Publications by authors named "Adebowale Adeyemo"

217 Publications

Genome-wide analyses of multiple obesity-related cytokines and hormones informs biology of cardiometabolic traits.

Genome Med 2021 Oct 7;13(1):156. Epub 2021 Oct 7.

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, 12 South Drive Bldg 12A rm 4047, Bethesda, MD, 20814, USA.

Background: A complex set of perturbations occur in cytokines and hormones in the etiopathogenesis of obesity and related cardiometabolic conditions such as type 2 diabetes (T2D). Evidence for the genetic regulation of these cytokines and hormones is limited, particularly in African-ancestry populations. In order to improve our understanding of the biology of cardiometabolic traits, we investigated the genetic architecture of a large panel of obesity- related cytokines and hormones among Africans with replication analyses in African Americans.

Methods: We performed genome-wide association studies (GWAS) in 4432 continental Africans, enrolled from Ghana, Kenya, and Nigeria as part of the Africa America Diabetes Mellitus (AADM) study, for 13 obesity-related cytokines and hormones, including adipsin, glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), interleukin-1 receptor antagonist (IL1-RA), interleukin-6 (IL-6), interleukin-10 (IL-10), leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, visfatin, insulin, glucagon, and ghrelin. Exact and local replication analyses were conducted in African Americans (n = 7990). The effects of sex, body mass index (BMI), and T2D on results were investigated through stratified analyses.

Results: GWAS identified 39 significant (P value < 5 × 10) loci across all 13 traits. Notably, 14 loci were African-ancestry specific. In this first GWAS for adipsin and ghrelin, we detected 13 and 4 genome-wide significant loci respectively. Stratified analyses by sex, BMI, and T2D showed a strong effect of these variables on detected loci. Eight novel loci were successfully replicated: adipsin (3), GIP (1), GLP-1 (1), and insulin (3). Annotation of these loci revealed promising links between these adipocytokines and cardiometabolic outcomes as illustrated by rs201751833 for adipsin and blood pressure and locus rs759790 for insulin level and T2D in lean individuals.

Conclusions: Our study identified genetic variants underlying variation in multiple adipocytokines, including the first loci for adipsin and ghrelin. We identified population differences in variants associated with adipocytokines and highlight the importance of stratification for discovery of loci. The high number of African-specific loci detected emphasizes the need for GWAS in African-ancestry populations, as these loci could not have been detected in other populations. Overall, our work contributes to the understanding of the biology linking adipocytokines to cardiometabolic traits.
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http://dx.doi.org/10.1186/s13073-021-00971-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499470PMC
October 2021

Evolutionary genetics and acclimatization in nephrology.

Nat Rev Nephrol 2021 Sep 28. Epub 2021 Sep 28.

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Evolutionary processes, including mutation, migration and natural selection, have influenced the prevalence and distribution of various disorders in humans. However, despite a few well-known examples, such as the APOL1 variants - which have undergone positive genetic selection for their ability to confer resistance to Trypanosoma brucei infection but confer a higher risk of chronic kidney disease - little is known about the effects of evolutionary processes that have shaped genetic variation on kidney disease. An understanding of basic concepts in evolutionary genetics provides an opportunity to consider how findings from ancient and archaic genomes could inform our knowledge of evolution and provide insights into how population migration and genetic admixture have shaped the current distribution and landscape of human kidney-associated diseases. Differences in exposures to infectious agents, environmental toxins, dietary components and climate also have the potential to influence the evolutionary genetics of kidneys. Of note, selective pressure on loci associated with kidney disease is often from non-kidney diseases, and thus it is important to understand how the link between genome-wide selected loci and kidney disease occurs in relation to secondary nephropathies.
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http://dx.doi.org/10.1038/s41581-021-00483-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478000PMC
September 2021

Genome-Wide Scan for Parent-of-Origin Effects in a sub-Saharan African Cohort With Nonsyndromic Cleft Lip and/or Cleft Palate (CL/P).

Cleft Palate Craniofac J 2021 Aug 12:10556656211036316. Epub 2021 Aug 12.

Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa, IA, USA.

Objective: Nonsyndromic cleft lip and/or cleft palate (NSCL/P) have multifactorial etiology where genetic factors, gene-environment interactions, stochastic factors, gene-gene interactions, and parent-of-origin effects (POEs) play cardinal roles. POEs arise when the parental origin of alleles differentially impacts the phenotype of the offspring. The aim of this study was to identify POEs that can increase risk for NSCL/P in humans using a genome-wide dataset.

Methods: The samples (174 case-parent trios from Ghana, Ethiopia, and Nigeria) included in this study were from the African only genome wide association studies (GWAS) that was published in 2019. Genotyping of individual DNA using over 2 million multiethnic and African ancestry-specific single-nucleotide polymorphisms from the Illumina Multi-Ethnic Genotyping Array v2 15070954 A2 (genome build GRCh37/hg19) was done at the Center for Inherited Diseases Research. After quality control checks, PLINK was employed to carry out POE analysis employing the pooled subphenotypes of NSCL/P.

