Scientific Programme




   Pre- and Post-Congress Workshops









What I specifically like about the SingHealth Duke-NUS Scientific Congress is how it is separated into many streams and catered to various groups of people. Whether you are a doctor, nurse, allied health professional or researcher, there is something to gain for you.








~ Dr Dirk de Korne 
Deputy Director, Medical Innovation and Care Transformation,
KK Women's and Children's Hospital


Programme >

Immunotherapy Plenary
From Genotype to Phenotype


 Track type: Plenary


 Duration: 45 minutes


 Location: Academia, Level 1, L1-S1


 Speaker: Prof David Hafler


Genome wide association studies (GWAS) have identified genetic loci underlying human diseases and traits. However, the precise nucleotide changes and the mechanisms that cause heritable differences among individuals remain largely unknown. To identify and characterise the causal variants driving autoimmune disease risk, we leveraged a new generation of dense genotyping data and a novel algorithm for fine-mapping single nucleotide polymorphisms (SNPs) to explicitly predict for each individual SNP associated with 21 autoimmune diseases, the likelihood that it represents a causal mutation. We then integrated these data with transcription and cis-regulatory element annotations, which we derived by mapping RNA and chromatin state in key immune cell types, including CD4+ T-cell subsets in resting and activated states, FoxP3+ regulatory cells, CD8+ T-cells, B-cells, and monocytes. We find that the causal variants in 88% of GWAS loci are noncoding, with a majority mapping to immune-cell specific enhancers, many of which transcribe enhancer-associated ‘eRNAs’ and increase histone acetylation upon immune activation. 

Candidate causal variants tend to coincide with nucleosome-depleted regions bound by master regulators of immune differentiation and stimulus-dependent gene activation, including IRF4, PU.1, NFKB and AP-1 family transcription factors. However, our analysis suggests that only a minority of causal variants directly alter cognate transcription factor binding motifs. Rather, most variants that confer disease risk, including those that alter gene expression, instead alter adjacent, non-canonical sequence determinants. 

Finally, autoimmune disease results from untoward interactions between genetics and the environment. We recently showed that increased salt concentrations found locally under physiological conditions in vivo dramatically boost the induction of Th17 cells mediated by SGK1. The Th17 cells generated under high-salt display a highly pathogenic and stable phenotype characterized by the up-regulation of the pro-inflammatory cytokines GM-CSF, TNFα and IL-2. Mice fed with a high-salt diet develop a more severe form of EAE. It was of interest to observe that RNA array analyses of genes induced by NaCl were markedly enhanced among GWAS hits. Identifying specific sites where a single, non-coding nucleotide variant is responsible for disease risk may pinpoint specific disruptions of consensus transcription factor binding sites that ultimately define disease risk as related to environmental factors.

*Information is correct at time of update