Further replication studies of the EVE Consortium meta-analysis identifies 2 asthma risk loci in European Americans

Rachel A Myers,Lindsey A Roth,Benjamin A Raby,Scott T Weiss,Hita Vora,Harold J Farber,Carole Ober,Esteban G Burchard,Celeste Eng,Albert M Levin,Eugene R Bleecker,Jinghua Liu,Robert F Lemanske,Kathleen C Barnes,Shannon Thyne,Luisa N Borrell,Kelley Meade,Pedro C Avila,W James Gauderman,Deborah A Meyers,L Keoki Williams,Penelope E Graves,Denise Serebrisky,Michael A Lenoir,Blanca E Himes,Isabelle Romieu,Rajesh Kumar,Dan L Nicolae,Rasika A Mathias,Juan C Celedón,Dara G Torgerson,Christopher R Gignoux,Frank D Gilliland,Stephanie J London,David V Conti ,Fernando D Martínez ,William Rodríguez-Cintrón ,Jingjing Xie ,Tania Schink ,Manuel E Soto-Quirós ,James Yang ,José Rodríguez‐Santana ,James W Baurley ,Lydiana Ávila

doi:10.1016/j.jaci.2012.07.054

Abstract

Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk. We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis. We selected 3186 single nucleotide polymorphisms for replication based on the P values from the EVE Consortium meta-analysis. These single nucleotide polymorphisms were genotyped in ethnically diverse replication samples from 9 different studies, totaling 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study, and the resulting test statistics were combined in a meta-analysis. Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined odds ratio= 1.18; 95% CI, 1.10-1.25) and rs9570077 (combined odds ratio=1.20; 95% CI, 1.12-1.29) on chromosome 13q21. We could not replicate any additional associations in the African Americans or Latinos. This extended replication study identified 2 additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latinos highlights the difficulty in replicating associations in admixed populations.

Highlights

Asthma is a common and complex disease, affecting approximately 300 million people worldwide [1]
The EVE Consortium study reported associations with single nucleotide polymorphisms (SNPs) near the TSLP gene, which was reported in a sub-analysis in GABRIEL as well as in previous studies [12, 19], and identified a novel association among African American individuals with SNPs in the PYHIN1 gene
We investigated whether or not there was an enrichment of small p-values at the 0.01 level in each of the four meta-analyses, one each in the European American, African American, Latino, and combined sample

Summary

Introduction

Asthma is a common and complex disease, affecting approximately 300 million people worldwide [1]. Their findings included associations in or near the genes IL1RL1IL1RL18, HLA-DQ, IL33, SMAD3, and GSDMA/GSDMB (17q21). Most of these loci had been previously been implicated in asthma or asthma-related phenotypes (e.g., 17q21 [7], HLA-DQ [14,15,16], IL33 [17], IL1RL1 [17, 18]) Most of these associations were observed in the EVE Consortium meta-analysis, which included both primary and replication individuals from European American, African American and Latino populations. Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk

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