Results: We observed possible hints of POEs at a cluster of genes at a 1 mega base pair window at the major histocompatibility complex class 1 locus on chromosome 6, as well as at other loci encompassing candidate genes such as , , , , , , , , , lncRNAs, microRNA, antisense RNAs, , , and .

Conclusion: Findings from our study suggest that some loci may increase the risk for NSCL/P through POEs. Additional studies are required to confirm these suggestive loci in NSCL/P etiology.
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http://dx.doi.org/10.1177/10556656211036316DOI Listing
August 2021

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

Hum Mol Genet 2021 Jul 1. Epub 2021 Jul 1.

Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA.

Serum lipids are biomarkers of cardiometabolic disease risk, and understanding genomic factors contributing to their distribution is of interest. Studies of lipids in Africans are rare, though it is expected that such studies could identify novel loci. We conducted a GWAS of 4317 Africans enrolled from Nigeria, Ghana, and Kenya. We evaluated linear mixed models of high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), total cholesterol (CHOL), triglycerides (TG), and TG/HDLC. Replication was attempted in 9542 African Americans (AA). In our main analysis, we identified 28 novel associations in Africans. Of the 18 of these that could be tested in AA, three associations replicated (GPNMB-TG, ENPP1-TG, and SMARCA4-LDLC). Five additional novel loci were discovered upon meta-analysis with AA (rs138282551-TG, PGBD5-HDLC, CD80-TG/HDLC, SLC44A1-CHOL, 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. Among our novel findings are some loci with known connections to lipids pathways. For instance, rs147706369 (TLL2) alters a regulatory motif for sterol regulatory element-binding proteins (SREBPs), a family of transcription factors that control the expression of a range of enzymes involved in cholesterol, fatty acid, and triglyceride synthesis, and rs115749422 (SMARCA4), an independent association near the known LDLR locus that is rare or absent in populations without African ancestry. These findings demonstrate the utility of conducting genomic analyses in Africans for discovering novel loci and provide some preliminary evidence for caution against treating 'African ancestry' as a monolithic category.
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http://dx.doi.org/10.1093/hmg/ddab174DOI Listing
July 2021

Serum fructosamine and glycemic status in the presence of the sickle cell mutation.

Diabetes Res Clin Pract 2021 Jul 11;177:108918. Epub 2021 Jun 11.

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, 12 South Drive, Room 4047, Bethesda, MD 20892, United States. Electronic address:

Aims: The glycated hemoglobin (HbA1c) test can be unreliable in the presence of hemoglobinopathies. The co-existence of type 2 diabetes (T2D) with sickle cell anemia calls for alternative tests. Therefore, we established a reference interval for serum fructosamine and evaluated its utility as a potential glycemic biomarker that is not affected by abnormal hemoglobin.

Methods: The accuracies of serum fructosamine in monitoring and diagnosing T2D were evaluated using the Area under the Receiver Operating Characteristics and other measures in 618 Nigerians with or without sickle cell trait. The estimated diagnostic cut-off for serum fructosamine was then validated in an independent multi-ethnic cohort of 634 West Africans.

Results: Serum fructosamine was similar between individuals with or without sickle cell trait (median: 287 vs 275 umol/L, p = 0·11, respectively) despite statistically different HbA1c. Fructosamine was highly correlated with both HbA1c and fasting glucose independently of sickle cell trait. The areas under the curve (AUC) of serum fructosamine in identifying individuals with uncontrolled glycemia and individuals with T2D were similar and independent of sickle cell trait: 0·92 (95% confidence interval [95% CI ], 0·88-0·95 and 0.92 (95% CI, (0.89-0.95) respectively.

Conclusions: Serum fructosamine is a good alternative to HbA1c for monitoring and diagnosing T2D in the presence of sickle cell trait.
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http://dx.doi.org/10.1016/j.diabres.2021.108918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447861PMC
July 2021

Genome-wide DNA methylation analysis on C-reactive protein among Ghanaians suggests molecular links to the emerging risk of cardiovascular diseases.

