Using genomics to understand the relationship between nutrition, infection and neurodevelopmental outcomes in children

Nutritional deficiencies, infectious disease and poor developmental outcomes are interrelated and important health problems for young children living in Africa. We are using an epidemiological approach to investigate potential relationships and then a genomics approach to understand mechanisms and make causal inferences. With global and national collaborators, we are investigating these relationships in young children across multiple diverse populations in Africa. Micronutrient deficiencies, including iron and vitamin D, and anaemia are areas of interest.

Iron deficiency, anaemia, and infection

We estimate that approximately 50% and 60% of young children are iron deficient and anaemic, respectively (Muriuki et al, 2020). Anaemia has multiple causes, which often coexist in the same child. The relationship between infectious disease and iron/anaemia may be bi-directional since infections dysregulate iron homeostasis, while pathogens require iron to proliferate. Using a Mendelian randomization approach, we found that malaria is an important cause of iron deficiency in African children (Muriuki & Atkinson, 2018; Muriuki et al, 2021). In epidemiological studies, iron deficiency is associated with protection against malaria (Muriuki et al, 2019), and we are applying a Mendelian randomization approach to infer causality. In large-scale studies we found little evidence of an association between FPN Q248H, a mutation specific to African populations that increases intracellular iron export, and malaria or bacteraemia (Muriuki et al, 2019). Anaemia may also increase susceptibility to infections. Evidence suggests that children with anaemia, particularly with severe anaemia, have a higher risk of bacterial infections (Abuga et al., 2020). We are investigating the putative pathways through which anaemia (of varying severities and aetiologies) may be associated with infectious diseases in African children, including through dysregulation of iron status and immune responses (Abuga et al., 2020; Abuga et al., 2021).

Vitamin D deficiency

Vitamin D deficiency is one of the most common nutrient deficiencies world-wide and is a major public health concern due to its association with many infectious diseases. However, little is known about its prevalence, drivers, and genetics in Africa. In a systematic review of previous literature, we found that approximately a third of individuals living in Africa had vitamin D deficiency (Mogire et al, 2020). In a study of children living across the African continent we found that about 8% of children were vitamin D deficient and risk factors for deficiency included latitude, age, season, malaria, inflammation and vitamin D binding protein genotype (Mogire et al, 2021). We are currently studying the relationship between vitamin D and iron deficiency in African children. We also aim at evaluating the association between vitamin D and various diseases, including malaria, viral and bacterial diseases applying Mendelian Randomization analyses to infer causality.

Neurodevelopment

Children living in Sub-Saharan Africa are vulnerable to developmental delay due to exposure to risk factors including infections malnutrition and micronutrient deficiencies. Both vitamin D and iron are important for brain development. We conducted systematic reviews to evaluate the effects of vitamin D status (Mutua et al, 2020 ) and iron supplementation (Mutua et al, 2021) on neurobehavioural outcomes in children and found few studies from Africa and conflicting evidence. We evaluated the effect of vitamin D status on cognitive and motor outcomes using data from pre-school children in the Entebbe Mother and Baby Study (EMaBS) prospective birth cohort and found no evidence of an association with cognitive and motor outcomes. (Mutua et al, 2020). We are currently analyzing the EMaBS cohort dataset to investigate the effects of anaemia and iron status on neurobehavioural outcomes and will be applying a Mendelian randomization approach to infer causality.

Genomics and inferring causality

Despite rich genetic diversity, populations living in Africa are underrepresented in genomic studies. We are conducting genome-wide association studies of iron and vitamin D status in African children to identify genetic proxies that can be reliably applied in a Mendelian randomization framework to infer causality in the relationship between iron/vitamin D and infections, such as malaria, bacteraemia, and tuberculosis and neurodevelopment. Using genomics, we also seek to understand gene-pathways and putative mechanisms underlying the associations between nutrition and disease.

