Genome-Wide Association Study Identifies Pharmacogenomic Variants Associated With Metformin Glycemic Response in African American Patients With Type 2 Diabetes.

OBJECTIVE: Metformin is the most common treatment for type 2 diabetes (T2D). However, there have been no pharmacogenomic studies for T2D in which a population of color was used in the discovery analysis. This study sought to identify genomic variants associated with metformin response in African American patients with diabetes. RESEARCH DESIGN AND METHODS: Patients in the discovery set were adult, African American participants from the Diabetes Multi-omic Investigation of Drug Response (DIAMOND), a cohort study of patients with T2D from a health system serving southeast Michigan. DIAMOND participants had genome-wide genotype data and longitudinal electronic records of laboratory results and medication fills. The genome-wide discovery analysis identified polymorphisms correlated to changes in glycated hemoglobin (HbA1c) levels among individuals on metformin monotherapy. Lead associations were assessed for replication in an independent cohort of African American participants from Kaiser Permanente Northern California (KPNC) and in European American participants from DIAMOND. RESULTS: The discovery set consisted of 447 African American participants, whereas the replication sets included 353 African American KPNC participants and 466 European American DIAMOND participants. The primary analysis identified a variant, rs143276236, in the gene ARFGEF3, which met the threshold for genome-wide significance, replicated in KPNC African Americans, and was still significant in the meta-analysis (P = 1.17 × 10-9). None of the significant discovery variants replicated in European Americans DIAMOND participants. CONCLUSIONS: We identified a novel and biologically plausible genetic variant associated with a change in HbA1c levels among African American patients on metformin monotherapy. These results highlight the importance of diversity in pharmacogenomic studies.

Differences in Self-Reported Food Allergy and Food-Associated Anaphylaxis by Race and Ethnicity Among SAPPHIRE Cohort Participants.

BACKGROUND: Although food allergies are considered common, relatively little is known about disparities in food allergy by race in the United States. OBJECTIVE: To evaluate differences in reported food allergy and food-associated anaphylaxis among individuals enrolled in a longitudinal cohort study from metropolitan Detroit, Michigan. METHODS: Participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) were asked about food allergies, including the inciting food and associated symptoms. Individuals were considered to have food-associated anaphylaxis if symptoms coincided with established clinical criteria. Logistic regression was used to assess whether race difference persisted after adjusting for and stratifying by potential confounders. African genetic ancestry was individually estimated among African American SAPPHIRE participants to assess whether ancestry was associated with food allergy. RESULTS: Within the SAPPHIRE cohort, African American participants were significantly more likely to report food allergy (26.1% vs 17%; P = 3.47 × 10-18) and have food-associated anaphylactic symptoms (12.7% vs 7%; P = 4.65 × 10-14) when compared with European American participants. Allergy to seafood accounted for the largest difference (13.1% vs 4.6%; P = 1.38 × 10-31). Differences in food allergy by race persisted after adjusting for potential confounders including asthma status. Among African American participants, the proportion of African ancestry was not associated with any outcome evaluated. CONCLUSION: Compared with European Americans, African Americans appear to be at higher risk for developing food allergy and food-associated anaphylaxis, particularly with regard to seafood allergy. The lack of association with genetic ancestry suggests that socioenvironmental determinants may play a role in these disparities.

Predicting death from COVID-19 using pre-existing conditions: implications for vaccination triage.

INTRODUCTION: Global shortages in the supply of SARS-CoV-2 vaccines have resulted in campaigns to first inoculate individuals at highest risk for death from COVID-19. Here, we develop a predictive model of COVID-19-related death using longitudinal clinical data from patients in metropolitan Detroit. METHODS: All individuals included in the analysis had a laboratory-confirmed SARS-CoV-2 infection. Thirty-six pre-existing conditions with a false discovery rate p<0.05 were combined with other demographic variables to develop a parsimonious prediction model using least absolute shrinkage and selection operator regression. The model was then prospectively validated in a separate set of individuals with confirmed COVID-19. RESULTS: The study population consisted of 15 502 individuals with laboratory-confirmed SARS-CoV-2. The main prediction model was developed using data from 11 635 individuals with 709 reported deaths (case fatality ratio 6.1%). The final prediction model consisted of 14 variables with 11 comorbidities. This model was then prospectively assessed among the remaining 3867 individuals (185 deaths; case fatality ratio 4.8%). When compared with using an age threshold of 65 years, the 14-variable model detected 6% more of the individuals who would die from COVID-19. However, below age 45 years and its risk equivalent, there was no benefit to using the prediction model over age alone. DISCUSSION: Using a prediction model, such as the one described here, may help identify individuals who would most benefit from COVID-19 inoculation, and thereby may produce more dramatic initial drops in deaths through targeted vaccination.