NPJ Genom Med 2021 Jun 11;6(1):46. Epub 2021 Jun 11.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Molecular mechanisms at the intersection of inflammation and cardiovascular diseases (CVD) among Africans are still unknown. We performed an epigenome-wide association study to identify loci associated with serum C-reactive protein (marker of inflammation) among Ghanaians and further assessed whether differentially methylated positions (DMPs) were linked to CVD in previous reports, or to estimated CVD risk in the same population. We used the Illumina Infinium® HumanMethylation450 BeadChip to obtain DNAm profiles of blood samples in 589 Ghanaians from the RODAM study (without acute infections, not taking anti-inflammatory medications, CRP levels < 40 mg/L). We then used linear models to identify DMPs associated with CRP concentrations. Post-hoc, we evaluated associations of identified DMPs with elevated CVD risk estimated via ASCVD risk score. We also performed subset analyses at CRP levels ≤10 mg/L and replication analyses on candidate probes. Finally, we assessed for biological relevance of our findings in public databases. We subsequently identified 14 novel DMPs associated with CRP. In post-hoc evaluations, we found that DMPs in PC, BTG4 and PADI1 showed trends of associations with estimated CVD risk, we identified a separate DMP in MORC2 that was associated with CRP levels ≤10 mg/L, and we successfully replicated 65 (24%) of previously reported DMPs. All DMPs with gene annotations (13) were biologically linked to inflammation or CVD traits. We have identified epigenetic loci that may play a role in the intersection between inflammation and CVD among Ghanaians. Further studies among other Africans are needed to confirm our findings.
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http://dx.doi.org/10.1038/s41525-021-00213-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196035PMC
June 2021

A UGT1A1 variant is associated with serum total bilirubin levels, which are causal for hypertension in African-ancestry individuals.

NPJ Genom Med 2021 Jun 11;6(1):44. Epub 2021 Jun 11.

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Serum bilirubin is associated with several clinical outcomes, including hypertension, type 2 diabetes (T2D), and drug metabolism. Here, we describe findings from our genome-wide association studies (GWAS) of serum (TBIL) using a generalized linear mixed model in West Africans (n = 1127), with adjustment for age, sex, body mass index, T2D, significant principal components of population structure, and cryptic relatedness. Genome-wide conditional analysis and CAVIARBF were used to fine map significant loci. The causal effect of TBIL on hypertension was assessed by Mendelian randomization (MR) using the GWAS findings as instrumental variables (IVs) in African Americans (n = 3,067). The SNP rs887829 (UGT1A1) was significantly associated with TBIL levels (effect allele (T) frequency = 0.49, β (SE) = 0.59 (0.04), p = 9.13 × 10). Genome-wide conditional analysis and regional fine mapping pointed to rs887829 as a possible causal variant with a posterior inclusion probability of 0.99. The T allele of rs887829 is associated with lower hepatic expression of UGT1A1. Using rs887829 as an IV, two-stage least-squares MR showed a causal effect of bilirubin on hypertension (β = -0.76, 95% CI [-1.52, -0.01], p = 0.0459). Our finding confirms that UGT1A1 influences bilirubin levels. Notably, lower TBIL is causally associated with the increased risk of hypertension.
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http://dx.doi.org/10.1038/s41525-021-00208-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196001PMC
June 2021

Variant analyses of candidate genes in orofacial clefts in multi-ethnic populations.

Oral Dis 2021 Jun 1. Epub 2021 Jun 1.

Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, IA, USA.

Objectives: Cleft lip with/without cleft palate and cleft palate only is congenital birth defects where the upper lip and/or palate fail to fuse properly during embryonic facial development. Affecting ~1.2/1000 live births worldwide, these orofacial clefts impose significant social and financial burdens on affected individuals and their families. Orofacial clefts have a complex etiology resulting from genetic variants combined with environmental covariates. Recent genome-wide association studies and whole-exome sequencing for orofacial clefts identified significant genetic associations and variants in several genes. Of these, we investigated the role of common/rare variants in SHH, RORA, MRPL53, ACVR1, and GDF11.

Materials And Methods: We sequenced these five genes in 1255 multi-ethnic cleft lip with/without palate and cleft palate only samples in order to find variants that may provide potential explanations for the missing heritability of orofacial clefts. Rare and novel variants were further analyzed using in silico predictive tools.

Results: Ninteen total variants of interest were found, with variant types including stop-gain, missense, synonymous, intronic, and splice-site variants. Of these, 3 novel missense variants were found, one in SHH, one in RORA, and one in GDF11.

Conclusion: This study provides evidence that variants in SHH, RORA, MRPL53, ACVR1, and GDF11 may contribute to risk of orofacial clefts in various populations.
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http://dx.doi.org/10.1111/odi.13932DOI Listing
June 2021

Prevalence and predictors of vitamin D deficiency in young African children.

BMC Med 2021 05 20;19(1):115. Epub 2021 May 20.

Kenya Medical Research Institute (KEMRI) Centre for Geographic Medicine Coast, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.

Background: Children living in sub-Saharan Africa have a high burden of rickets and infectious diseases, conditions that are linked to vitamin D deficiency. However, data on the vitamin D status of young African children and its environmental and genetic predictors are limited. We aimed to examine the prevalence and predictors of vitamin D deficiency in young African children.

