Limits...
Generation of primary human intestinal T cell transcriptomes reveals differential expression at genetic risk loci for immune-mediated disease.

Raine T, Liu JZ, Anderson CA, Parkes M, Kaser A - Gut (2014)

Bottom Line: Gene expression patterns clearly differentiated intestinal T cells from counterparts in peripheral blood and revealed distinct signalling pathways for each intestinal T cell subset.We have demonstrated that careful processing of mucosal biopsies allows the generation of transcriptomes from as few as 1000 highly purified cells with minimal interindividual variation.Bioinformatic integration of transcriptomic data with recent GWAS data identified specific candidate genes and cell types for inflammatory pathologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

Show MeSH

Related in: MedlinePlus

Annotation of disease-associated SNPs with genes showing differential expression in intestinal TEM populations. For each of disease SNP-differential gene list combinations for which the degree of overlap reaches statistical significance (as shown in figure 3), those risk loci (encompassing a 0.2 cM window either side of the focal SNP) that contain a gene differentially expressed in a gut TEM cell population are shown. Also indicated are the positional candidate genes identified as of interest in the original papers reporting genetic association. Where a risk locus is associated with a specific disease, the intersection between the locus (rows) and disease (columns) is shaded; where this is associated with a differentially expressed gene, the gene name(s) are indicated in the subcolumn for the appropriate TEM population. Note that where there is an association between a risk locus and a disease, but no differentially expressed gene at that risk locus in a given TEM subpopulation, the corresponding cell is shaded, but left empty. Note also that for risk loci shared between different diseases, the focal SNP may vary between diseases as indicated in the figure footnote. BMI, body mass index; IEL, intraepithelial lymphocytes; LPL, lamina propria lymphocytes; MS, multiple sclerosis; PBC, primary biliary cirrhosis; RhA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; T1D, Type 1 diabetes; TEM, T effector memory.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4316924&req=5

GUTJNL2013306657F4: Annotation of disease-associated SNPs with genes showing differential expression in intestinal TEM populations. For each of disease SNP-differential gene list combinations for which the degree of overlap reaches statistical significance (as shown in figure 3), those risk loci (encompassing a 0.2 cM window either side of the focal SNP) that contain a gene differentially expressed in a gut TEM cell population are shown. Also indicated are the positional candidate genes identified as of interest in the original papers reporting genetic association. Where a risk locus is associated with a specific disease, the intersection between the locus (rows) and disease (columns) is shaded; where this is associated with a differentially expressed gene, the gene name(s) are indicated in the subcolumn for the appropriate TEM population. Note that where there is an association between a risk locus and a disease, but no differentially expressed gene at that risk locus in a given TEM subpopulation, the corresponding cell is shaded, but left empty. Note also that for risk loci shared between different diseases, the focal SNP may vary between diseases as indicated in the figure footnote. BMI, body mass index; IEL, intraepithelial lymphocytes; LPL, lamina propria lymphocytes; MS, multiple sclerosis; PBC, primary biliary cirrhosis; RhA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; T1D, Type 1 diabetes; TEM, T effector memory.

Mentions: We next tested a number of diseases where the inflammatory pathology occurs outside of the intestine. We did not detect any significant enrichment for asthma, primary biliary cirrhosis, rheumatoid arthritis or systemic lupus erythematosus. However, there was a highly significant overlap between Type 1 diabetes (T1D)-associated loci and genes upregulated in CD4+ and CD8+ LPLs and CD8+ IELs. Likewise, we found significant overlap for psoriasis risk loci and genes upregulated in both LPL TEM populations; for multiple sclerosis (MS), risk loci showed significant overlap with genes upregulated in CD4+ LPL TEM cells, but also with genes downregulated in CD8+ IEL and LPL TEM cell populations. Several of these immune diseases share multiple genetic susceptibility loci. However, the enrichment around SNPs associated with extraintestinal pathology was not solely restricted to those genetic loci shared with GI inflammatory diseases (figure 4).


