Clement Adebamowo

Integrating common and rare genetic variation in diverse human populations.

Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called ‘HapMap 3’, includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of ≤5%, and demonstrated the feasibility of imputing newly discovered CNPs and SNPs. This expanded public resource of genome variants in global populations supports deeper interrogation of genomic variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.

Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 × 10−12 for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

Non-communicable diseases in sub-Saharan Africa: what we know now

BACKGROUND Sub-Saharan Africa (SSA) has a disproportionate burden of both infectious and chronic diseases compared with other world regions. Current disease estimates for SSA are based on sparse data, but projections indicate increases in non-communicable diseases (NCDs) caused by demographic and epidemiologic transitions. We review the literature on NCDs in SSA and summarize data from the World Health Organization and International Agency for Research on Cancer on the prevalence and incidence of cardiovascular diseases, diabetes mellitus Type 2, cancer and their risk factors. METHODS We searched the PubMed database for studies on each condition, and included those that were community based, conducted in any SSA country and reported on disease or risk factor prevalence, incidence or mortality. RESULTS We found few community-based studies and some countries (such as South Africa) were over-represented. The prevalence of NCDs and risk factors varied considerably between countries, urban/rural location and other sub-populations. The prevalence of stroke ranged from 0.07 to 0.3%, diabetes mellitus from 0 to 16%, hypertension from 6 to 48%, obesity from 0.4 to 43% and current smoking from 0.4 to 71%. Hypertension prevalence was consistently similar among men and women, whereas women were more frequently obese and men were more frequently current smokers. CONCLUSIONS The prevalence of NCDs and their risk factors is high in some SSA settings. With the lack of vital statistics systems, epidemiologic studies with a variety of designs (cross-sectional, longitudinal and interventional) capable of in-depth analyses of risk factors could provide a better understanding of NCDs in SSA, and inform health-care policy to mitigate the oncoming NCD epidemic.

Milk consumption and acne in teenaged boys

OBJECTIVE We sought to examine the association between dietary dairy intake and teenaged acne among boys. METHODS This was a prospective cohort study. We studied 4273 boys, members of a prospective cohort study of youths and of lifestyle factors, who reported dietary intake on up to 3 food frequency questionnaires from 1996 to 1998 and teenaged acne in 1999. We computed multivariate prevalence ratios and 95% confidence intervals for acne. RESULTS After adjusting for age at baseline, height, and energy intake, the multivariate prevalence ratios (95% confidence interval; P value for test of trend) for acne comparing highest (>2 servings/d) with lowest (<1/wk) intake categories in 1996 were 1.16 (1.01, 1.34; 0.77) for total milk, 1.10 (0.94, 1.28; 0.83) for whole/2% milk, 1.17 (0.99, 1.39; 0.08) for low-fat (1%) milk, and 1.19 (1.01, 1.40; 0.02) for skim milk. LIMITATIONS Not all members of the cohort responded to the questionnaire. Acne assessment was by self-report and boys whose symptoms might have been part of an underlying disorder were not excluded. We did not adjust for steroid use and other lifestyle factors that may affect occurrence of acne. CONCLUSION We found a positive association between intake of skim milk and acne. This finding suggests that skim milk contains hormonal constituents, or factors that influence endogenous hormones, in sufficient quantities to have biological effects in consumers.

Optimisation of breast cancer management in low-resource and middle-resource countries: executive summary of the Breast Health Global Initiative consensus, 2010

The purpose of the Breast Health Global Initiative (BHGI) 2010 summit was to provide a consensus analysis of breast cancer control issues and implementation strategies for low-income and middle-income countries (LMCs), where advanced stages at presentation and poor diagnostic and treatment capacities contribute to lower breast cancer survival rates than in high-income countries. Health system and patient-related barriers were identified that create common clinical scenarios in which women do not present for diagnosis until their cancer has progressed to locally advanced or metastatic stages. As countries progress to higher economic status, the rate of late presentation is expected to decrease, and diagnostic and treatment resources are expected to improve. Health-care systems in LMCs share many challenges including national or regional data collection, programme infrastructure and capacity (including appropriate equipment and drug acquisitions, and professional training and accreditation), the need for qualitative and quantitative research to support decision making, and strategies to improve patient access and compliance as well as public, health-care professional, and policy-maker awareness that breast cancer is a cost-effective, treatable disease. The biggest challenges identified for low-income countries were little community awareness that breast cancer is treatable, inadequate advanced pathology services for diagnosis and staging, and fragmented treatment options, especially for the administration of radiotherapy and the full range of systemic treatments. The biggest challenges identified for middle-resource countries were the establishment and maintenance of data registries, the coordination of multidisciplinary centres of excellence with broad outreach programmes to provide community access to cancer diagnosis and treatment, and the resource-appropriate prioritisation of breast cancer control programmes within the framework of existing, functional health-care systems.

