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

▶

Mar 02, 2024 496 likes •786 views

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

SLIDE 1

GENETICS & IMMUNITY

IN ALLERGY AND ASTHMA

DAVID MARTINO

SENIOR RESEARCH FELLOW CENTRE FOR FOOD AND ALLERGY RESEARCH

SLIDE 2

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

SLIDE 3

Immunity, genes and the environment

TH2 immunity TH1 immunity COUNTER-REGULATION

SLIDE 4

Selective pressures drive population diversity

Adapted from Sanchez-Mazas et al (2012). Philos Trans R Soc Lond, B, Biol Sci

TH2 immunity TH1 immunity INFLAMMATION

SLIDE 5

Evolution and allergy genes

Fumagalli M, et al (2010). BMC Evol Biol Cytokine signaling Mediated inflammation Integrin signaling Thyrotropin hormone signaling

Biological networks of helminth associated genes

SLIDE 6

The HealthNuts study

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

SLIDE 7

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

SLIDE 8

Differential susceptibility by ancestry

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

SLIDE 9

Caucasian Asian

Lee et al Asia Pacific Allergy

Not explained by environmental factors

SLIDE 10

Genotype Genotype Genotype Genotype

POPULATION MIGRATION AND GENE FLOW

SLIDE 11

Selective pressures and population diversity

SLIDE 12

Selective pressures and population diversity

SLIDE 13

Selective pressures and population diversity

Genotype Genotype Genotype Genotype

POPULATION MIGRATION AND GENE FLOW

Noor Suaini

Are genes associated with helminth and

inflammatory pathways enriched for Asian ancestry?

Are they associated with food allergy?

SLIDE 14

Candidate gene studies in food allergy

Skin barrier integrity: FLG SPINK5 Immune response: IL10 IL13 TGFBR1, II, SMAD3 CD14 STAT6 FOXP3

SLIDE 15

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

SLIDE 16

Genome-wide association study of peanut allergy

AA.DRB1.37

Genotyped SNPS Amino acids 2-digit alleles 4-digit alleles Chromosome 6

Martino et al, CEA 2016 (Accepted)

SLIDE 17

Caucasians only SNP rs9325072 rs3815741 rs17641748 rs4705054 rs9325071 Caucasians only SNP A1

F_FA F_NA P P OR 95% CI (L95 - U95) 0.01 1.65 1.10 2.48 0.01 1.65 1.10 2.46 0.01 1.69 1.13 2.54 0.05 1.42 1.00 2.03 0.10 1.34 0.94 1.89 SPINK5 expression in the skin by rs9325071

SPINK5 association with clinical food allergy Sarah Ashley et al, Allergy 2016, under review

SLIDE 18

Genetic susceptibility in allergic disease

Gupta et al, JACI 2016.

SLIDE 19

Coeliac disease genomic risk score

Abraham et al, PLoS Genetics 2014.

From single gene hits…. To multi-gene risk scores

SLIDE 20

GENETIC FACTORS NON-GENETIC FACTORS

SNPS
Recombination
Insertions/Deletions
DNA methylation
Histone modification
Non coding RNA

Traditional environment Modern environment

SLIDE 21

Biological sensors of environmental stimuli

SLIDE 22

Biological sensors of environmental stimuli

Metabolic signals Stress Toxins Inflammation

SLIDE 23

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 role in development. Supplementation with folic acid is recommended in pregnancy, but evidence has linked high folate consumption to asthma and allergy. Does maternal folate consumption in pregnancy alter the fetal DNA methylation profile? FASEB J, 2014 vol 28.(9)

Maternal folate Low High APC CD4 T-cell Cord blood DNA Methylation analysis Trimester 3 health and allergy assessment 12-month health and allergy assessment

SLIDE 24

Hyomethylation of ZFP57

Chr6

qPCR Gene expression Promoter histone acetylation levels

SLIDE 25

Martino et al 2014, Epigenetic

Differential DNA methylation and gene expression

SLIDE 26

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

Conclusions

SLIDE 27

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