Search

We explored the role of genetic ancestry in shaping the genetic architecture of whole blood gene expression using whole genome and RNA sequencing data from 2,733 African American and Hispanic/Latino children. We find that heritability of gene expression significantly increases with greater proportion of genome-wide African ancestry and decreases with higher levels of Indigenous American ancestry. Fine-mapping of expression quantitative trait loci (eQTLs) in individuals with predominantly African or Indigenous American ancestry revealed ancestry-specific eQTLs in over 30% of heritable genes. We leveraged our data to train genetically derived transcriptome prediction models, which identified significantly more associated genes than GTEx or MESA models when applied to 28 traits from a multi-ancestry population. Our findings underscore the importance of increasing representation from ancestrally diverse populations in genomic studies to enable new discoveries and ensure their equitable translation., {"references":["Kachuri L, Mak ACY, Hu D et al. (2022) Gene expression in African Americans and Latinos reveals ancestry-specific patterns of genetic architecture. bioRxiv. doi:10.1101/2021.08.19.456901"]}

Background: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations. Objective: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles. Methods: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases. Results: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (C5orf46) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels. Conclusions: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2. This work was funded by the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033 and the European Regional Development Fund 'ERDF A way of making Europe' by the European Union grant [SAF2017-83417R], and by MCIN/AEI/10.13039/501100011033 [grant PID2020-116274RB-I00]. Whole-genome sequencing for the TOPMed (Trans-Omics in Precision Medicine) program was supported by the NHLBI. Whole-genome sequencing for GALA II (NHLBI TOPMed: Genes-environments and Admixture in Latino Americans) Study (phs000920) was performed at the New York Genome Center [3R01HL117004-01S3]. Centralised read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center [3R01HL-117626-02S1]. Phenotype harmonization, data management, sample-identity quality control, and general study coordination were provided by the TOPMed Data Coordinating Center [3R01HL-120393-02S1]. WGS of part of GALA II was performed by New York Genome Center under The Centers for Common Disease Genomics of the Genome Sequencing Program (GSP) Grant [UM1 HG008901]. The GSP Coordinating Center [U24 HG008956] contributed to cross-program scientific initiatives and provided logistical and general study coordination. GSP is funded by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and the National Eye Institute [NA]. This work was also supported by the Sandler Family Foundation[NA], the American Asthma Foundation [NA], the RWJF Amos Medical Faculty Development Program [NA], Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II [NA], the National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL117004, R01HL128439, R01HL135156, X01HL134589, R01HL155024, R01AI079139, R01HL141845, R01HL118267 and R01DK113003], the National Institute of Health and Environmental Health Sciences [R01ES015794 and R21ES24844], the National Institute on Minority Health and Health Disparities [R01MD010443 and R56MD013312], the Tobacco-Related Disease Research Program [Award Number 24RT-0025 and 27IR-0030]. The BAMSE study was funded by the Swedish Heart-Lung Foundation and the Swedish Research Council and Region Stockholm (ALF project and database maintenance). The INMA study was funded by the Instituto de Salud Carlos III [Red INMA G03/176, CB06/02/0041], Spanish Ministry of Health [FIS-FEDER PI16/1288, FIS-FEDER PI19/1338; Miguel Servet FEDER 15/0025 and 20/0006], Generalitat Valenciana [BEST/2020/ 059]. This work was also partially funded by Fundación Canaria Instituto de Investigación Sanitaria de Canarias [PIFIISC19/17]. JV was funded by ISCIII and the European Regional Development Fund 'ERDF A way of making Europe' by the European Union [PI16/00049 and PI19/00141]. MP-Y was funded by the Ramón y Cajal Program [RYC-2015-17205] by MCIN/AEI/10.13039/501100011033 and by the European Social Fund 'ESF Investing in your future' and by the EAACI Allergopharma Award 2021. JV and M.P.-Y were funded Instituto de Salud Carlos III (ISCIII) [CB06/06/1088]. EH-L was supported by a fellowship awarded by MCIN/AEI/10.13039/501100011033 and by 'ESF Investing in your future' [PRE2018-083837]. JP-G was supported by a fellowship awarded by the Spanish Ministry of Universities [FPU19/02175].

Type 2 T helper (T(H)2) cells are protective against parasitic worm infections but also aggravate allergic inflammation. Although the role of dendritic cells (DCs) in T(H)2 cell differentiation is well established, the underlying mechanisms are largely unknown. Here, we show that DC induction of T(H)2 cells depends on membrane-associated RING-CH-1 (MARCH1) ubiquitin ligase. The pro-T(H)2 effect of MARCH1 relied on lymph node (LN)–resident DCs, which triggered T cell receptor (TCR) signaling and induced GATA-3 expression from naïve CD4(+) T cells independent of tissue-driven migratory DCs. Mice with mutations in the ubiquitin acceptor sites of MHCII and CD86, the two substrates of MARCH1, failed to develop T(H)2 cells. These findings suggest that T(H)2 cell development depends on ubiquitin-mediated clearance of antigen-presenting and costimulatory molecules by LN-resident DCs and consequent control of TCR signaling.

The purposes of this study were to examine the thermoregulatory and body fluid balance responses in chronically heat acclimatized children, i.e., indigenous to a tropical climate, during exercise in four outdoor conditions and the effects of dehydration on their thermoregulatory response. Nine children (age = 13.3 ± 1.9 yr, VO2 max = 45.5 ± 9.2 ml · kg-1 · min-1 ) cycled at 60% VO2 max each under four conditions: sun exposure voluntary drinking (SuVD), sun exposure forced drinking (SuFD), shaded voluntary drinking (ShVD), and shaded forced drinking (ShFD). Exercise sessions consisted of four 20-min exercise bouts alternating with 25-min rest periods. Globe temperature and the WBGT index were higher during SuVD and SuFD compared to ShVD and ShFD (P < 0.05). The change in rectal temperature, metabolic heat production, and heat storage did not differ among the conditions. Total water intake (% IBW) was higher during SuFD (4.1 ± 0.01) and ShFD (3.7 ± 0.1) compared to SuVD (2.1 ± 0.1) and ShVD (1.0 ± 0.1) and during SuVD compared to ShVD (P < 0.05). Sweating rate (L · hr-1 ) was higher during SuFD (0.7 ± 0.1) and ShFD (0.6 ± 0.1) compared to SuVD (0.5 ± 0.1) and ShVD (0.4 ± 0.1) (P < 0.05). Total fluid loss did not differ among conditions (SuVD = 1.7 ± 0.4; SuFD = 1.5 ± 0.4; ShVD = 2.1 ± 0.2; ShFD = 1.3 ± 0.3). Results indicate that when exercising in a tropical climate, chronically heat acclimatized children demonstrate mild voluntary dehydration and adequate heat dissipation. © 1995 Wiley-Liss, Inc.