GENETICS & IMMUNITY IN ALLERGY AND ASTHMA DAVID MARTINO SENIOR - PowerPoint PPT Presentation

GENETICS & IMMUNITY IN ALLERGY AND ASTHMA DAVID MARTINO SENIOR RESEARCH FELLOW CENTRE FOR FOOD AND ALLERGY RESEARCH

Overview • Evolution of human Th2 genes and their role in allergy • Population differences in disease susceptibility • What we (don’t) know about genetics of allergy and asthma • New insights from epigenetic mechanisms

Immunity, genes and the environment TH2 immunity COUNTER-REGULATION TH1 immunity

Selective pressures drive population diversity TH2 immunity INFLAMMATION Adapted from Sanchez-Mazas et al (2012). Philos Trans R Soc Lond, B, Biol Sci TH1 immunity

Evolution and allergy genes Biological networks of helminth associated genes Cytokine signaling Mediated inflammation Thyrotropin hormone signaling Integrin signaling Fumagalli M, et al (2010). BMC Evol Biol

The HealthNuts study SPT (peanut, egg, milk, sesame) and Population sample of 5300 infants Questionnaire at age 1 (73% participation) Follow-up at age 2, 4, 6 and 10yrs Oral food challenge for all sensitized children (1089) SPT negative controls (200)

Genetic diversity within HealthNuts CEU: Utah Residents (CEPH) with Northern and Western European Ancestry GBR: British in England and Scotland FIN: Finnish in Finland IBS: Iberian Population in Spain TSI: Toscani in Italia MXL: Mexican Ancestry from Los Angeles USA CLM: Colombians from Medellin, Colombia PUR: Puerto Ricans from Puerto Rico ASW: Americans of African Ancestry in SW USA YRI: Yoruba in Ibadan, Nigeria LWK: Luhya in Webuye, Kenya CHB: Han Chinese in Bejing, China JPT: Japanese in Tokyo, Japan CHS: Southern Han Chinese

Differential susceptibility by ancestry Food allergy and eczema 3-4 times higher in children of Asian ancestry Koplin et al, Allergy 2014

Caucasian Asian Not explained by environmental factors Lee et al Asia Pacific Allergy

POPULATION MIGRATION AND GENE FLOW Genotype Genotype Genotype Genotype

Selective pressures and population diversity

Selective pressures and population diversity

Selective pressures and population diversity POPULATION MIGRATION AND GENE FLOW Noor Suaini • Are genes associated with helminth and inflammatory pathways enriched for Asian Genotype Genotype ancestry? • Are they associated with food allergy? Genotype Genotype

Candidate gene studies in food allergy Skin barrier integrity: FLG SPINK5 Immune response: IL10 IL13 TGFBR1, II, SMAD3 CD14 STAT6 FOXP3

HealthNuts GWAS of peanut allergy 73 cases and 148 non-allergic controls defined by oral food challenge ~400,000 SNPs genotyped on the Illumina Omni v2.5 array ~3.4M SNPs imputed 102 classical 2-digit HLA alleles, 187 4-digit alleles, 2,205 polymorphic amino acid residues, 2,412 HLA SNPs Ancestry was inferred genetically and all analyses were adjusted for ancestry strata Association with case-control status was tested using logistic regression under an additive model, adjusted for sex and ancestry

Genome-wide association study of peanut allergy Genotyped SNPS 2-digit alleles 4-digit alleles Amino acids AA.DRB1.37 Martino et al, CEA 2016 (Accepted) Chromosome 6

SPINK5 association with clinical food allergy SPINK5 expression in the skin by rs9325071 Caucasians only Caucasians only SNP SNP A1 P F_FA OR F_NA 95% CI (L95 - U95) P rs9325072 0.01 1.65 1.10 2.48 rs3815741 0.01 1.65 1.10 2.46 rs17641748 0.01 1.69 1.13 2.54 rs4705054 0.05 1.42 1.00 2.03 rs9325071 0.10 1.34 0.94 1.89 Sarah Ashley et al, Allergy 2016, under review

Genetic susceptibility in allergic disease Gupta et al, JACI 2016.

Coeliac disease genomic risk score From single gene hits…. To multi-gene risk scores Abraham et al, PLoS Genetics 2014.

NON-GENETIC GENETIC FACTORS FACTORS • DNA methylation • SNPS • Histone modification • Recombination • Non coding RNA • Insertions/Deletions Traditional environment Modern environment

Biological sensors of environmental stimuli

Biological sensors of environmental stimuli Metabolic signals Stress Toxins Inflammation

Epigenetic sensors of dietary folate Folic acid is a dietary one-carbon methyl donor that is a substrate for DNA methylation and plays a central Trimester 3 health Maternal folate and allergy role in development. assessment Supplementation with folic acid is recommended in pregnancy, but evidence has linked high folate Low High consumption to asthma and allergy. CD4 T-cell Does maternal folate consumption in pregnancy alter the fetal DNA methylation profile? Cord blood APC DNA Methylation 12-month health analysis and allergy assessment FASEB J, 2014 vol 28.(9)

Hyomethylation of ZFP57 Promoter histone acetylation levels Chr6 qPCR Gene expression

Differential DNA methylation and gene expression Martino et al 2014, Epigenetic

Conclusions We have evolved for optimal fitness to our • environments, but the environment has changed The genome is complex and regulated across • multiple levels in time and space as well as influenced by the environment The predisposition to disease risk is to an extent • probabilistic/stochastic Susceptibility to disease differs in different • populations as a result of genetic ancestry

Acknowledgements Katie Allen, Richard Saffery, Susan Prescott Manori Amarasekera, Harald Renz, Hani Harab, Dorthe Kersper Sarah Ashley, Noor Suaini, Thanh Dang, Jennifer Koplin, Alex Sexton Oates, Leonie Thiel, Helen Czech, John Molloy, Shyamali Dharmage, Lyle Gurrin, Mimi Tang HealthNuts volunteers and families