Mapping the 17q12-21.1 Locus for Variants Associated with Early-Onset Asthma in African Americans.

Rationale: The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants.Objectives: To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals.Methods: We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) (n = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (n = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) (n = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant.Measurements and Main Results: The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of GSDMB (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms.Conclusions: A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.

Asthma and its relationship to mitochondrial copy number: Results from the Asthma Translational Genomics Collaborative (ATGC) of the Trans-Omics for Precision Medicine (TOPMed) program.

BACKGROUND: Mitochondria support critical cellular functions, such as energy production through oxidative phosphorylation, regulation of reactive oxygen species, apoptosis, and calcium homeostasis. OBJECTIVE: Given the heightened level of cellular activity in patients with asthma, we sought to determine whether mitochondrial DNA (mtDNA) copy number measured in peripheral blood differed between individuals with and without asthma. METHODS: Whole genome sequence data was generated as part of the Trans-Omics for Precision Medicine (TOPMed) Program on participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) and the Study of African Americans, Asthma, Genes, & Environment II (SAGE II). We restricted our analysis to individuals who self-identified as African American (3,651 asthma cases and 1,344 controls). Mitochondrial copy number was estimated using the sequencing read depth ratio for the mitochondrial and nuclear genomes. Respiratory complex expression was assessed using RNA-sequencing. RESULTS: Average mitochondrial copy number was significantly higher among individuals with asthma when compared with controls (SAPPHIRE: 218.60 vs. 200.47, P<0.001; SAGE II: 235.99 vs. 223.07, P<0.001). Asthma status was significantly associated with mitochondrial copy number after accounting for potential explanatory variables, such as participant age, sex, leukocyte counts, and mitochondrial haplogroup. Despite the consistent relationship between asthma status and mitochondrial copy number, the latter was not associated with time-to-exacerbation or patient-reported asthma control. Mitochondrial respiratory complex gene expression was disproportionately lower in individuals with asthma when compared with individuals without asthma and other protein-encoding genes. CONCLUSIONS: We observed a robust association between asthma and higher mitochondrial copy number. Asthma having an effect on mitochondria function was also supported by lower respiratory complex gene expression in this group.

Integrative approach identifies corticosteroid response variant in diverse populations with asthma.

BACKGROUND: Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved nonwhite populations. OBJECTIVE: We sought to identify genetic predictors of ICS response in multiple population groups with asthma. METHODS: The discovery group comprised African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) who underwent 6 weeks of monitored ICS therapy (n = 244). A genome-wide scan was performed to identify single nucleotide polymorphism (SNP) variants jointly associated (ie, the combined effect of the SNP and SNP × ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in 3 additional groups: African Americans (n = 803 and n = 563) and Latinos (n = 1461). RNA sequencing data from 408 asthmatic patients and 405 control subjects were used to examine whether genotype was associated with gene expression. RESULTS: One variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P = 7.79 × 10-8) and was jointly associated with asthma exacerbations in 3 validation cohorts (P = .023, P = .029, and P = .041). RNA sequencing analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P = 6.10 × 10-4). RNASE2 encodes eosinophil-derived neurotoxin, and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (ie, high pretreatment eosinophil-derived neurotoxin levels or blood eosinophil counts). CONCLUSION: We identified a variant, rs3827907, that appears to influence response to ICS treatment in multiple population groups and likely mediates its effect through eosinophils.