Methods: We measured 25-hydroxyvitamin D (25(OH)D) and typed the single nucleotide polymorphisms, rs4588 and rs7041, in the GC gene encoding the vitamin D binding protein (DBP) in 4509 children aged 0-8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. We evaluated associations between vitamin D status and country, age, sex, season, anthropometric indices, inflammation, malaria and DBP haplotypes in regression analyses.

Results: Median age was 23.9 months (interquartile range [IQR] 12.3, 35.9). Prevalence of vitamin D deficiency using 25(OH)D cut-offs of < 30 nmol/L and < 50 nmol/L was 0.6% (95% CI 0.4, 0.9) and 7.8% (95% CI 7.0, 8.5), respectively. Overall median 25(OH)D level was 77.6 nmol/L (IQR 63.6, 94.2). 25(OH)D levels were lower in South Africa, in older children, during winter or the long rains, and in those with afebrile malaria, and higher in children with inflammation. 25(OH)D levels did not vary by stunting, wasting or underweight in adjusted regression models. The distribution of Gc variants was Gc1f 83.3%, Gc1s 8.5% and Gc2 8.2% overall and varied by country. Individuals carrying the Gc2 variant had lower median 25(OH)D levels (72.4 nmol/L (IQR 59.4, 86.5) than those carrying the Gc1f (77.3 nmol/L (IQR 63.5, 92.8)) or Gc1s (78.9 nmol/L (IQR 63.8, 95.5)) variants.

Conclusions: Approximately 0.6% and 7.8% of young African children were vitamin D deficient as defined by 25(OH)D levels < 30 nmol/L and < 50 nmol/L, respectively. Latitude, age, season, and prevalence of inflammation and malaria should be considered in strategies to assess and manage vitamin D deficiency in young children living in Africa.
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http://dx.doi.org/10.1186/s12916-021-01985-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136043PMC
May 2021

DNA methylation as the link between migration and the major noncommunicable diseases: the RODAM study.

Epigenomics 2021 May 23;13(9):653-666. Epub 2021 Apr 23.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

We assessed epigenome-wide DNA methylation (DNAm) differences between migrant and non-migrant Ghanaians. We used the Illumina Infinium HumanMethylation450 BeadChip to profile DNAm of 712 Ghanaians in whole blood. We used linear models to detect differentially methylated positions (DMPs) associated with migration. We performed multiple post hoc analyses to validate our findings. We identified 13 DMPs associated with migration (delta-beta values: 0.2-4.5%). Seven DMPs in , , , , , and were independent of extrinsic genomic influences in public databases. Two DMPs in were associated with duration of stay in Europe among migrants. All DMPs were biologically linked to migration-related factors. Our findings provide the first insights into DNAm differences between migrants and non-migrants.
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http://dx.doi.org/10.2217/epi-2020-0329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173498PMC
May 2021

Plasma cell immunoglobulin heavy chain repertoire dynamics before and after tetanus booster vaccination.

Immunogenetics 2021 08 25;73(4):321-332. Epub 2021 Mar 25.

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.

Antibody sequence repertoire analysis of plasma cells (PC) isolated before and 1 week after a vaccine provides time-specific snapshots of the antibody response. Comparison of the immunoglobulin (Ig) sequences pre- and post-vaccination allows analysis of maturation over time and identification of antigen specific Ig. Here we compare the Ig heavy chain (Ig-H) repertoire of circulating PCs isolated from 10 peripheral blood mononuclear cells (PBMC) collected by apheresis 1 week after a tetanus toxoid vaccine booster with the Ig-H repertoire of PCs collected 2 and 11 weeks prior to the booster. A total of 21,060 unique Ig nucleotide sequences encoding 14,307 unique heavy chain complementarity determining region 3 (CDR-H3) amino acid sequences, also called clonotypes, were identified. Only 466 clonotypes (3.3%) were present at all 3 time points. In contrast, 90% of the 30 highest frequency CDR-H3 regions at +1w were also identified at another time point and 50% were present at all time points, suggesting the rapid expansion of a memory B cell population. The tetanus toxoid specificity of the CDR-H3 region with the 7th highest frequency at +1w was confirmed using immunoprecipitation and mass spectroscopy, and two public tetanus toxoid-specific CDR-H3 regions were also overrepresented at +1w. In summary, we have used the tetanus vaccine model system to demonstrate that bulk PC Ig repertoire analysis can identify PC populations that expand and mature following antigen exposure. The application of this approach before and after clinical infections should advance our understanding of clinical protection and facilitate vaccine design.
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http://dx.doi.org/10.1007/s00251-021-01215-8DOI Listing
August 2021

Evolutionary forces in diabetes and hypertension pathogenesis in Africans.