Dietary flavonols and flavonol-rich foods intake and the risk of breast cancer

Laboratory and animal studies suggest that dietary flavonols may reduce breast cancer risk but there are limited epidemiological studies. We computed flavonol intakes from dietary data collected by validated food frequency questionnaires in 1991 and 1995 from 90,630 women in the Nurses Health Study II. Using multivariate relative risks (RR) and 95% confidence intervals (95% CI), we evaluated the association of flavonol intake with breast cancer risk in women who were premenopausal and aged between 26 and 46 years at baseline in 1991. During 8 years of follow‐up, we documented 710 cases of invasive breast cancer. The multivariate RR (95% CI), comparing highest to lowest quintiles of cumulative average intake, was 1.05 (0.83, 1.34; p‐value for test of trend = 0.96) for the sum of flavonols and there were no associations seen between individual flavonols such as kaempferol, quercetin and myricetin and breast cancer risk. The multivariate RR (95% CI), comparing highest to lowest quintiles of cumulative average intake, was 0.94 (0.72, 1.22; p‐value for test of trend = 0.54) for sum of flavonol‐rich foods. Among the major food sources of flavonols, we found a significant inverse association with intake of beans or lentils but not with tea, onions, apples, string beans, broccoli, green pepper and blueberries. The multivariate RR (95% CI), comparing the highest category (2 or more times a week) of cumulative average beans or lentils intake with the lowest category (less than once a month), was 0.76 (0.57, 1.00; p‐value for test of trend = 0.03). While we found no overall association between intake of flavonols and risk of breast cancer, there was an inverse association with intake of beans or lentils that merits further evaluation.

Polymorphic variation at the BAT-25 and BAT-26 loci in individuals of African origin. Implications for microsatellite instability testing.

Instability in the repeat size of microsatellite sequences has been described in both hereditary nonpolyposis and sporadic colorectal cancers. Tumors expressing microsatellite instability are identified through the comparison of the repeat sizes at multiple microsatellite loci between tumor and matched normal tissue DNA. The use of a five-marker panel including two mononucleotide repeat microsatellites, BAT-25 and BAT-26, has recently been suggested for the clinical determination of tumor microsatellite instability. The BAT-25 and BAT-26 loci included in this panel have both demonstrated sensitivity to microsatellite instability and normal quasimonomorphic allelic patterns, which has simplified the distinction between normal and unstable alleles. However, in this study, we identified allelic variations in the size of the poly(A) tract at BAT-26 in 12.6% of 103 healthy African-Americans screened. In addition, 18.4% exhibited allelic size variations in the poly(T) tract at BAT-25. Finally, 2.9% showed variant alleles at both BAT-25 and BAT-26 loci. Screening a small population of Nigerians confirmed the polymorphic nature of both loci and the ethnic origin of alleles not identified in other populations studied thus far. Our results dispute the quasimonomorphic nature of both BAT-25 and BAT-26 in all populations and support the need for thorough population studies to define the different allelic profiles and frequencies at microsatellite loci.

