Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network

Gallego, Carlos J.; Burt, Amber; Sundaresan, Agnes S.; Ye, Zi; Shaw, Christopher; Crosslin, David R.; Crane, Paul K.; Fullerton, Stephanie M.; Hansen, Kristen J.; Carrell, David; Kuivaniemi, Helena; Derr, Kimberly; Andrade, Mariza de; McCarty, Catherine A.; Kitchner, Terrie; Ragon, Brittany Knick; Stallings, Sarah; Papa, Gabriella; Bochenek, Joseph; Smith, Maureen E.; Aufox, Sharon; Pacheco, Jennifer A.; Patel, Vaibhav; Friesema, Elisha M.; Erwin, Angelika; Gottesman, Omri; Gerhard, Glenn S.; Ritchie, Marylyn D.; Motulsky, Arno G.; Kullo, Iftikhar J.; Larson, Eric B.; Tromp, Gerard; Brilliant, Murray H.; Böttinger, Erwin P.; Denny, Joshua C.; Roden, Dan M.; Williams, Marc S.; Jarvik, Gail P.

doi:10.1016/j.ajhg.2015.08.008

Cited by 46 publications

(44 citation statements)

References 28 publications

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“…Among patients with hemochromatosis, or iron-overload-related disease, the prevalence of C282Y homozygotes in the human hemochromatosis ( HFE ) allele was investigated in three studies (Allen et al, 2008; McLaren et al, 2008; Scotet et al, 2005). HFE regulates iron uptake by controlling the relationship between transferrin and the transferrin receptor (Gallego et al, 2015). All three studies observed significant associations between C282Y and fatigue.…”

Section: Resultsmentioning

confidence: 99%

A systematic review of the association between fatigue and genetic polymorphisms

Wang

Yin

Miller

et al. 2017

Brain, Behavior, and Immunity

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Fatigue is one of the most common and distressing symptoms, leading to markedly decreased quality of life among a large subset of patients with a variety of disorders. Susceptibility to fatigue may be influenced by genetic factors including single nucleotide polymorphisms (SNPs), especially in the regulatory regions, of relevant genes. To further investigate the association of SNPs with fatigue in various patient populations, a systematic search was conducted on Pubmed, CINAHL, PsycINFO, and Sociological Abstracts Database for fatigue related-terms in combination with polymorphisms or genetic variation-related terms. Fifty papers in total met the inclusion and exclusion criteria for this analysis. These 50 papers were further classified into three subgroups for evaluation: chronic fatigue syndrome (CFS), cancer-related fatigue (CRF) and other disease-related fatigue. SNPs in regulatory pathways of immune and neurotransmitter systems were found to play important roles in the etiologies of CFS, CRF and other disease-related fatigue. Evidence for associations between elevated fatigue and specific polymorphisms in TNFα, IL1b, IL4 and IL6 genes was revealed for all three subgroups of fatigue. We also found CFS shared a series of polymorphisms in HLA, IFN-γ, 5-HT and NR3C1 genes with other disease-related fatigue, however these SNPs (excluding IFN-γ) were not found to be adequately investigated in CRF. Gaps in knowledge related to fatigue etiology and recommendations for future research are further discussed.

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Section: Resultsmentioning

confidence: 99%

A systematic review of the association between fatigue and genetic polymorphisms

Wang

Yin

Miller

et al. 2017

Brain, Behavior, and Immunity

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“…1:16) in the Caucasian population, but accounts for a phenotype only in a minority of cases . A more common HH variant (MAF = 17% in the 1000 Genomes European population) is c.187C > G, p.His63Asp, which causes a milder degree of iron overabsorption and is most relevant to disease when paired with the allele for p.Cys282Tyr in compound heterozygotes . In the context of increased intestinal iron absorption, HFE mutations could protect against the development of iron deficiency.…”

Section: Introductionmentioning

confidence: 99%

The role of TMPRSS6 and HFE variants in iron deficiency anemia in celiac disease

et al. 2017

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We investigated the role of HFE C282Y, H63D, and TMPRSS6 A736V variants in the pathogenesis of iron deficiency anemia (IDA) in celiac disease (CD) patients, at diagnosis and after 1 year of gluten-free diet (GFD). Demographic and clinical features were prospectively recorded for all CD patients between 2013 and 2017. C282Y, H63D, and A736V variants were evaluated for CD patients and controls. Finally, 505 consecutive CD patients and 539 age-matched control subjects were enrolled. At diagnosis, 229 CD subjects had IDA (45.3%), with a subgroup of anemic patients (45.4%) presented persistent IDA at follow-up. C282Y allele frequency was significantly increased in CD compared with controls (1.1% vs 0.2%, P = .001), whereas H63D and A736V allele frequencies were similar among patients and controls (P = .92 and .84, respectively). At diagnosis, C282Y variant in anemic CD patients was significantly increased compared to nonanemic group (2% and 0.5%, P = .04). At follow-up, A736V was significantly increased in IDA persistent than in IDA not persistent (57.7% vs 35.2%, P < .0001). CD patients with H63D mutation showed higher Hb, MCV, serum iron, and ferritin levels than subjects without HFE mutations. Decreased hepcidin values were observed in anemic compared to nonanemic subjects at follow-up (1.22 ± 1.14 vs 2.08 ± 2.15, P < .001). This study suggests a protective role of HFE in IDA CD patients and confirms the role of TMPRSS6 in predicting oral iron response modulating hepcidin action on iron absorption. Iron supplementation therapeutic management in CD could depend on TMPRSS6 genotype that could predict persistent IDA despite iron supplementation and GFD.

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“…For example, genetic results could influence management of iron supplementation or influence iron level monitoring. 10 Indeed, multiple genes seem to have an effect on iron levels, and these should be considered as candidates that influence disease penetrance. 11…”

Section: Heritable Disease and Penetrancementioning

confidence: 99%

Genomic Sequencing Expansion and Incomplete Penetrance

Shieh

2019

Pediatrics

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BACKGROUND: Genetic data have the potential to impact patient care significantly. In primary care and in the ICU, patients are undergoing genetic testing. Genetics is also transforming cancer care and undiagnosed diseases. Optimal personalized medicine relies on the understanding of disease penetrance. In this article, I examine the complexity of penetrance. METHODS: In this article, I assess how variable penetrance can be seen with many diseases, including those of different modes of inheritance, and how genomic testing is being applied effectively for many diseases. In this article, I also identify challenges in the field, including the interpretation of gene variants. RESULTS: Using advancing bioinformatics and detailed phenotypic assessment, we can increase the yield of genomic testing, particularly for highly penetrant conditions. The technologies are useful and applicable to different medical situations. CONCLUSIONS: There are now effective genome diagnostics for many diseases. However, the best personalized application of these data still requires skilled interpretation.

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Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network

Cited by 46 publications

References 28 publications

A systematic review of the association between fatigue and genetic polymorphisms

A systematic review of the association between fatigue and genetic polymorphisms

The role of TMPRSS6 and HFE variants in iron deficiency anemia in celiac disease

Genomic Sequencing Expansion and Incomplete Penetrance

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