Hum Mol Genet 2021 Apr;30(R1):R110-R118

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Rates of type 2 diabetes (T2D) and hypertension are increasing rapidly in urbanizing sub-Saharan Africa (SSA). While lifestyle factors drive the increases in T2D and hypertension prevalence, evidence across populations shows that genetic variation, which is driven by evolutionary forces including a natural selection that shaped the human genome, also plays a role. Here we report the evidence for the effect of selection in African genomes on mechanisms underlying T2D and hypertension, including energy metabolism, adipose tissue biology, insulin action and salt retention. Selection effects found for variants in genes PPARA and TCF7L2 may have enabled Africans to respond to nutritional challenges by altering carbohydrate and lipid metabolism. Likewise, African-ancestry-specific characteristics of adipose tissue biology (low visceral adipose tissue [VAT], high intermuscular adipose tissue and a strong association between VAT and adiponectin) may have been selected for in response to nutritional and infectious disease challenges in the African environment. Evidence for selection effects on insulin action, including insulin resistance and secretion, has been found for several genes including MPHOSPH9, TMEM127, ZRANB3 and MC3R. These effects may have been historically adaptive in critical conditions, such as famine and inflammation. A strong correlation between hypertension susceptibility variants and latitude supports the hypothesis of selection for salt retention mechanisms in warm, humid climates. Nevertheless, adaptive genomics studies in African populations are scarce. More work is needed, particularly genomics studies covering the wide diversity of African populations in SSA and Africans in diaspora, as well as further functional assessment of established risk loci.
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http://dx.doi.org/10.1093/hmg/ddaa238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117438PMC
April 2021

Genetic risk scores for cardiometabolic traits in sub-Saharan African populations.

Int J Epidemiol 2021 08;50(4):1283-1296

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Background: 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. GRS for cardiometabolic traits were evaluated in sub-Saharan Africans in comparison with African Americans and European Americans.

Methods: 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 (EUR; 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 the increase in discriminatory ability over traditional risk factors [age, sex and body mass index (BMI)], with adjustment for ancestry-derived principal components.

Results: Across all traits, GRS showed up to a 5-fold and 20-fold greater predictive utility in EUR relative to AA and AF, respectively. Predictive utility was most consistent for lipid traits, with percentage increase in explained variation attributable to GRS ranging from 10.6% to 127.1% among EUR, 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 EUR relative to AA and up to 44-fold greater in EUR relative to AF. Obesity and blood pressure traits showed a similar pattern of greater predictive utility among EUR.

Conclusions: This work demonstrates the poorer performance of GRS in AF and highlights the need to improve representation of multiple ethnic populations in genomic studies to ensure equitable clinical translation of GRS.
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http://dx.doi.org/10.1093/ije/dyab046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407873PMC
August 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Trans-ethnic meta-analysis identifies new loci associated with longitudinal blood pressure traits.

Sci Rep 2021 Feb 18;11(1):4075. Epub 2021 Feb 18.

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Genome-wide association studies (GWAS) have identified thousands of genetic loci associated with cross-sectional blood pressure (BP) traits; however, GWAS based on longitudinal BP have been underexplored. We performed ethnic-specific and trans-ethnic GWAS meta-analysis using longitudinal and cross-sectional BP data of 33,720 individuals from five cohorts in the US and one in Brazil. In addition to identifying several known loci, we identified thirteen novel loci with nine based on longitudinal and four on cross-sectional BP traits. Most of the novel loci were ethnic- or study-specific, with the majority identified in African Americans (AA). Four of these discoveries showed additional evidence of association in independent datasets, including an intergenic variant (rs4060030, p = 7.3 × 10) with reported regulatory function. We observed a high correlation between the meta-analysis results for baseline and longitudinal average BP (rho = 0.48). BP trajectory results were more correlated with those of average BP (rho = 0.35) than baseline BP(rho = 0.18). Heritability estimates trended higher for longitudinal traits than for cross-sectional traits, providing evidence for different genetic architectures. Furthermore, the longitudinal data identified up to 20% more BP known associations than did cross-sectional data. Our analyses of longitudinal BP data in diverse ethnic groups identified novel BP loci associated with BP trajectory, indicating a need for further longitudinal GWAS on BP and other age-related traits.
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http://dx.doi.org/10.1038/s41598-021-83450-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893038PMC
February 2021

Exome Sequencing and Congenital Heart Disease in Sub-Saharan Africa.

Circ Genom Precis Med 2021 02 15;14(1):e003108. Epub 2021 Jan 15.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda (A.F.M., B.O., C.T.-N., Y.A.A., M.M., P.K.).

Background: Congenital heart disease (CHD) is the most common birth defect and affects roughly 1% of the global population. There have been many large CHD sequencing projects in developing countries but none in sub-Saharan Africa. In this exome sequencing study, we recruited families from Lagos, Nigeria, affected by structural heart disease.

