Biology subjects

Rotimi, C. N.

Publications and source records attributed to Rotimi, C. N..

6 recordsLinked to original sources

bioRxiv2021

ACE2 Pathway Regulates Thermogenesis and Energy Metabolism

Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. ACE2 knockout mice (ACE2-/y), Mas knockout mice (Mas-/-), and the mice transplanted with brown adipose tissue from Mas-/- mice displayed impaired thermogenesis. In contrast, impaired thermogenesis of db/db obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of ACE2 or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel therapeutic targets for the treatment of metabolic disorders.

molecular biology↗

bioRxiv2020

GWAS in Africans identifies novel lipids loci and demonstrates heterogenous association within Africa

BackgroundSerum lipids are biomarkers of cardiometabolic disease risk, and understanding the genomic factors contributing to their distribution has been of considerable interest. Large genome-wide association studies (GWAS) have identified over 150 lipids loci; however, GWAS of Africans (AF) are rare. Given the genomic diversity among those of African ancestry, it is expected that a GWAS in Africans could identify novel lipids loci. While GWAS have been conducted in African Americans (AA), such studies are not proxies for studies in continental Africans due to the drastically different environmental context. Therefore, we conducted a GWAS of 4,317 Africans enrolled in the Africa America Diabetes Mellitus study. Methods and ResultsWe used linear mixed models of the inverse normal transformations of covariate-djusted residuals of high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), total cholesterol (CHOL), triglycerides (TG), and TG/HDLC, with adjustment for three principal components and the random effect of relatedness. Replication of loci associated at p<5x10-8 was attempted in 9,542 AA. Meta-analysis of AF and AA was also conducted. We also conducted analyses that excluded the relatively small number of East Africans. We evaluated known lipids loci in Africans using both exact replication and "local" replication, which accounts for interethnic differences in linkage disequilibrium. In our main analysis, we identified 23 novel associations in Africans. Of the 14 of these that were able to be tested in AA, two associations replicated (GPNMB-TG and ENPP1-TG). Two additional novel loci were discovered upon meta-analysis with AA (rs138282551-TG and TLL2-CHOL). Analyses considering only those with predominantly West African ancestry (Nigeria, Ghana, and AA) yielded new insights: ORC5-LDLC and chr20:60973327-CHOL. ConclusionsWhile functional work will be useful to confirm and understand the biological mechanisms underlying these associations, this study demonstrates the utility of conducting large-scale genomic analyses in Africans for discovering novel loci. The functional significance of some of these loci in relation to lipids remains to be elucidated, yet some have known connections to lipids pathways. For instance, rs147706369 (intronic, TLL2) alters a regulatory motif for sterol regulatory element-binding proteins (SREBPs), which are a family of transcription factors that control the expression of a range of enzymes involved in cholesterol, fatty acid, and triglyceride synthesis.

genomics↗

bioRxiv2020

Genetic Risk Scores for Cardiometabolic Traits in Sub-Saharan African Populations

There is growing support for the use of genetic risk scores (GRS) in routine clinical settings. Due to the limited diversity of current genomic discovery samples, there are concerns that the predictive power of GRS will be limited in non-European ancestry populations. Here, we evaluated the predictive utility of GRS for 12 cardiometabolic traits in sub-Saharan Africans (AF; n=5200), African Americans (AA; n=9139), and European Americans (EA; n=9594). GRS were constructed as weighted sums of the number of risk alleles. Predictive utility was assessed using the additional phenotypic variance explained and increase in discriminatory ability over traditional risk factors (age, sex and BMI), with adjustment for ancestry-derived principal components. Across all traits, GRS showed upto a 5-fold and 20-fold greater predictive utility in EA relative to AA and AF, respectively. Predictive utility was most consistent for lipid traits, with percent increase in explained variation attributable to GRS ranging from 10.6% to 127.1% among EA, 26.6% to 65.8% among AA, and 2.4% to 37.5% among AF. These differences were recapitulated in the discriminatory power, whereby the predictive utility of GRS was 4-fold greater in EA relative to AA and up to 44-fold greater in EA relative to AF. Obesity and blood pressure traits showed a similar pattern of greater predictive utility among EA. This work demonstrates the poorer performance of GRS in AF and highlights the need to improve representation of multiethnic populations in genomic studies to ensure equitable clinical translation of GRS. Key MessagesO_LIGenetic Risk Score (GRS) prediction is markedly poorer in sub-Saharan Africans compared with African Americans and European Americans C_LIO_LITo ensure equitable clinical translation of GRS, there is need need to improve representation of multiethnic populations in genomic studies C_LI

genomics↗

bioRxiv2019

A Novel Type 2 Diabetes Locus in sub-Saharan Africans, ZRANB3, is Implicated in Beta Cell Proliferation

Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report the largest genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyzed ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. TCF7L2 rs7903156 was the most significant locus (p=7.288 x 10-13). We identified a novel genome wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP chr2:136064024, T allele frequency=0.034, p=2.831x10-9). Knockdown of the zebrafish ortholog resulted in reduction in pancreatic beta cell number in the developing organism, suggesting a potential mechanism for its effect on glucose hemostasis. We also showed transferability in our study of 32 established T2D loci. Our findings provide evidence of a novel candidate T2D locus and advance understanding of the genetics of T2D in non-European ancestry populations.

genetics↗

bioRxiv2019

Genome-wide Interaction Studies by the CHARGE Gene-Lifestyle Interactions Working Group: what we have learned and what is coming next.

The CHARGE Gene-Lifestyle Interactions Working Group is a unique initiative formed to improve our understanding of the role and biological significance of gene-environment interactions in human traits and diseases. The consortium published several multi-ancestry genome-wide interaction studies (GWIS) involving up to 610,475 individuals for three lipids and four blood pressure traits while accounting for interaction effects with drinking and smoking exposures. Here we used GWIS summary statistics from these studies to decipher potential differences in genetic associations and GxE interactions across phenotype-exposure-population trios, and to derive new insights on the potential mechanistic underlying GxE through in-silico functional analyses. Our comparative analysis shows first that interaction effects likely contribute to the commonly reported ancestry-specific genetic effect in complex traits, and second, that some phenotype-exposures pairs are more likely to benefit from a greater detection power when accounting for interactions. It also highlighted a negligible correlation between main and interaction effects, providing material for future methodological development and biological discussions. We also estimated contributions to phenotypic variance, including in particular the genetic heritability conditional on the exposure, and heritability partitioned across a range of functional annotations and cell-types. In these analyses, we found multiple instances of heterogeneity of functional partitions between exposed and unexposed individuals, providing new evidence for likely exposure-specific genetic pathways. Finally, along this work we identified potential biases in methods used to jointly meta-analyses genetic and interaction effects. We performed a series of simulations to characterize these limitations and to provide the community with guideline for future GxE studies.

genetics↗

bioRxiv2017

Whole genome sequence-based haplotypes reveal single origin of the sickle allele during the Holocene Wet Phase

Five classical designations of sickle haplotypes are based on the presence/absence of restriction sites and named after ethnic groups or geographic regions from which patients originated. Each haplotype is thought to represent an independent occurrence of the sickle mutation. We investigated the origins of the sickle mutation using whole genome sequence data. We identified 156 carriers from the 1000 Genomes Project, the African Genome Variation Project, and Qatar. We defined a new haplotypic classification using 27 polymorphisms in linkage disequilibrium with rs334. Network analysis revealed a common haplotype that differed from the ancestral haplotype only by the derived sickle mutation at rs334 and correlated collectively with the Central African Republic/Bantu, Cameroon, and Arabian/Indian designations. Other haplotypes were derived from this haplotype and fell into two clusters, one comprised of haplotypes correlated with the Senegal designation and the other comprised of haplotypes correlated with both the Benin and Senegal designations. The near-exclusive presence of the original sickle haplotype in the Central African Republic, Kenya, Uganda, and South Africa is consistent with this haplotype predating the Bantu Expansion. Modeling of balancing selection indicated that the heterozygote advantage was 15.2%, an equilibrium frequency of 12.0% was reached after 87 generations, and the selective environment predated the mutation. The posterior distribution of the ancestral recombination graph yielded an age of the sickle mutation of 259 generations, corresponding to 7,300 years and the Holocene Wet Phase. These results clarify the origin of the sickle allele and improve and simplify the classification of sickle haplotypes.

genetics↗