Fasil Tekola Ayele

HLA Class II Locus and Susceptibility to Podoconiosis

BACKGROUND Podoconiosis is a tropical lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. The World Health Organization recently designated it as a neglected tropical disease. Podoconiosis develops in only a subgroup of exposed people, and studies have shown familial clustering with high heritability (63%). METHODS We conducted a genomewide association study of 194 case patients and 203 controls from southern Ethiopia. Findings were validated by means of family-based association testing in 202 family trios and HLA typing in 94 case patients and 94 controls. RESULTS We found a genomewide significant association of podoconiosis with the single-nucleotide polymorphism (SNP) rs17612858, located 5.8 kb from the HLA-DQA1 locus (in the allelic model: odds ratio, 2.44; 95% confidence interval [CI], 1.82 to 3.26; P=1.42×10(-9); and in the additive model: odds ratio, 2.19; 95% CI, 1.66 to 2.90; P=3.44×10(-8)), and suggestive associations (P<1.0×10(-5)) with seven other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1. We confirmed these associations using family-based association testing. HLA typing showed the alleles HLA-DRB1*0701 (odds ratio, 2.00), DQA1*0201 (odds ratio, 1.91), and DQB1*0202 (odds ratio, 1.79) and the HLA-DRB1*0701-DQB1*0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis. CONCLUSIONS Association between variants in HLA class II loci with podoconiosis (a noncommunicable disease) suggests that the condition may be a T-cell-mediated inflammatory disease and is a model for gene-environment interactions that may be relevant to other complex genetic disorders. (Funded by the Wellcome Trust and others.).

Genome-wide associated loci influencing interleukin (IL)-10, IL-1Ra, and IL-6 levels in African Americans

Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma levels of IL-10, IL-1Ra, and IL-6 are associated with metabolic conditions, show large inter-individual variations, and are under strong genetic control. Therefore, elucidation of the genetic variants that influence levels of these ILs provides useful insights into mechanisms of immune response and pathogenesis of diseases. We conducted a genome-wide association study (GWAS) of IL-10, IL-1Ra, and IL-6 levels in 707 non-diabetic African Americans using 5,396,780 imputed and directly genotyped single nucleotide polymorphisms (SNPs) with adjustment for gender, age, and body mass index. IL-10 levels showed genome-wide significant associations (p < 5 × 10−8) with eight SNPs, the most significant of which was rs5743185 in the PMS1 gene (p = 2.30 × 10−10). We tested replication of SNPs that showed genome-wide significance in 425 non-diabetic individuals from West Africa, and successfully replicated rs17365948 in the YWHAZ gene (p = 0.02). IL-1Ra levels showed suggestive associations with two SNPs in the ASB3 gene (p = 2.55 × 10−7), ten SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p = 1.04 × 10−6 to 1.75 × 10−6), and 23 SNPs near the IL1A gene (p = 1.22 × 10−6 to 1.63 × 10−6). We also successfully replicated rs4251961 (p = 0.009); this SNP was reported to be associated with IL-1Ra levels in a candidate gene study of Europeans. IL-6 levels showed genome-wide significant association with one SNP (RP11-314E23.1; chr6:133397598; p = 8.63 × 10−9). To our knowledge, this is the first GWAS on IL-10, IL-1Ra, and IL-6 levels. Follow-up of these findings may provide valuable insight into the pathobiology of IL actions and dysregulations in inflammation and human diseases.

Parasitological, serological and clinical evidence for high prevalence of podoconiosis (non-filarial elephantiasis) in Midakegn district, central Ethiopia

Objective  To determine whether the elephantiasis in Midakegn district, central Ethiopia, is filarial or non‐filarial (podoconiosis) using serological, parasitological and clinical examinations, and to estimate its prevalence.

Using a "genomics tool" to develop disease prevention strategy in a low-income setting: lessons from the podoconiosis research project.