Methods: Ninety-eight participants with CHD and an average age of 3.6 years were recruited from Lagos, Nigeria. Exome sequencing was performed on probands and parents when available. For genes of high interest, we conducted functional studies in using a cardiac-specific RNA interference-based gene silencing system.

Results: The 3 most common CHDs were tetralogy of Fallot (20%), isolated ventricular septal defect (14%), and transposition of the great arteries (8%). Ten percent of the cohort had pathogenic or likely pathogenic variants in genes known to cause CHD. In 64 complete trios, we found 34 de novo variants that were not present in the African population in the Genome Aggregation Database (v3). Nineteen loss of function variants were identified using the genome-wide distribution of selection effects for heterozygous protein-truncating variants (s). Nine genes caused a significant mortality when silenced in the heart, including 4 novel disease genes not previously associated with CHD (, and ).

Conclusions: This study identifies novel candidate genes and variants for CHD and facilitates comparisons with previous CHD sequencing studies in predominantly European cohorts. The study represents an important first step in genomic studies of CHD in understudied populations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01952171.
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http://dx.doi.org/10.1161/CIRCGEN.120.003108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887052PMC
February 2021

Time-to-event modeling of hypertension reveals the nonexistence of true controls.

Elife 2020 12 1;9. Epub 2020 Dec 1.

Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, United States.

Given a lifetime risk of ~90% by the ninth decade of life, it is unknown if there are true controls for hypertension in epidemiological and genetic studies. Here, we compared Bayesian logistic and time-to-event approaches to modeling hypertension. The median age at hypertension was approximately a decade earlier in African Americans than in European Americans or Mexican Americans. The probability of being free of hypertension at 85 years of age in African Americans was less than half that in European Americans or Mexican Americans. In all groups, baseline hazard rates increased until nearly 60 years of age and then decreased but did not reach zero. Taken together, modeling of the baseline hazard function of hypertension suggests that there are no true controls and that controls in logistic regression are cases with a late age of onset.
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http://dx.doi.org/10.7554/eLife.62998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707825PMC
December 2020

Genome-wide association study of prevalent and persistent cervical high-risk human papillomavirus (HPV) infection.

BMC Med Genet 2020 11 23;21(1):231. Epub 2020 Nov 23.

Department of Epidemiology and Public Health, University of Maryland School of Medicine, 660 West Redwood Street, Howard Hall, Room 119, Baltimore, MD, 21201, USA.

Background: Genetic factors may influence the susceptibility to high-risk (hr) human papillomavirus (HPV) infection and persistence. We conducted the first genome-wide association study (GWAS) to identify variants associated with cervical hrHPV infection and persistence.

Methods: Participants were 517 Nigerian women evaluated at baseline and 6 months follow-up visits for HPV. HPV was characterized using SPF/LiPA. hrHPV infection was positive if at least one carcinogenic HPV genotype was detected in a sample provided at the baseline visit and persistent if at least one carcinogenic HPV genotype was detected in each of the samples provided at the baseline and follow-up visits. Genotyping was done using the Illumina Multi-Ethnic Genotyping Array (MEGA) and imputation was done using the African Genome Resources Haplotype Reference Panel. Association analysis was done for hrHPV infection (125 cases/392 controls) and for persistent hrHPV infection (51 cases/355 controls) under additive genetic models adjusted for age, HIV status and the first principal component (PC) of the genotypes.

Results: The mean (±SD) age of the study participants was 38 (±8) years, 48% were HIV negative, 24% were hrHPV positive and 10% had persistent hrHPV infections. No single variant reached genome-wide significance (p < 5 X 10). The top three variants associated with hrHPV infections were intronic variants clustered in KLF12 (all OR: 7.06, p = 1.43 × 10). The top variants associated with cervical hrHPV persistence were in DAP (OR: 6.86, p = 7.15 × 10), NR5A2 (OR: 3.65, p = 2.03 × 10) and MIR365-2 (OR: 7.71, p = 2.63 × 10) gene regions.

Conclusions: This exploratory GWAS yielded suggestive candidate risk loci for cervical hrHPV infection and persistence. The identified loci have biological annotation and functional data supporting their role in hrHPV infection and persistence. Given our limited sample size, larger discovery and replication studies are warranted to further characterize the reported associations.
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http://dx.doi.org/10.1186/s12881-020-01156-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682060PMC
November 2020

High-depth African genomes inform human migration and health.

Nature 2020 10 28;586(7831):741-748. Epub 2020 Oct 28.

Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health.
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http://dx.doi.org/10.1038/s41586-020-2859-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759466PMC
October 2020

Genetic modifiers of long-term survival in sickle cell anemia.

Clin Transl Med 2020 Aug;10(4):e152

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Sickle cell anemia (SCA) is a clinically heterogeneous, monogenic disorder. Medical care has less-than-optimal impact on clinical outcomes in SCA in Africa due to several factors, including patient accessibility, poor access to resources, and non-availability of specific effective interventions for SCA.