Generation of primary human intestinal T cell transcriptomes reveals differential expression at genetic risk loci for immune-mediated disease.

Raine T, Liu JZ, Anderson CA, Parkes M, Kaser A - Gut (2014)

Annotation of disease-associated SNPs with genes showing differential expression in intestinal TEM populations. For each of disease SNP-differential gene list combinations for which the degree of overlap reaches statistical significance (as shown in figure 3), those risk loci (encompassing a 0.2 cM window either side of the focal SNP) that contain a gene differentially expressed in a gut TEM cell population are shown. Also indicated are the positional candidate genes identified as of interest in the original papers reporting genetic association. Where a risk locus is associated with a specific disease, the intersection between the locus (rows) and disease (columns) is shaded; where this is associated with a differentially expressed gene, the gene name(s) are indicated in the subcolumn for the appropriate TEM population. Note that where there is an association between a risk locus and a disease, but no differentially expressed gene at that risk locus in a given TEM subpopulation, the corresponding cell is shaded, but left empty. Note also that for risk loci shared between different diseases, the focal SNP may vary between diseases as indicated in the figure footnote. BMI, body mass index; IEL, intraepithelial lymphocytes; LPL, lamina propria lymphocytes; MS, multiple sclerosis; PBC, primary biliary cirrhosis; RhA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; T1D, Type 1 diabetes; TEM, T effector memory.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4316924&req=5

GUTJNL2013306657F4: Annotation of disease-associated SNPs with genes showing differential expression in intestinal TEM populations. For each of disease SNP-differential gene list combinations for which the degree of overlap reaches statistical significance (as shown in figure 3), those risk loci (encompassing a 0.2 cM window either side of the focal SNP) that contain a gene differentially expressed in a gut TEM cell population are shown. Also indicated are the positional candidate genes identified as of interest in the original papers reporting genetic association. Where a risk locus is associated with a specific disease, the intersection between the locus (rows) and disease (columns) is shaded; where this is associated with a differentially expressed gene, the gene name(s) are indicated in the subcolumn for the appropriate TEM population. Note that where there is an association between a risk locus and a disease, but no differentially expressed gene at that risk locus in a given TEM subpopulation, the corresponding cell is shaded, but left empty. Note also that for risk loci shared between different diseases, the focal SNP may vary between diseases as indicated in the figure footnote. BMI, body mass index; IEL, intraepithelial lymphocytes; LPL, lamina propria lymphocytes; MS, multiple sclerosis; PBC, primary biliary cirrhosis; RhA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; T1D, Type 1 diabetes; TEM, T effector memory.
Mentions: We next tested a number of diseases where the inflammatory pathology occurs outside of the intestine. We did not detect any significant enrichment for asthma, primary biliary cirrhosis, rheumatoid arthritis or systemic lupus erythematosus. However, there was a highly significant overlap between Type 1 diabetes (T1D)-associated loci and genes upregulated in CD4+ and CD8+ LPLs and CD8+ IELs. Likewise, we found significant overlap for psoriasis risk loci and genes upregulated in both LPL TEM populations; for multiple sclerosis (MS), risk loci showed significant overlap with genes upregulated in CD4+ LPL TEM cells, but also with genes downregulated in CD8+ IEL and LPL TEM cell populations. Several of these immune diseases share multiple genetic susceptibility loci. However, the enrichment around SNPs associated with extraintestinal pathology was not solely restricted to those genetic loci shared with GI inflammatory diseases (figure 4).

Bottom Line: Gene expression patterns clearly differentiated intestinal T cells from counterparts in peripheral blood and revealed distinct signalling pathways for each intestinal T cell subset.We have demonstrated that careful processing of mucosal biopsies allows the generation of transcriptomes from as few as 1000 highly purified cells with minimal interindividual variation.Bioinformatic integration of transcriptomic data with recent GWAS data identified specific candidate genes and cell types for inflammatory pathologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

Show MeSH
Related in: MedlinePlus