RESUMO
OBJECTIVE: The objective of this study was to identify genetic variants associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. PARTICIPANTS AND METHODS: We carried out a genome-wide association study in 175 individuals with ACE inhibitor-associated angioedema and 489 ACE inhibitor-exposed controls from Nashville (Tennessee) and Marshfield (Wisconsin). We tested for replication in 19 cases and 57 controls who participated in Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). RESULTS: There were no genome-wide significant associations of any single-nucleotide polymorphism (SNP) with angioedema. Sixteen SNPs in African Americans and 41 SNPs in European Americans were associated moderately with angioedema (P<10) and evaluated for association in ONTARGET. The T allele of rs500766 in PRKCQ was associated with a reduced risk, whereas the G allele of rs2724635 in ETV6 was associated with an increased risk of ACE inhibitor-associated angioedema in the Nashville/Marshfield sample and ONTARGET. In a candidate gene analysis, rs989692 in the gene encoding neprilysin (MME), an enzyme that degrades bradykinin and substance P, was significantly associated with angioedema in ONTARGET and Nashville/Marshfield African Americans. CONCLUSION: Unlike other serious adverse drug effects, ACE inhibitor-associated angioedema is not associated with a variant with a large effect size. Variants in MME and genes involved in immune regulation may be associated with ACE inhibitor-associated angioedema.
Assuntos
Angioedema/induzido quimicamente , Angioedema/genética , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Isoenzimas/genética , Neprilisina/genética , Proteína Quinase C/genética , Proteínas Proto-Oncogênicas c-ets/genética , Ramipril/efeitos adversos , Proteínas Repressoras/genética , Negro ou Afro-Americano/genética , Angioedema/enzimologia , Angioedema/etnologia , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Benzoatos/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Proteína Quinase C-theta , Ramipril/administração & dosagem , Ramipril/uso terapêutico , Telmisartan , População Branca/genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
We repurposed existing genotypes in DNA biobanks across the Electronic Medical Records and Genomics network to perform a genome-wide association study for primary hypothyroidism, the most common thyroid disease. Electronic selection algorithms incorporating billing codes, laboratory values, text queries, and medication records identified 1317 cases and 5053 controls of European ancestry within five electronic medical records (EMRs); the algorithms' positive predictive values were 92.4% and 98.5% for cases and controls, respectively. Four single-nucleotide polymorphisms (SNPs) in linkage disequilibrium at 9q22 near FOXE1 were associated with hypothyroidism at genome-wide significance, the strongest being rs7850258 (odds ratio [OR] 0.74, p = 3.96 × 10(-9)). This association was replicated in a set of 263 cases and 1616 controls (OR = 0.60, p = 5.7 × 10(-6)). A phenome-wide association study (PheWAS) that was performed on this locus with 13,617 individuals and more than 200,000 patient-years of billing data identified associations with additional phenotypes: thyroiditis (OR = 0.58, p = 1.4 × 10(-5)), nodular (OR = 0.76, p = 3.1 × 10(-5)) and multinodular (OR = 0.69, p = 3.9 × 10(-5)) goiters, and thyrotoxicosis (OR = 0.76, p = 1.5 × 10(-3)), but not Graves disease (OR = 1.03, p = 0.82). Thyroid cancer, previously associated with this locus, was not significantly associated in the PheWAS (OR = 1.29, p = 0.09). The strongest association in the PheWAS was hypothyroidism (OR = 0.76, p = 2.7 × 10(-13)), which had an odds ratio that was nearly identical to that of the curated case-control population in the primary analysis, providing further validation of the PheWAS method. Our findings indicate that EMR-linked genomic data could allow discovery of genes associated with many diseases without additional genotyping cost.
Assuntos
Fatores de Transcrição Forkhead/genética , Hipotireoidismo/genética , Idoso , Algoritmos , Feminino , Marcadores Genéticos , Variação Genética , Genoma , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Sistemas Computadorizados de Registros Médicos , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos TestesRESUMO
Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system with a prominent genetic component. The primary genetic risk factor is the human leukocyte antigen (HLA)-DRB1*1501 allele; however, much of the remaining genetic contribution to MS has not been elucidated. The authors investigated the relation between variation in DNA repair pathway genes and risk of MS. Single-locus association testing, epistatic tests of interactions, logistic regression modeling, and nonparametric Random Forests analyses were performed by using genotypes from 1,343 MS cases and 1,379 healthy controls of European ancestry. A total of 485 single nucleotide polymorphisms within 72 genes related to DNA repair pathways were investigated, including base excision repair, nucleotide excision repair, and double-strand breaks repair. A single nucleotide polymorphism variant within the general transcription factor IIH, polypeptide 4 gene, GTF2H4, on chromosome 6p21.33 was significantly associated with MS (odds ratio = 0.7, P = 3.5 x 10(-5)) after accounting for multiple testing and was not due to linkage disequilibrium with HLA-DRB1*1501. Although other candidate genes examined here warrant further follow-up studies, collectively, these results derived from a well-powered study do not support a strong role for common variation within DNA repair pathway genes in MS.