Methods: Against this background, we investigated 192 African participants who underwent whole exome sequencing. Participants included 105 SCA patients spanning variable clinical expression: a "long survivor" group (age over 40 years), a "stroke" group (at least one episode of overt stroke), and a "random" group (patients younger than 40 years without overt cerebrovascular disease). Fifty-eight ethnically matched homozygous hemoglobin A controls were also studied. Findings were validated in an independently recruited sample of 29 SCA patients. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated for each group, and gene-set association tests were conducted to test differences between groups.

Results: In the "long survivor" group, deleterious/loss-of-function variants were enriched in genes including CLCN6 (a voltage-dependent chloride channel for which rare deleterious variants have been associated with lower blood pressure) and OGHDL (important in arginine metabolism, which is a therapeutic target in SCA). In the "stroke" group, significant genes implicated were associated with increased activity of the blood coagulation cascade and increased complement activation, for example, SERPINC1, which encodes antithrombin. Oxidative stress and glutamate biosynthesis pathways were enriched in "long survivors" group. Published transcriptomic evidence provides functional support for the role of the identified pathways.

Conclusions: This study provides new gene sets that contribute to variability in clinical expression of SCA. Identified genes and pathways suggest new avenues for other interventions.
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http://dx.doi.org/10.1002/ctm2.152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423184PMC
August 2020

Genetics of Circulating Resistin Level, a Biomarker for Cardiovascular Diseases, Is Informed by Mendelian Randomization and the Unique Characteristics of African Genomes.

Circ Genom Precis Med 2020 10 2;13(5):488-503. Epub 2020 Sep 2.

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.

Background: Resistin, a protein linked with inflammation and cardiometabolic diseases, is one of few proteins for which genome-wide association studies consistently report variants within and near the coding gene (). Here, we took advantage of the reduced linkage disequilibrium in African populations to infer genetic causality for circulating resistin levels by performing genome-wide association studies, whole-exome analysis, fine mapping, Mendelian randomization, and transcriptomic data analyses.

Methods: Genome-wide association studies and fine-mapping analyses for resistin were performed in 5621 African-ancestry individuals, including 3754 continental Africans and 1867 African Americans. Causal variants identified were subsequently used as an instrumental variable in Mendelian randomization analyses for homeostatic modeling-derived insulin resistance index, body mass index, and type 2 diabetes.

Results: The lead variant (rs3219175, in the promoter region of ) for the single locus detected was the same for continental Africans (=5.0×10) and for African Americans (9.5×10), respectively explaining 12.1% and 8.5% of variance in circulating resistin. Fine-mapping analyses and functional annotation revealed this variant as likely causal affecting circulating resistin levels as a cis-eQTL increasing expression. Additional variants regulating resistin levels were upstream of with genes , , and showing the strongest association using integrative analysis of genome-wide association studies with transcriptomic data. Mendelian randomization analyses did not provide evidence for resistin increasing insulin resistance, body mass index, or type 2 diabetes risk in African-ancestry populations.

Conclusions: Taking advantage of the fine-mapping resolution power of African genomes, we identified a single variant (rs3219175) as the likely causal variant responsible for most of the variability in circulating resistin levels. In contrast to findings in some other ancestry populations, we showed that resistin does not seem to increase insulin resistance and related cardiometabolic traits in African-ancestry populations.
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http://dx.doi.org/10.1161/CIRCGEN.120.002920DOI Listing
October 2020

Non-random distribution of deleterious mutations in the DNA and protein-binding domains of IRF6 are associated with Van Der Woude syndrome.

Mol Genet Genomic Med 2020 08 17;8(8):e1355. Epub 2020 Jun 17.

School of Public Health, Addis Ababa University, Addis Ababa, Ethiopia.

Background: The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well-organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA-binding (exon 3, 4) or protein-binding domains (exon 7-9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico.

Methods: We used PubMed with the search terms; "Van der Woude syndrome," "Popliteal pterygium syndrome," "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percentage of deleterious variants.

Results: Twenty-one new mutations were identified from nine papers. The majority of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7-9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein-binding domain (exon 7-9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported nonsense mutations (p.Ser424*and p.Arg250*).

Conclusion: Mutations in the protein and DNA-binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.
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http://dx.doi.org/10.1002/mgg3.1355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434609PMC
August 2020

Epigenome-wide association study for perceived discrimination among sub-Saharan African migrants in Europe - the RODAM study.

Sci Rep 2020 03 18;10(1):4919. Epub 2020 Mar 18.

Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.