Investigators: John Muriuki, Reagan Mogire, Kelvin Abuga, Agnes Mutua, Mercy Kimani, Kelvinson Mwangi, Tom Williams, Amina Abubakar, Sarah Atkinson

Publications:

1. MogireM., Morovat A., Muriuki J.M., Mentzer A.J., Webb E.L., Kimita W., Ndungu F.M., Macharia A.W., Cutland C., Sirima S.B., Diarra A., Tiono A.B., Lule S.A., Madhi S.A., Sandhu MS, Prentice A.M., Bejon P., Pettifor J.M., Elliott A.M., Adeyemo A., Williams T.N., Atkinson S.H. Prevalence and Predictors of vitamin D deficiency in young African children. BMC Med. 19, 115 (2021). https://doi.org/10.1186/s12916-021-01985-8
2. Muriuki J.M., Mentzer A.J., Mitchell R., Webb E.L., Etyang A.O., Kyobutungi C., Morovat A., Kimita W., Ndungu F.M., Macharia A.W., Ngetsa CJ, Makale J, Lule S.A., Musani SK, Raffield LM, Cutland C., Sirima S.B., Diarra A., Tiono A.B., Fried M, Gwamaka M, Adu-Afarwuah S, Wirth JP, Wegmuller R, Madhi S.A., Snow RW, Hill A.V.S., Rockett KA, Sandhu MS, Kwiatkowski D.P., Prentice A.M., Byrd KA, Ndjebayi A, Stewart CP, Engle-Stone R, Green TJ, Karakochuk CD, Suchdev P.S., Bejon P., Duffy PE, Davey Smith G, Elliott AM, Williams T.N., Atkinson SH. Malaria is a cause of iron deficiency in African children” Nature Medicine. 2021 Feb 22 https://pubmed.ncbi.nlm.nih.gov/33619371
3. Abuga KM, Muriuki JM, Williams T.N., Atkinson SH. How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children. Int J Mol Sci. 2020 Sep 22;21(18): E6976. doi: 10.3390/ijms21186976. PMID: 32972031.
4. Mutua AM, Nampijja M, Elliott A.M., Pettifor J.M., Williams TN, Abubakar A., Webb EL, Atkinson, SH. Vitamin D Status Is Not Associated with Cognitive or Motor Function in Pre-School Ugandan Children. Nutrients 2020; 12(6):1662 doi: 3390/nu12061662
5. Bundi CK, Nalwoga A, Lubyayi L, Muriuki JM, Mogire RM, Opi H, Mentzer AJ, Mugyenyi CK, Mwacharo J,Webb EL, Bejon P, Williams TN, Gikunju JK, Beeson JG, Elliott AM, Ndungu FM, Atkinson SH. Iron deficiency is associated with reduced levels of Plasmodium falciparum-specific antibodies in African children. Clin Infect Dis. 2020 Jun 7:ciaa728. doi: 10.1093/cid/ciaa728.
6. Abuga K.M., Rocket K.A., Muriuki J.M., Kock O., Nairz M., Sirugo G., Bejon P., Kwiatkowski D.P., Prentice A.M., Atkinson S.H. Interferon-gamma polymorphisms and risk of iron deficiency and anaemia in Gambian children. Wellcome Open Research. 2020 March. http://dx.doi.org/10.12688/wellcomeopenres.15750.1
7. Mutua A.M., Mogire R.M., Elliott A.M., Williams T.N., Webb E.L., Abubakar A., Atkinson S.H. Effects of vitamin D deficiency on neurobehavioural outcomes in children: a systematic review. Wellcome Open Research. 2020 February. https://wellcomeopenresearch.org/articles/5-28/v1
8. Muriuki J.M., Mentzer A.J., Webb E.L., Morovat A., Kimita W., Ndungu F.M., Macharia A.W., Crane R.J., Berkley J.A., Lule S.A., Cutland C., Sirima S.B., Diarra A., Tiono A.B., Bejon P., Madhi S.A., Hill A.V.S., Prentice A.M., Suchdev P.S., Elliott A.M., Williams T.N., Atkinson S.H. Estimating the burden of iron deficiency among African children. BMC Med. 2020 Feb 27;18(1):31. doi: 10.1186/s12916-020-1502-7.
