Convergent evolution in European and Rroma populations reveals pressure exerted by plague on Toll-like receptors

Laayouni, Hafid; Oosting, Marije; Luisi, Pierre; Ioana, Mihai; Alonso, Santos; Ricaño-Ponce, Isis; Trynka, Gosia; Zhernakova, Alexandra; Plantinga, Theo S.; Cheng, Shih-Chin; Meer, J.W.M. van der; Popp, Radu A.; Sood, Ajit; Thelma, B.K.; Wijmenga, Cisca; Joosten, Leo A. B.; Bertranpetit, Jaume; Netea, Mihai G.

doi:10.1073/pnas.1317723111

Cited by 84 publications

(79 citation statements)

References 30 publications

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“…In this regard, toll-like receptors, including TLR1, have roles in metabolic syndrome in macrophages and other cell types [72], and TLR1 recently was described as having been under selective pressure in Roma gypsy and European populations in response to Yersinia pestis , the agent of plague [73]. TLR4 variants support GxE interactions with obesity traits and smoking in an Argentinean population of European ancestry [74].…”

Section: Resultsmentioning

confidence: 99%

CardioGxE, a catalog of gene-environment interactions for cardiometabolic traits

et al. 2014

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BackgroundGenetic understanding of complex traits has developed immensely over the past decade but remains hampered by incomplete descriptions of contribution to phenotypic variance. Gene-environment (GxE) interactions are one of these contributors and in the guise of diet and physical activity are important modulators of cardiometabolic phenotypes and ensuing diseases.ResultsWe mined the scientific literature to collect GxE interactions from 386 publications for blood lipids, glycemic traits, obesity anthropometrics, vascular measures, inflammation and metabolic syndrome, and introduce CardioGxE, a gene-environment interaction resource. We then analyzed the genes and SNPs supporting cardiometabolic GxEs in order to demonstrate utility of GxE SNPs and to discern characteristics of these important genetic variants. We were able to draw many observations from our extensive analysis of GxEs. 1) The CardioGxE SNPs showed little overlap with variants identified by main effect GWAS, indicating the importance of environmental interactions with genetic factors on cardiometabolic traits. 2) These GxE SNPs were enriched in adaptation to climatic and geographical features, with implications on energy homeostasis and response to physical activity. 3) Comparison to gene networks responding to plasma cholesterol-lowering or regression of atherosclerotic plaques showed that GxE genes have a greater role in those responses, particularly through high-energy diets and fat intake, than do GWAS-identified genes for the same traits. Other aspects of the CardioGxE dataset were explored.ConclusionsOverall, we demonstrate that SNPs supporting cardiometabolic GxE interactions often exhibit transcriptional effects or are under positive selection. Still, not all such SNPs can be assigned potential functional or regulatory roles often because data are lacking in specific cell types or from treatments that approximate the environmental factor of the GxE. With research on metabolic related complex disease risk embarking on genome-wide GxE interaction tests, CardioGxE will be a useful resource.

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Section: Resultsmentioning

confidence: 99%

CardioGxE, a catalog of gene-environment interactions for cardiometabolic traits

et al. 2014

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“…Recent studies have suggested that the function of TLR10 differs from other TLRs, as it was shown to inhibit TLR2-driven innate immune activation [68][69][70]. By contrast, TLR10 has also been described as a stimulatory receptor in the innate immune recognition [ TLR6 sequence variant rs5743810 (Pro249Ser) leads to the substitution of proline for serine at amino-acid position 249 of the TLR6 protein.…”

Section: Toll-like Receptorsmentioning

confidence: 99%

“…TLR6 sequence variant rs5743810 is associated with susceptibility to tuberculosis [16], complicated skin and skin structure infections [22], aspergillosis [23] and malaria [20]. [69][70]78]. How these TLR10 sequence variants precisely exert their effect remains unknown, but the location of rs4129009 in the LRR region and rs11096955 in the TIR domain could indicate involvement in the recognition of PAMPs or signal transduction, respectively.…”

Section: Toll-like Receptorsmentioning

confidence: 99%

Genetic Variation in Pattern Recognition Receptors: Functional Consequences and Susceptibility to Infectious Disease

et al. 2015

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Cells of the innate immune system are equipped with surface and cytoplasmic receptors for microorganisms called pattern recognition receptors (PRRs). PRRs recognize specific pathogen-associated molecular patterns and as such are crucial for the activation of the immune system. Currently, five different classes of PRRs have been described: Toll-like receptors, C-type lectin receptors, nucleotide-binding oligomerization domain-like receptors, retinoic acid-inducible gene I-like receptors and absent in melanoma 2-like receptors. Following their discovery, many sequence variants in PRR genes have been uncovered and shown to be implicated in human infectious diseases. In this review, we will discuss the effect of genetic variation in PRRs and their signaling pathways on susceptibility to infectious diseases in humans.

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“…Several immunity related genes, such as the Toll-like receptor (TLR) TLR1/TLR6/TLR19 gene cluster, [77] the caspase-12 gene ( CASP12) , involved in cytokine production upon bacterial lipopolysaccharide stimulation, evolved under strong selective pressure and show racial variation [78]. …”

Section: Immune Systemmentioning

confidence: 99%

Racial Differences in Cancer Susceptibility and Survival: More Than the Color of the Skin?

2017

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Epidemiological studies point to race as a determining factor in cancer susceptibility. In US registries recording cancer incidence and survival by race (distinguishing “Black versus White”), individuals of African ancestry have a globally increased risk of malignancies compared to Caucasians and Asian Americans. Differences in socioeconomic status and health care access play a key role. However, the lesser disease susceptibility of Hispanic populations with comparable life-styles and socioeconomic status as African Americans, (“Hispanic paradox”) points to the concomitant importance of genetic determinants. Here, we overview the molecular basis of racial disparity in cancer susceptibility ranging from genetic polymorphisms and cancer-driver gene mutations to obesity, chronic inflammation and immune responses. We discuss implications for race-adapted cancer screening programs and clinical trials to reduce disparities in cancer burden.

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Convergent evolution in European and Rroma populations reveals pressure exerted by plague on Toll-like receptors

Cited by 84 publications

References 30 publications

CardioGxE, a catalog of gene-environment interactions for cardiometabolic traits

CardioGxE, a catalog of gene-environment interactions for cardiometabolic traits

Genetic Variation in Pattern Recognition Receptors: Functional Consequences and Susceptibility to Infectious Disease

Racial Differences in Cancer Susceptibility and Survival: More Than the Color of the Skin?

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