Sub-Saharan African (SSA) migrants in Europe experience psychosocial stressors, such as perceived discrimination (PD). The effect of such a stressor on health could potentially be mediated via epigenetics. In this study we performed an epigenome-wide association study (EWAS) to assess the association between levels of PD with genome-wide DNA methylation profiles in SSA migrants. The Illumina 450 K DNA-methylation array was used on whole blood samples of 340 Ghanaian adults residing in three European cities from the cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) study. PD was assessed using sum scores of the Everyday Discrimination Scale (EDS). Differentially methylated positions and regions (DMPs and DMRs) were identified through linear regression analysis. Two hypo-methylated DMPs, namely cg13986138 (CYFIP1) and cg10316525(ANKRD63), were found to be associated with PD. DMR analysis identified 47 regions associated with the PD. To the best of our knowledge, this survey is the first EWAS for PD in first generation SSA migrants. We identified two DMPs associated with PD. Whether these associations underlie a consequence or causal effect within the scope of biological functionality needs additional research.
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http://dx.doi.org/10.1038/s41598-020-61649-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080832PMC
March 2020

Gut Microbiome Profiles Are Associated With Type 2 Diabetes in Urban Africans.

Front Cell Infect Microbiol 2020 25;10:63. Epub 2020 Feb 25.

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.

Gut dysbiosis has been associated with several disease outcomes including diabetes in human populations. Currently, there are no studies of the gut microbiome composition in relation to type 2 diabetes (T2D) in Africans. Here, we describe the profile of the gut microbiome in non-diabetic adults (controls) and investigate the association between gut microbiota and T2D in urban West Africans. Gut microbiota composition was determined in 291 Nigerians (98 cases, 193 controls) using fecal 16S V4 rRNA gene sequencing done on the Illumina MiSeq platform. Data analysis of operational taxonomic units (OTU) was conducted to describe microbiome composition and identify differences between T2D and controls. The most abundant phyla were , and . , and were significantly lower in cases than controls ( < 0.001). Feature selection analysis identified a panel of 18 OTUs enriched in cases that included . A panel of 17 OTUs that was enriched in the controls included , and . OTUs with strain-level annotation showing the largest fold-change included (logFC = -3.1; = 4.2 × 10), (logFC = -2.5; = 0.005), (logFC = -1.76; = 0.01), all lower in cases. These findings are notable because supplementation with and has been shown to improve hyperglycemia and reduce insulin resistance in murine models. This first investigation of gut microbiome and diabetes in urban Africans shows that T2D is associated with compositional changes in gut microbiota highlighting the possibility of developing strategies to improve glucose control by modifying bacterial composition in the gut.
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http://dx.doi.org/10.3389/fcimb.2020.00063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052266PMC
April 2021

Congenital heart disease in school children in Lagos, Nigeria: Prevalence and the diagnostic gap.

Am J Med Genet C Semin Med Genet 2020 03 13;184(1):47-52. Epub 2020 Feb 13.

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Congenital heart disease (CHD) in low-and-middle income countries (LMIC) is often characterized by late presentation resulting from inadequate screening and healthcare access in these regions. Accurate estimates of the burden of CHD among school children are often lacking. The objective of this study was to determine the prevalence and distribution of CHD among school children in two communities (urban and semi-urban) in south western Nigeria. Using clinical assessment and portable echocardiography, 4107 school children aged 5 years to 16 years in Lagos, Nigeria, were selected using a multistage sampling procedure and screened for CHD. Diagnosis of CHD was made after echocardiography. Children identified with CHD were referred to a tertiary hospital for appropriate cardiac care. The 4,107 children screened had a mean age of 11.3 ± 2.7 years and 53.7% were females. Twenty seven children had echocardiography-confirmed CHD, representing a prevalence of CHD among school children in Lagos, Nigeria of 6.6 per 1000 children. Acyanotic CHD constituted 96.3% of detected cases. Two children diagnosed with CHD (Tetralogy of Fallot and severe pulmonary valve stenosis respectively) had successful intervention. The prevalence of previously undiagnosed CHD among school children in Lagos Nigeria is substantial and highlights gaps in the health care system and school health programs. Echocardiographic screening of school children provides an opportunity for missed early diagnosis and treatment of CHD and reduces the prevalence of first-diagnosed CHD in adulthood. Therefore, focused clinical examination of school children followed by echocardiography is a strategy that could bridge this diagnostic and treatment gap in CHD.
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http://dx.doi.org/10.1002/ajmg.c.31779DOI Listing
March 2020

and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry.

Proc Natl Acad Sci U S A 2020 01 23;117(1):552-562. Epub 2019 Dec 23.

Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305.

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant * and * alleles were associated with overall SSc risk, and the * allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the * and * alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of in defining autoantibody subtypes. The association of the * allele with the ATA subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and * allele frequency in multiple populations was observed ( = 0.98, = 3 × 10). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.
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http://dx.doi.org/10.1073/pnas.1906593116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955366PMC
January 2020
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