9. Mogire R.M., Mutua A., Kimita W., Kamau A., Bejon P., Pettifor J.M., Adeyemo A., Williams T.N., Atkinson S.H. Prevalence of vitamin D deficiency in Africa – a systematic review and meta-analysis. Lancet Global Health. 2020 Jan;8(1):e134-e142. Doi:10.1016/S2214-109X(19)30457-7. Epub 2019 Nov 27.
10. Muriuki J.M., Mentzer, A.J., Band G., Gilchrist J.J., Carstensen T., Lule S.A., Goheen M.M., Joof F., Kimita W., Mogire R., Cutland C., Diarra A., Rautanen A., Pomilla C., Gurdasani D., Rockett K., Mturi N., Ndungu F.M., Scott J.A.G, Sirima S.B., Morovat A., Prentice A.M., Madhi S.A., Webb E.L., Elliott A.M., Bejon P., Sandhu M.S., Hill A.V.S., Kwiatkowski D.P., Williams T.N., Cerami C., Atkinson S.H. The ferroportin Q248H mutation protects against anemia, but not malaria or bacteremia. Science Advances. 2019 Sept 4;5(9): Ecollection 2019 Sep https://advances.sciencemag.org/content/5/9/eaaw0109
11. Muriuki J.M., Atkinson S.H. How Eliminating Malaria May Also Prevent Iron Deficiency in African Children. 2018 Oct 1;11(4).
12. Muriuki J.M., Mentzer, A.J., Kimita W., Ndungu F.M., Macharia A.W., Webb E.L., Lule S.A., Morovat A., Hill A.V.S., Bejon P., Elliott A.M., Williams T.N., Atkinson S.H. Iron Status and Associated Malaria Risk Among African Children. Clinical Infectious Diseases. 2018 Sep 14. Doi:10.1093/cid/ciy791.
13. Yates T.A. and Atkinson S.H. Ironing out sex differences in tuberculosis prevalence. J. Tuberc. Lung Dis. 2017 May 1;21(5):483-484.
14. Atkinson S.H., Uyoga S.M., Armitage A.E., Khandwala S., Mugyenyi, C.K., Bejon P.A., Marsh, K., Beeson J.G., Prentice A.M., Drakesmith H., Williams T.N. Malaria and age variably but critically control hepcidin throughout childhood in Kenya. EBioMedicine. 2015 Aug 8; 2 (10): 1478-86. April 2015.
15. Atkinson S.H., Armitage A.E., Khandwala S., Mwangi T.W., Uyoga S., Bejon P.A., Williams T.N., Prentice A.M., Drakesmith H. Combinatorial effects of malaria season, iron deficiency, and inflammation determine plasma hepcidin concentration in African children. Blood. 2014 May 22;123(21):3221-9. Plenary Paper with accompanying editorial.
16. Pasricha S.R.*, Atkinson S.H.*, Armitage A.E., Khandwala S., Veenemans J., Cox S.E., Eddowes L.A., Hayes T., Doherty C.P., Demir A.Y., Tijhaar E., Verhoef H., Prentice A.M., Drakesmith H. Expression of the iron hormone hepcidin distinguishes different types of anemia in African children. Sci Transl Med. 2014 May 7;6(235):235re3. *Joint first authors.
17. Atkinson S.H., Uyoga S.M., Nyatichi E., Macharia A.W., Nyutu G., Ndila C., Kwiatkowski D.P., Rockett K.A., Williams T.N. Epistasis between the haptoglobin common variant and α+thalassemia influences risk of severe malaria in Kenyan children. Blood. 2014 Mar 27;123(13):2008-16.