Randomised controlled trials for Ebola: practical and ethical issues

2 months ago, when the numbers known to have died from Ebola in west Africa could still be counted in hundreds, WHO made an important statement about investigational drugs and vaccines. This crisis is so acute, WHO declared, that it is ethical to offer interventions with potential benefits but unknown efficacy and side-effects, though every effort should be made to evaluate benefits and risks and share all data generated. The need for drugs and vaccines was urgent then. With cases now rising exponentially and health systems overwhelmed, it is even greater today. Vaccine safety trials are underway in the USA and the UK, and poised to roll out to Africa soon. But treatments for those with infection are required too. Besides playing a direct part in containing the epidemic, interventions that could improve outcomes for the sick would help to rebuild the confidence of affected communities in health services, a critical step if Ebola is to be overcome. A fast-track initiative for evaluating investigational drugs was launched in September, 2014.1 But although the question of whether unproven treatments should be offered at all is now settled, the question of how they should be deployed and tested is not. Still at issue is whether such treatments should be made available only in the context of randomised controlled trials (RCTs) in which patients receive either a new intervention and conventional care, or conventional care alone or with a placebo. Advocates of this RCT approach2 state that as this experimental design will create the most robust evidence for the future, and is what regulators are used to, it is the only approach that should be considered. We disagree. While we concur that RCTs provide robust evidence, and support their use where this is ethical and practical, we do not believe that either consideration is likely to be satisfied in the context of this epidemic. The priority must be to generate data about effectiveness and safety as swiftly as possible, so that the most useful new treatments can be identified for rapid deployment. Alternative trial designs have the potential to do this more quickly, and with greatest social and ethical acceptability. The first objection to RCTs in which investigational drugs plus conventional care are compared purely with conventional care is ethical. Such randomisation is ethical when there is equipoise—when there is genuine uncertainty about whether an untested treatment has benefits or risks that exceed those of conventional care. Equipoise is a useful principle, but it can break down when conventional care offers little benefit and mortality is extremely high. This is precisely the problem with Ebola: current conventional care does not much affect clinical outcomes and mortality is as high as 70%. When conventional care means such a high probability of death, it is problematic to insist on randomising patients to it when the intervention arm holds out at least the possibility of benefit. Ethical arguments are not the same for all levels of risk. No-one insisted that western medical workers offered zMapp and other investigational products were randomised to receive the drug or conventional care plus a placebo. None of us would consent to be randomised in such circumstances. In cancers with a poor prognosis for which there are no good treatments, evidence from studies without a control group can be accepted as sufficient for deployment, and even for licensing by regulators, with fuller analysis following later. There is no need for rules to be bent or corners to be cut: the necessary procedures already exist, and are used. The second objection is practical. Even if randomisation were ethically acceptable, it might not be deliverable in the context of health-care systems, and indeed wider social order, that are breaking down as in Liberia, Guinea, and Sierra Leone. Populations who are terrified by the progress of the epidemic, and who lack trust in health-care and aid workers, and in public authorities in the aftermath of civil wars, cannot be expected to offer informed consent to such randomised trials. It is also unclear that any capacity exists to impose controlled conditions during a raging epidemic. Insisting on RCTs could even worsen the epidemic, by undermining trust in the Ebola treatment centres that are central to containing it. Randomisation is not, moreover, the only way to gather reliable information about the safety and effectiveness of potential Ebola therapies. Indeed, other methods might be more appropriate for achieving the key objective, which is to identify drug regimens that improve outcomes over existing methods of care, quickly, so that WHO can recommend their use and lives can be saved. One viable approach would be to try different treatments in parallel and at different sites, following observational studies that document mortality under standard care. This approach could effectively triage treatments into those with great benefits that should be rolled out immediately, those with no effect that should be discarded quickly, and those with promise needing follow-up in randomised trials. These trials can be designed adaptively, meaning that patient enrolment can be altered as efficacy data emerge, minimising the numbers of individuals who get ineffective treatments and increasing the numbers getting those that show benefits. This is not different from phase 2 studies as currently conducted and accepted by regulatory authorities for other diseases. It will also enable quick follow-up trials of combinations of antivirals and new treatments that have already shown evidence of activity. A different type of RCT might also become an option once more than one drug has shown efficacy—even efficacy in animal models. Then, patients could ethically be randomised to one investigational drug or another. No-one would get only standard care. We accept that RCTs can generate strong evidence in ordinary circumstances; not, however, in the midst of the worst Ebola epidemic in history. The urgent need is to establish whether new investigational drugs offer survival benefits, and thus which, if any, should be recommended by WHO to save lives. We have innovative but proven trial designs for doing exactly that. We should be using them, rather than doggedly insisting on gold standards that were developed for different settings and purposes.

Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor α (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case∶control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2×10−3), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9×10−4) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9×10−7), was without significant heterogeneity between ancestries (Phet = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

Parity and breastfeeding are protective against breast cancer in Nigerian women

As the relation between reproductive factors and breast cancer risk has not been systematically studied in indigenous women of sub-Saharan Africa, we examined this in a case–control study in Nigeria. In-person interviews were conducted using structured questionnaires to collect detailed reproductive history in 819 breast cancer cases and 569 community controls between 1998 and 2006. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI). Compared with women with menarcheal age <17 years, the adjusted OR for women with menarcheal age ⩾17 years was 0.72 (95% CI: 0.54–0.95, P=0.02). Parity was negatively associated with risk (P-trend=0.02) but age at first live birth was not significant (P=0.16). Importantly, breast cancer risk decreased by 7% for every 12 months of breastfeeding (P-trend=0.005). It is worth noting that the distribution of reproductive risk factors changed significantly from early to late birth cohorts in the direction of increasing breast cancer incidence. Our findings also highlight the heterogeneity of breast cancer aetiology across populations, and indicate the need for further studies among indigenous sub-Saharan women.