 12,361 women with histologically confirmed breast cancer diagnosed at age ≥20 years during (i) 2009–2011 from South Africas national cancer registry (public sector) and (ii) 2011–2013 from Namibias only cancer hospital were included. Crude, age, and age + laboratory–adjusted ORs of receptor status were analyzed using logistic regression, and age–incidence curves were analyzed using Poisson regression. Results: A total of 10,047 (81%) women had known ER status. Ranking of subtypes was consistent across races: ER+/PR+HER2− was most common (race-specific percentage range, 54.6%–64.8%), followed by triple-negative (17.4%–21.9%), ER+/PR+HER2+ (9.6%–13.9%), and ER−PR−HER2+ (7.8%–10.9%). Percentages in black versus white women were 33.8% [95% confidence (CI), 32.5–35.0] versus 26.0% (24.0–27.9) ER−; 20.9% (19.7–22.1) versus 17.5% (15.4–19.6) triple-negative; and 10.7% (9.8–11.6) versus 7.8% (6.3–9.3) ER−PR−HER2+. Indian/Asian and mixed-ancestry women had intermediate values. Age–incidence curves had similar shapes across races: rates increased by 12.7% per year (12.2–13.1) across ER subtypes under the age of 50 years, and thereafter slowed for ER+ (1.95%) and plateaued for ER− disease (−0.1%). Conclusions: ER+ breast cancer dominates in all Southern African races, but black women have a modest excess of aggressive subtypes. Impact: On the basis of the predominant receptor-defined breast tumors in Southern Africa, improving survival for the growing breast cancer burden should be achievable through earlier diagnosis and appropriate treatment. Cancer Epidemiol Biomarkers Prev; 23(11); 2311–21. ©2014 AACR.

First report of genotype e of hepatitis B virus in an Indian population.

Twenty-one hepatitis B virus (HBV) isolates from the state of Haryana (North India) were studied for genotype, subgenotype, serotype distribution and precore mutations. Assays of alanine aminotransminase (ALT) and HBeAg were performed on all samples. Genotypes, subgenotypes and serotypes were determined by amplification of pre-S1/S2 regions followed by RFLP and also by phylogenetic analysis of amplified products. Mutations were studied by amplification and sequencing of the precore region. Twenty-four percent of the samples had high ALT levels and 90% were HBeAg negative. It was observed that 90% of the samples were HBV D genotype, (subgenotype D1, serotype ayw2), 5% HBV A genotype (subgenotype A1, serotype adw2), and the remaining 5% were HBV E genotype (serotype ayw4). The subgenotype A1 was quite similar to the South African isolates. Phylogenetic analysis of the HBV isolates, based on the pre-S1/S2 gene sequences, confirmed genotype E. Amplification and sequencing of the precore region showed 1762A–T and 1764G–A mutations in 38 and 15% of the samples, respectively. 1809T was observed in 5% of the cases under study. This is the first report of the genotype E of hepatitis B virus in the Indian population. Efforts are underway to amplify and sequence the full length of this genotype E isolate.

Childhood cancer incidence patterns by race, sex and age for 2000-2006: a report from the South African National Cancer Registry.

Higher childhood cancer incidence rates are generally reported for high income countries although high quality information on descriptive patterns of childhood cancer incidence for low or middle income countries is limited, particularly in Sub‐Saharan Africa. There is a need to quantify global differences by cancer types, and to investigate whether they reflect true incidence differences or can be attributed to under‐diagnosis or under‐reporting. For the first time, we describe childhood cancer data reported to the pathology report‐based National Cancer Registry of South Africa in 2000–2006 and compare our results to incidence data from Germany, a high income country. The overall age‐standardized incidence rate (ASR) for South Africa in 2000–2006 was 45.7 per million children. We observed substantial differences by cancer types within South Africa by racial group; ASRs tended to be 3–4‐fold higher in South African Whites compared to Blacks. ASRs among both Black and White South Africans were generally lower than those from Germany with the greatest differences observed between the Black population in South Africa and Germany, although there was marked variation between cancer types. Age‐specific rates were particularly low comparing South African Whites and Blacks with German infants. Overall, patterns across South African population groups and in comparison to Germans were similar for boys and girls. Genetic and environmental reasons may probably explain rather a small proportion of the observed differences. More research is needed to understand the extent to which under‐ascertainment and under‐diagnosis of childhood cancers drives differences in observed rates.

Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide

Background Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. Methods and findings We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35–85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (–0.46 cm [95% CI: −0.53, −0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was −0.24 cm (95% CI: −0.34, −0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (−0.38 cm [95% CI: −0.44, −0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. Conclusions Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

International Consortium on Mammographic Density: Methodology and population diversity captured across 22 countries.

Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses.

Occult Hepatitis B Virus infection in Chacma baboons, South Africa

During previous studies of susceptibility to hepatitis B virus (HBV) infection, HBV DNA was detected in 2/6 wild-caught baboons. In the present study, HBV DNA was amplified from 15/69 wild-caught baboons. All animals were negative for HBV surface antigen and antibody against HBV core antigen. Liver tissue from 1 baboon was immunohistochemically negative for HBV surface antigen but positive for HBV core antigen. The complete HBV genome of an isolate from this liver clustered with subgenotype A2. Reverse transcription PCR of liver RNA amplified virus precore and surface protein genes, indicating replication of virus in baboon liver tissue. Four experimentally naive baboons were injected with serum from HBV DNA–positive baboons. These 4 baboons showed transient seroconversion, and HBV DNA was amplified from serum at various times after infection. The presence of HBV DNA at relatively low levels and in the absence of serologic markers in the baboon, a nonhuman primate, indicates an occult infection.