Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations
NATURE GENETICS
Authors: Torgerson, Dara G.; Ampleford, Elizabeth J.; Chiu, Grace Y.; Gauderman, W. James; Gignoux, Christopher R.; Graves, Penelope E.; Himes, Blanca E.; Levin, Albert M.; Mathias, Rasika A.; Hancock, Dana B.; Baurley, James W.; Eng, Celeste; Stern, Debra A.; Celedon, Juan C.; Rafaels, Nicholas; Capurso, Daniel; Conti, David V.; Roth, Lindsey A.; Soto-Quiros, Manuel; Togias, Alkis; Li, Xingnan; Myers, Rachel A.; Romieu, Isabelle; Van Den Berg, David J.; Hu, Donglei; Hansel, Nadia N.; Hernandez, Ryan D.; Israel, Elliott; Salam, Muhammad T.; Galanter, Joshua; Avila, Pedro C.; Avila, Lydiana; Rodriquez-Santana, Jose R.; Chapela, Rocio; Rodriguez-Cintron, William; Diette, Gregory B.; Adkinson, N. Franklin; Abel, Rebekah A.; Ross, Kevin D.; Shi, Min; Faruque, Mezbah U.; Dunston, Georgia M.; Watson, Harold R.; Mantese, Vito J.; Ezurum, Serpil C.; Liang, Liming; Ruczinski, Ingo; Ford, Jean G.; Huntsman, Scott; Chung, Kian Fan; Vora, Hita; Li, Xia; Calhoun, William J.; Castro, Mario; Sienra-Monge, Juan J.; del Rio-Navarro, Blanca; Deichmann, Klaus A.; Heinzmann, Andrea; Wenzel, Sally E.; Busse, William W.; Gern, James E.; Lemanske, Robert F., Jr.; Beaty, Terri H.; Bleecker, Eugene R.; Raby, Benjamin A.; Meyers, Deborah A.; London, Stephanie J.; Gilliland, Frank D.; Burchard, Esteban G.; Martinez, Fernando D.; Weiss, Scott T.; Williams, L. Keoki; Barnes, Kathleen C.; Ober, Carole; Nicolae, Dan L.
Abstract
Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 x 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
Polymorphisms in interferon pathway genes and risk of Mycobacterium tuberculosis infection in contacts of tuberculosis cases in Brazil
INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES
Authors: Cubillos-Angulo, Juan Manuel; Arriaga, Maria B.; Melo, Mayla G. M.; Silva, Elisangela C.; Alvarado-Arnez, Lucia Elena; de Almeida, Alexandre S.; Moraes, Milton O.; Moreira, Adriana S. R.; Lapa e Silva, Jose R.; Fukutani, Kiyoshi F.; Sterling, Timothy R.; Hawn, Thomas R.; Kritski, Afranio L.; Oliyeira, Martha M.; Andrade, Bruno B.
Abstract
Background: Host genetic polymorphisms may be important in determining susceptibility to Mycobacterium tuberculosis (Mtb) infection, but their role is not fully understood. Detection of microbial DNA and activation of type I interferon (IFN) pathways regulate macrophage responses to Mtb infection. Methods: We examined whether seven candidate gene SNPs were associated with tuberculin skin test (TST) positivity in close contacts of microbiologically confirmed pulmonary TB patients in Brazil. Independent associations with TST positivity were tested using multivariable logistic regression (using genotypes and clinical variables) and genetic models. Results: Among 482 contacts of 145 TB index cases, 296 contacts were TST positive. Multivariable regression analysis adjusted for population admixture, age, family relatedness, sex and clinical variables related to increased TB risk demonstrated that SNPs in PYHIN1-IFI16-AIM2 rs1101998 (adjusted OR [aOR]: 3.72; 95% CI = 1.15-12.0; p = 0.028) and in PYHIN1-IFI16-AIM2 rs1633256 (aOR = 24.84; 95%CI = 2.26-272.95; p = 0.009) were associated with TST positivity in a recessive model. Furthermore, an IRF7 polymorphism (rs11246213) was associated with reduced odds of TST positivity in a dominant model (aOR: 0.50, 95%CI: 0.26-0.93; p = 0.029). Conclusions: Polymorphisms in PYHIN1-IFI16-AIM2 rs1633256, rs1101998 and in IRF7 rs11246213 were associated with altered susceptibility to Mtb infection in this Brazilian cohort. (C) 2019 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
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