Meta-Analysis of Hodgkin Lymphoma and Asthma Genome-Wide Association Scans reveals common variants in GATA3
Authors: Kong Yinfei , Khankhanian Pouya , Himmelstein Daniel , Hwang Amie E. , Rand Kristin A , Li Dalin , Van Den Berg David J. , Diepstra Arjan , Conti David V. , Bhatia Smita , Gourraud Pierre-Antoine , Glaser Sally L. , Mack Thomas M. , Oksenberg Jorge , Onel Kenan , Van Den Berg Anke , Jarrett Ruth F. , McKay James D. , Hjalgrim Henrik , Baranzini Sergio , Gilliland Frank D. , Gauderman W. James , Cozen Wendy 
Published: October 2019

Abstract
Both Hodgkin lymphoma (HL) and asthma are associated with relative isolation from early childhood infectious exposures (hygiene hypothesis) and a T-helper-2 (Th2)-skewed immune response. To test the hypothesis that there is some component of shared genetic etiology between HL and asthma, we examined the genetic overlap in data from genome-wide association study (GWAS) meta-analyses of the two diseases conducted in populations of European ancestry. The HL GWAS meta-analysis consisted of 1,816 HL cases and 7,877 controls, and the asthma GWAS meta-analysis consisted of 2,088 asthma cases and 2,743 controls. The combined HL-asthma GWAS data resulted in 904,634 common single nucleotide polymorphisms (SNPs) genotyped with both arrays. We observed a total of 9 common SNPs associated with both HL and asthma at p<0.0001, compared to 3 SNPs expected in both data sets at that significance level. Out of 66 genetic risk variants associated with HL at a genome-wide significance level of p<10-8, 5 variants replicated in the asthma GWAS dataset at p < 0.05. In a meta-analysis combining the HL and asthma GWAS data, we found genome-wide significant associations with two correlated SNPs (r2 =0.91) in the Th2 transcription factor gene GATA3 (rs422628, ORHL-asthma meta =1.25, p=3.36 x 10-9 and rs444929, ORHL-asthma meta = 1.26, p=2.09 x 10-8) that were not genome-wide significant in either disease alone (Table 1). The association with one SNP remained genome-wide significant in the meta-analysis combined with the nodular sclerosis subset (rs422628, ORHL-asthma meta =1.32, p=3.75 x 10-9), but not with other HL subtypes. An association with a SNP in IKZF3, a gene involved in B lymphocyte differentiation and proliferation, reached genome-wide significance only in the meta-analysis with the HL subset positive for Epstein-Barr virus (EBV) in the tumor (rs9909593, ORHL-asthma meta = 1.19, p=3.80 x 10-8). In a genetic diseasome analysis based on an ontological analysis of published GWAS data, HL, especially nodular sclerosis HL, was more closely related to asthma than to solid cancers. Recognition of overlap in genetic predisposition to HL and other immune diseases sheds light on the complex etiology of HL and may enable novel diagnostic and therapeutic approaches.
Abstract 135. Table 1 Genome-wide significant results of a meta-analysis combining Hodgkin lymphoma (HL) and asthma GWAS1data. HL GWAS1 Asthma GWAS1 Combined GWAS1 SNP2 Chr3 BP4 Gene OR5 P-value6 OR5 P-value6 OR5 P-value6 rs422628a 10 8151415 GATA3 1.24 1.13 x 10-5 1.31 6.39 x10-5 1.25 3.26 x 10-9 rs444929b 10 8150030 GATA3 1.26 3.24x 10-6 1.28 8.90 x 10-4 1.26 2.09 x 10-8 rs422628c 10 8151415 GATA3 1.33 7.77 x 10-6 1.31 6.39 x10-5 1.32 3.75 x 10-9 rs9909593d 17 35223675 IKZF3 1.11 2.60 x 10-1 1.25 5.06 x 10-8 1.19 3.80 x 10-8 1Genome-wide association scan 2Single nucleotide polymorphism 3Chromosome 4Base pair position 5Odds ratio 6P-values are derived from a meta-analysis using a fixed effects model with weights proportional to the square root of the number of cases. aAll Hodgkin lymphoma cases bAll Hodgkin lymphoma cases, SNP association reported in Cozen et al., Nat Comm, 2014 cNodular sclerosis cases only dEBV-positive cases only

Disclosures
No relevant conflicts of interest to declare.