Lipid traits and type 2 diabetes risk in African ancestry individuals: A Mendelian Randomization study

Soremekun, Opeyemi; Karhunen, Ville; He, Yiyan; Rajasundaram, Skanda; Liu, Bowen; Gkatzionis, Apostolos; Soremekun, Chisom; Udosen, Brenda; Musa, Hanan; Silva, Sarah; Kintu, Christopher; Mayanja, Richard; Nakabuye, Mariam; Machipisa, Tafadzwa; Mason, Amy M.; Vujkovic, Marijana; Zuber, Verena; Soliman, Mahmoud E. S.; Mugisha, Joseph; Nash, Oyekanmi; Kaleebu, Pontiano; Nyirenda, Moffat; Chikowore, Tinashe; Nitsch, Dorothea; Burgess, Stephen; Fatumo, Segun

doi:10.1016/j.ebiom.2022.103953

Cited by 23 publications

(17 citation statements)

References 46 publications

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“…Recently, we showed that genetic risk score derived from data of African American individuals enhance polygenic prediction of lipid traits and T2DM in Sub-Sahara African, but prediction varied greatly between another dataset from South Africa and our East African genomic data (Chikowore et al ., 2022, Kamiza et al ., 2022). We have also demonstrated the Mendelian randomisation evidence of relation between lipid trait and T2DM (Soremekun et al ., 2022), metabolic traits and stroke (Fatumo et al ., 2021). Collectively, our studies show a need for improved representation of Africans in genomic studies and ensuring the generalisation of findings for genomic medicine.…”

Section: Introductionsupporting

confidence: 71%

Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa

Fatumo

Mugisha

Soremekun

et al. 2022

Preprint

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The Uganda Genome Resource (UGR) is a well characterised genomic database, with a range of phenotypic communicable and non-communicable diseases and risk factors generated from the Uganda General Population Cohort (GPC) - a population-based open cohort study established in 1989 by the Medical Research Council (MRC) UK in collaboration with the Uganda Virus Research Institute (UVRI).In 2011, UGR was launched with genotype data on ∼5000 and whole genome sequence data on ∼2000 Ugandan individuals from 9 ethno-linguistic groups. Leveraging other available platforms at the MRC Uganda such as Biorepository centre for sample storage, Clinical Diagnostic Laboratory Service (CDLS) for sample diagnostic testing, sequencing platform for DNA extraction, Uganda Medical informatics Unit (UMIC) for large-scale data analysis, GPC for additional sample collection, UGR is strategically poised to expand and generate scientific discoveries.Here, we describe UGR and highlight the important genetic findings thus far including how UGR is providing opportunities to: (1) discover novel disease susceptibility genetic loci; (2) refine association signals at new and existing loci; (3) develop and test Polygenic Risk Score (PRS) to determine individual’s disease risk; 4) assess how some risk factors including infectious diseases are causally related to non-communicable diseases (NCDs) in Africa; (5) develop research capacity for genomics in Africa; and (6) enhance African participation in the global genomics research arena. Leveraging established research infrastructure, expertise, local genomic leadership, global collaboration and strategic funding, we anticipate that UGR can develop further to a comparable level of European and Asian large-scale genomic initiatives.

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Section: Introductionsupporting

confidence: 71%

Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa

Fatumo

Mugisha

Soremekun

et al. 2022

Preprint

Self Cite

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“…Conversely, a 2 × 2 factorial Mendelian randomization study including 425,354 participants from the UK Biobank did not observe an association between lower PCSK9 concentrations and type 2 diabetes [ 41 ]. Similar conclusions were reached by a Mendelian randomization analysis evaluating the causal effect of various lipid traits on type 2 diabetes liability in roughly 70,000 individuals of African ancestry (odds ratio = 0.94; 95%CI 0.82–1.08) [ 43 ].…”

Section: Does Pcsk9 Raise the Risk Of Nod? Genetic And Clinical Evidencesupporting

confidence: 65%

PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

Carugo

Sirtori

Corsini

et al. 2022

Curr Atheroscler Rep

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Purpose of Review Since the clinical benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors occurs in a setting of reducing low-density lipoprotein-cholesterol (LDL-C) to unprecedentedly low levels, it becomes of interest to investigate possible adverse effects pertaining to the risk of new-onset diabetes (NOD). Recent Findings While safety results reported in either meta-analyses or cardiovascular outcome trials FOURIER (with evolocumab) and ODYSSEY (with alirocumab) did not rise the incidence of NOD, Mendelian randomization analyses were almost concordant in showing an increased risk of NOD. This evidence was in line with post-marketing safety reports highlighting that evolocumab and alirocumab were primarily related to mild hyperglycaemia rather than diabetes, with most of the hyperglycaemic events occurring during the first 6 months of treatment. Summary Considering the different nature of genetic studies and of randomized controlled trials, with careful monitoring of patients, particularly in the earlier phases of treatment, and the identification of those more susceptible to develop NOD, treatment with PCSK9 inhibitors should be of minimal concern.

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“…Standard terms and key concepts in MR studies: continued population and a positive association in an African population [13][14][15]. A recent study further identified that the diabetogenic effect of low levels of LDL-cholesterol might be mediated by increased BMI [16].…”

Section: Weak Instrument Biasmentioning

confidence: 99%

Causal factors underlying diabetes risk informed by Mendelian randomisation analysis: evidence, opportunities and challenges

2023

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Diabetes and its complications cause a heavy disease burden globally. Identifying exposures, risk factors and molecular processes causally associated with the development of diabetes can provide important evidence bases for disease prevention and spur novel therapeutic strategies. Mendelian randomisation (MR), an epidemiological approach that uses genetic instruments to infer causal associations between an exposure and an outcome, can be leveraged to complement evidence from observational and clinical studies. This narrative review aims to summarise the evidence on potential causal risk factors for diabetes by integrating published MR studies on type 1 and 2 diabetes, and to reflect on future perspectives of MR studies on diabetes. Despite the genetic influence on type 1 diabetes, few MR studies have been conducted to identify causal exposures or molecular processes leading to increased disease risk. In type 2 diabetes, MR analyses support causal associations of somatic, mental and lifestyle factors with development of the disease. These studies have also identified biomarkers, some of them derived from the gut microbiota, and molecular processes leading to increased disease risk. These studies provide valuable data to better understand disease pathophysiology and explore potential therapeutic targets. Because genetic association studies have mostly been restricted to participants of European descent, multi-ancestry cohorts are needed to examine the role of different types of physical activity, dietary components, metabolites, protein biomarkers and gut microbiome in diabetes development. Graphical abstract

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Lipid traits and type 2 diabetes risk in African ancestry individuals: A Mendelian Randomization study

Cited by 23 publications

References 46 publications

Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa

Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa

PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

Causal factors underlying diabetes risk informed by Mendelian randomisation analysis: evidence, opportunities and challenges

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