Genomics research is making significant contributions to our understanding of the biology and treatment of several human diseases. With varying degrees of success, genomics has also contributed to the development of new diagnostic tools and prevention strategies in the public health settings (Brand et al. 2008). A high proportion of diseases with significant public health impact occur due to the interplay between genetic and environmental factors. In this regard, conducting genomics research on diseases with strong environmental determinants is useful not only to identify genetic causes but also to improve public health approaches that aim to modify environmental risk factors (Agurs-Collins et al. 2008; Burke et al. 2010). Genomics research may contribute to the latter by presenting evidence for stratifying targeted population by level of genetic risk. This risk stratification approach has the potential to refine disease prevention strategies by more effectively targeting individuals differentially affected by the disease (Khoury et al. 2005). Moreover, given that most common complex diseases have both genetic and environmental components, community health interventions that utilize information from both risk factors promise to have higher impact (Morabia and Costanza 2005). Family health history (FHH) is the most commonly applied genomics/genetics tool in the stratification of disease risk at community level. FHH of a disease is a composite indicator of the effects of factors such as genetics, environment, culture, behavior, and the complex interplay between these factors in families. It is a “low tech” but powerful community health genomics tool for risk prediction and stratification, disease prevention and control, and health promotion (Yoon et al. 2002). For example, a study showed that 86 % of early strokes aggregated in 11 % of families, and 72 % of all early chronic heart disease cases clustered in only 14 % of families (Williams et al. 2001), demonstrating the efficiency of FHH in predicting disease risk (Scheuner 2003). Moreover, a randomized clinical trial showed effectiveness of family-oriented education and behavioral interventions. Individuals that received preventive messages tailored to an individuals familial risk had more compliance to the recommendations than those that received standard prevention messages (Ruffin et al. 2011). Despite existing knowledge gaps, the important role of the FHH tool for clinical and primary health practice was reflected in the National Institutes of Healths Consensus Development Program (http://consensus.nih.gov/2009/familyhistory.htm). Importantly, FHH offers unique values for disease prevention in low-income countries for several reasons including the fact that it is well proven, free, and is readily available to all persons (Guttmacher et al. 2004). However, there is paucity of practical evidence on applicability of FHH for informing disease prevention programs in low-income countries, particularly in Africa. The aim of this article is to describe a practical lesson gained from epidemiologic and genetic studies in Ethiopia that informed community-based prevention approaches for targeting children at high risk for podoconiosis. First, we provide a brief description of podoconiosis and the resource challenges of prevention in endemic communities. Second, we review evidence for the role of genetic and environmental risk factors for podoconiosis, and the usefulness of FHH as a “genomics tool” capturing both risk factors for identification of high risk individuals and resource targeting. Third, we discuss an experience from a pedigree study and a community-based genomics research project that demonstrated the scientific basis and feasibility of FHH. Fourth, we highlight the practical application of this approach by the local community-oriented organization in developing a model podoconiosis prevention program that targets children at high risk. Finally, we point out a strategic direction that can be implemented at primary health care facilities in Ethiopia for systematizing and scaling up the implementation of FHH to speed up elimination of podoconiosis.

Prediction of HLA Class II Alleles Using SNPs in an African Population

Background Despite the importance of the human leukocyte antigen (HLA) gene locus in research and clinical practice, direct HLA typing is laborious and expensive. Furthermore, the analysis requires specialized software and expertise which are unavailable in most developing country settings. Recently, in silico methods have been developed for predicting HLA alleles using single nucleotide polymorphisms (SNPs). However, the utility of these methods in African populations has not been systematically evaluated. Methodology/Principal Findings In the present study, we investigate prediction of HLA class II (HLA-DRB1 and HLA-DQB1) alleles using SNPs in the Wolaita population, southern Ethiopia. The subjects comprised 297 Ethiopians with genome-wide SNP data, of whom 188 had also been HLA typed and were used for training and testing the model. The 109 subjects with SNP data alone were used for empirical prediction using the multi-allelic gene prediction method. We evaluated accuracy of the prediction, agreement between predicted and HLA typed alleles, and discriminative ability of the prediction probability supplied by the model. We found that the model predicted intermediate (two-digit) resolution for HLA-DRB1 and HLA-DQB1 alleles at accuracy levels of 96% and 87%, respectively. All measures of performance showed high accuracy and reliability for prediction. The distribution of the majority of HLA alleles in the study was similar to that previously reported for the Oromo and Amhara ethnic groups from Ethiopia. Conclusions/Significance We demonstrate that HLA class II alleles can be predicted from SNP genotype data with a high level of accuracy at intermediate (two-digit) resolution in an African population. This finding offers new opportunities for HLA studies of disease epidemiology and population genetics in developing countries.

Launch of the International Podoconiosis Initiative

In the past 5 years, important progress in podoconiosis research and control has been made. The global distribution of this ascending, geochemical lymphoedema has been updated, advances have been made in disease assessment and treatment, and advocacy has successfully brought podoconiosis to the global stage. We highlight some of this progress here, and announce the launch of a new international initiative.

Using Genomic Knowledge to Improve Health Promotion Interventions in the Developing World

There has been considerable optimism about the potential to use new genomic knowledge to address public health challenges in the developing world. In this chapter, we describe how emerging genomic knowledge could lead to improvements in interventions to promote health behaviors in the over 100 countries with low or middle income per capita (LMICs). We suggest two possible, and as yet untested, opportunities for applying genomics-informed health promotion efforts in LMICs: (a) to inform risk stratification and allocation of limited health promotion resources and (b) to develop targeted risk communications and motivate adherence to behavioral recommendations. We consider these opportunities against the backdrop of social challenges presented by LMIC contexts. To do so, we draw from the experiences of an ongoing program of research among genetically high-risk families in rural Ethiopia. We conclude with recommendations for future formative and comparative effectiveness research to bring evidence to ongoing debates about the potential for genomic contributions to promote health globally.