Genome-wide association study identifies PERLD1 as asthma candidate gene

Abstract

BackgroundRecent genome-wide association studies (GWAS) for asthma have been successful in identifying novel associations which have been well replicated. The aim of this study is to identify the genetic variants that influence predisposition towards asthma in an ethnic Chinese population in Singapore using a GWAS approach.MethodsA two-stage GWAS was performed in case samples with allergic asthma, and in control samples without asthma and atopy. In the discovery stage, 490 case and 490 control samples were analysed by pooled genotyping. Significant associations from the first stage were evaluated in a replication cohort of 521 case and 524 control samples in the second stage. The same 980 samples used in the discovery phase were also individually genotyped for purposes of a combined analysis. An additional 1445 non-asthmatic atopic control samples were also genotyped.Results19 promising SNPs which passed our genome-wide P value threshold of 5.52 × 10-8 were individually genotyped. In the combined analysis of 1011 case and 1014 control samples, SNP rs2941504 in PERLD1 on chromosome 17q12 was found to be significantly associated with asthma at the genotypic level (P = 1.48 × 10-6, ORAG = 0.526 (0.369-0.700), ORAA = 0.480 (0.361-0.639)) and at the allelic level (P = 9.56 × 10-6, OR = 0.745 (0.654-0.848)). These findings were found to be replicated in 3 other asthma GWAS studies, thus validating our own results. Analysis against the atopy control samples suggested that the SNP was associated with allergic asthma and not to either the asthma or allergy components. Genotyping of additional SNPs in 100 kb flanking rs2941504 further confirmed that the association was indeed to PERLD1. PERLD1 is involved in the modification of the glycosylphosphatidylinositol anchors for cell surface markers such as CD48 and CD59 which are known to play multiple roles in T-cell activation and proliferation.ConclusionsThese findings reveal the association of a PERLD1 as a novel asthma candidate gene and reinforce the involvement of genes on the 17q12-21 chromosomal region in the etiology of asthma.

Complex genetics of pulmonary diseases: lessons from genome-wide association studies and next-generation sequencing

“…Other groups performed GWAS with focus on patients of Asian descent 12–14 . Two groups specifically identified susceptibility polymorphisms of PERLD1 and HLA-DPA1 genes in Chinese and Japanese peoples, respectively (Table 1).…”

“…Two groups specifically identified susceptibility polymorphisms of PERLD1 and HLA-DPA1 genes in Chinese and Japanese peoples, respectively (Table 1). PERLD1 particularly has some effects on activation and proliferation of T-cells 14 . Hirota et al also performed a GWAS in a cohort composed of more than 7,000 and 27,000 asthmatic and control adult Japanese individuals, respectively.…”

“…In addition, our review did not find GWASs identifying lung disease polymorphisms specific to males or females (gender specific polymorphisms). For instance, while there is a slightly higher prevalence of asthma attack among women (53.5%) 92 , GWASs failed to identify gender specific asthma polymorphisms when looking for it 10,14,18 . As another example, the male gender is one the risk factors for predicting the outcome of IPF 93 , yet, Fingerlin et al did not find any significant association of SNPs with gender 45 .…”

Genes Associated with RSV Lower Respiratory Tract Infection and Asthma: The Application of Genetic Epidemiological Methods to Understand Causality

“…More recently, many of these large-scale GWAS have been performed on the spectrum of asthma phenotypes in diverse populations [76–104], identifying genetic associations with asthma. While both candidate gene and GWAS have been successful in identifying and replicating associations, very few have been proven to be causal, reflecting a polygenic inheritance pattern and environmental components.…”

Genetic Susceptibility to Asthma and Genetic Interactions in the 5q31-q33 and 16p11 Regions in Sudanese Families

“…These cytokines are well known mediators in the pathogenesis of asthma [16]. Genetic polymorphisms of those cytokine and their receptors are the focus of many genetic association studies [12][13][14][15]. Associations of these cytokines with susceptibility to asthma have been found in many different populations around the world but none was done in Sudan.…”