<i>FADS1</i> and <i>FADS2</i> expression across 44 human tissues.

<p>Boxplots of <i>FADS1</i> (top) and <i>FADS2</i> (bottom) mRNA expression (log₁₀RPKM—y axis) are shown across tissues (x-axis) from GTEx; outliers are shown as circles; median expression is represented as the center line.</p

rs174548 genotype associations with <i>FADS1</i> and <i>FADS2</i> across tissues.

<p>Nominal associations (effect size and 95% confidence interval) between rs174548 genotypes (G, alt allele vs C, ref allele) with <i>FADS1</i> (A) and <i>FADS2</i> (B) are shown across GTEx tissues. The effect size of the eQTLs was defined as the slope of the linear regression, comparing the alt allele (G) to the reference allele (C).</p

<i>FADS1</i> and <i>FADS2</i> expression by rs174548 genotype.

<p><i>FADS1</i> (A) <i>FADS2</i> (B) rank normalized gene expression (Y-axis) by rs174548 genotype (G: alt allele, C: ref allele) in the five tissues with significant (FDR<0.05) associations between rs174548 and <i>FADS1</i> and <i>FADS2</i> in the same tissues.</p

Tissue-specific impact of <i>FADS</i> cluster variants on <i>FADS1</i> and <i>FADS2</i> gene expression

<div><p>Omega-6 (n-6) and omega-3 (n-3) long (≥ 20 carbon) chain polyunsaturated fatty acids (LC-PUFAs) play a critical role in human health and disease. Biosynthesis of LC-PUFAs from dietary 18 carbon PUFAs in tissues such as the liver is highly associated with genetic variation within the fatty acid desaturase (<i>FADS)</i> gene cluster, containing <i>FADS1</i> and <i>FADS2</i> that encode the rate-limiting desaturation enzymes in the LC-PUFA biosynthesis pathway. However, the molecular mechanisms by which <i>FADS</i> genetic variants affect LC-PUFA biosynthesis, and in which tissues, are unclear. The current study examined associations between common single nucleotide polymorphisms (SNPs) within the <i>FADS</i> gene cluster and <i>FADS1</i> and <i>FADS2</i> gene expression in 44 different human tissues (sample sizes ranging 70–361) from the Genotype-Tissue Expression (GTEx) Project. <i>FADS1</i> and <i>FADS2</i> expression were detected in all 44 tissues. Significant cis-eQTLs (within 1 megabase of each gene, False Discovery Rate, FDR<0.05, as defined by GTEx) were identified in 12 tissues for <i>FADS1</i> gene expression and 23 tissues for <i>FADS2</i> gene expression. Six tissues had significant (FDR< 0.05) eQTLs associated with both <i>FADS1</i> and <i>FADS2</i> (including artery, esophagus, heart, muscle, nerve, and thyroid). Interestingly, the identified eQTLs were consistently found to be associated in opposite directions for <i>FADS1</i> and <i>FADS2</i> expression. Taken together, findings from this study suggest common SNPs within the <i>FADS</i> gene cluster impact the transcription of <i>FADS1</i> and <i>FADS2</i> in numerous tissues and raise important questions about how the inverse expression of these two genes impact intermediate molecular (such a LC-PUFA and LC-PUFA-containing glycerolipid levels) and ultimately clinical phenotypes associated with inflammatory diseases and brain health.</p></div

Image_2_HLA-associated outcomes in peanut oral immunotherapy trials identify mechanistic and clinical determinants of therapeutic success.pdf

RationalePrevious studies identified an interaction between HLA and oral peanut exposure. HLA-DQA1*01:02 had a protective role with the induction of Ara h 2 epitope-specific IgG4 associated with peanut consumption during the LEAP clinical trial for prevention of peanut allergy, while it was a risk allele for peanut allergy in the peanut avoidance group. We have now evaluated this gene-environment interaction in two subsequent peanut oral immunotherapy (OIT) trials - IMPACT and POISED - to better understand the potential for the HLA-DQA1*01:02 allele as an indicator of higher likelihood of desensitization, sustained unresponsiveness, and peanut allergy remission.MethodsWe determined HLA-DQA1*01:02 carrier status using genome sequencing from POISED (N=118, age: 7-55yr) and IMPACT (N=126, age: 12-ResultsWhile not quite statistically significant, a higher proportion of HLA-DQA1*01:02 carriers receiving OIT in IMPACT were desensitized (93%) compared to non-carriers (78%); odds ratio (OR)=5.74 (p=0.06). In this sample we also observed that a higher proportion of carriers achieved remission (35%) compared to non-carriers (22%); OR=1.26 (p=0.80). In POISED, carriers more frequently attained continued desensitization (80% versus 61% among non-carriers; OR=1.28, p=0.86) and achieved SU (52% versus 31%; OR=2.32, p=0.19). psIgG4 associations with HLA-DQA1*01:02 in the OIT arm of IMPACT which included younger study subjects recapitulated patterns noted in LEAP, but no associations of note were observed in the older POISED study subjects.ConclusionsFindings across three clinical trials show a pattern of a gene environment interaction between HLA and oral peanut exposure. Age, and prior sensitization contribute additional determinants of outcomes, consistent with a mechanism of restricted antigen recognition fundamental to driving protective immune responses to OIT.</p

Image_1_HLA-associated outcomes in peanut oral immunotherapy trials identify mechanistic and clinical determinants of therapeutic success.pdf

RationalePrevious studies identified an interaction between HLA and oral peanut exposure. HLA-DQA1*01:02 had a protective role with the induction of Ara h 2 epitope-specific IgG4 associated with peanut consumption during the LEAP clinical trial for prevention of peanut allergy, while it was a risk allele for peanut allergy in the peanut avoidance group. We have now evaluated this gene-environment interaction in two subsequent peanut oral immunotherapy (OIT) trials - IMPACT and POISED - to better understand the potential for the HLA-DQA1*01:02 allele as an indicator of higher likelihood of desensitization, sustained unresponsiveness, and peanut allergy remission.MethodsWe determined HLA-DQA1*01:02 carrier status using genome sequencing from POISED (N=118, age: 7-55yr) and IMPACT (N=126, age: 12-ResultsWhile not quite statistically significant, a higher proportion of HLA-DQA1*01:02 carriers receiving OIT in IMPACT were desensitized (93%) compared to non-carriers (78%); odds ratio (OR)=5.74 (p=0.06). In this sample we also observed that a higher proportion of carriers achieved remission (35%) compared to non-carriers (22%); OR=1.26 (p=0.80). In POISED, carriers more frequently attained continued desensitization (80% versus 61% among non-carriers; OR=1.28, p=0.86) and achieved SU (52% versus 31%; OR=2.32, p=0.19). psIgG4 associations with HLA-DQA1*01:02 in the OIT arm of IMPACT which included younger study subjects recapitulated patterns noted in LEAP, but no associations of note were observed in the older POISED study subjects.ConclusionsFindings across three clinical trials show a pattern of a gene environment interaction between HLA and oral peanut exposure. Age, and prior sensitization contribute additional determinants of outcomes, consistent with a mechanism of restricted antigen recognition fundamental to driving protective immune responses to OIT.</p