Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload

McLaren, Christine E.; Emond, Mary J.; Subramaniam, V. Nathan; Phatak, Pradyumna D.; Barton, James C.; Adams, Paul C.; Goh, Justin B.; McDonald, Cameron; Powell, Lawrie W.; Gurrin, Lyle C.; Allen, Katrina J.; Nickerson, Deborah A.; Louie, Tin; Ramm, Grant A.; Anderson, Gregory J.; McLaren, Gordon D.

doi:10.1002/hep.27711

Cited by 75 publications

(91 citation statements)

References 47 publications

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“…McLaren et al (1) recently used whole-exome sequencing to show that GNPAT p.D519G (rs11558492) is associated with a high-iron phenotype in HFE C282Y homozygous men. Three other studies examined this association in different Caucasian populations with conflicting results.…”

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confidence: 99%

GNPAT variant is associated with iron phenotype in healthy Taiwanese women: A population without the HFE C282Y mutation

2016

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McLaren et al.(1) recently used whole-exome sequencing to show that GNPAT p.D519G (rs11558492) is associated with a high-iron phenotype in HFE C282Y homozygous men. Three other studies examined this association in different Caucasian populations with conflicting results. (2)(3)(4) However, the role of GNPAT in the absence of iron overload or in the HFE wild-type population remains unclear.Here, we investigated iron indices before and after iron supplementation and their association with genetic polymorphisms. This study was approved by the ethics committee, and informed consent was obtained from all participants. We screened healthy reproductive-age women and excluded those with renal insufficiency, anemia, gastrointestinal bleeding, or chronic inflammation and those that were pregnant or breastfeeding; thus, 83 healthy female volunteers were eligible for analysis. Participants fasted overnight, and baseline iron parameters were measured at 8 AM. They were then administered sodium ferrous citrate (element iron, 100 mg), and blood was sampled 2 hours later. Data are presented in Table 1.Regarding TMPRSS6 rs855791, iron parameters at baseline or after iron challenge did not significantly differ between genotypes. For GNPAT rs11558492, 64 participants were wild type (A/A) and 19 carried variants (18 A/G and 1 G/G). The G allele frequency was 12% (20 of 166), similar to 14% in the general population in 1000 Genomes (chi-square test: P 5 0.416). Fasting serum iron levels were higher in subjects with GNPAT variants than in wild-type subjects (131.2 vs. 110.5 lg/dL; P 5 0.045), but there was no significant difference in fasting transferrin saturation (TS; 38.2% vs. 33.7%; P 5 0.153). After iron supplementation, serum iron levels and TS were both significantly higher in GNPAT variants (iron, 320.2 vs. 284.5 lg/dL; P 5 0.025; TS, 85.8% vs. 78.9%; P 5 0.040). Furthermore, multivariate analysis showed that the GNPAT genotype was an independent factor associated with baseline iron levels (P 5 0.045; adjusted R 2 5 0.037); the factors analyzed included age,

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Section: To the Editormentioning

confidence: 99%

GNPAT variant is associated with iron phenotype in healthy Taiwanese women: A population without the HFE C282Y mutation

2016

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“…A genome-wide association study (GWAS) identified the rs3811647 Tf polymorphism as the only SNP significantly associated with iron metabolism through serum transferrin and iron levels, indicating an indirect link with the phenotypic presentation of HFE-HH142 . More recently, in an exome sequencing study, a p.D519G variant in the glyceronephosphate Oacyltransferase (GNPAT) gene showed the most significant association with severe iron overload143 . Yet, this association has not been confirmed in a different hemochromatosis population144 .…”

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Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years Since Hepcidin

Pietrangelo¹

2015

Gastroenterology

124

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The discovery of hepcidin in 2000 and the subsequent unprecedented explosion of research and discoveries in the iron field have dramatically changed our understanding of human disorders of iron metabolism. Today, hereditary hemochromatosis, the paradigmatic iron-loading disorder, is recognized as an endocrine disease due to the genetic loss of hepcidin, the iron hormone produced by the liver. This syndrome is due to unchecked transfer of iron into the bloodstream in the absence of increased erythropoietic needs and its toxic effects in parenchymatous organs. It is caused by mutations that affect any of the proteins that help hepcidin to monitor serum iron, including HFE and, in rarer instances, transferrin-receptor 2 and hemojuvelin, or make its receptor ferroportin, resistant to the hormone. In Caucasians, C282Y HFE homozygotes are numerous, but they are only predisposed to hemochromatosis; complete organ disease develops in a minority, due to alcohol abuse or concurrent genetic modifiers that are now being identified. HFE gene testing can be used to diagnose hemochromatosis in symptomatic patients, but analyses of liver histology and full gene sequencing are required to identify patients with rare, non-HFE forms of the disease. Due to the central pathogenic role of hepcidin, it is anticipated that nongenetic causes of hepcidin loss (eg, end-stage liver disease) can cause acquired forms of hemochromatosis. The mainstay of hemochromatosis management is still removal of iron by phlebotomy, first introduced in 1950s, but identification of hepcidin has not only shed new light on the pathogenesis of the disease and the approach to diagnosis, but etiologic therapeutic applications from these advances are now foreseen.

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“…Archived sequence data may also become clinically relevant as sequence variants that affect disease severity (modifier genes) are identified, as evidenced by HFE dependent HH modifier gene, GNPAT. [14]…”

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confidence: 99%

Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis

Farrell

Parker

Phillips

2015

Blood Cells, Molecules, and Diseases

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Diagnostic genetic testing for hereditary hemochromatosis is readily available for clinically relevant HFE variants (i.e., those that generate the C282Y, H63D and S65C HFE polymorphisms); however, genetic testing for other known causes of iron overload, including mutations affecting genes encoding hemojuvelin, transferrin receptor 2, HAMP, and ferroportin is not. As an alternative to conventional genetic testing we propose diagnostic use of whole exome sequencing for characterization of non-HFE hemochromatosis. To illustrate the effectiveness of whole exome sequencing as a diagnostic tool, we present the case of an 18-year-old female with a probable case of juvenile hemochromatosis, who was referred for specialty care after testing negative for commonly occurring HFE variants. Whole exome sequencing offered complete coverage of target genes and is a fast, cost effective diagnostic tool for characterization of non-HFE hemochromatosis.

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Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload

Cited by 75 publications

References 47 publications

GNPAT variant is associated with iron phenotype in healthy Taiwanese women: A population without the HFE C282Y mutation

GNPAT variant is associated with iron phenotype in healthy Taiwanese women: A population without the HFE C282Y mutation

Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years Since Hepcidin

Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis

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