medigraphic.com
Órgano Oficial de la Asociación Mexicana de Hepatología

2017, Number 3

<< Back Next >>

Ann Hepatol 2017; 16 (3)

GNPAT rs11558492 is not a Major Modifier of Iron Status: Study of Italian Hemochromatosis Patients and Blood Donors

Greni F, Valenti L, Mariani R, Pelloni I, Rametta R, Busti F, Ravasi G, Girelli D, Fargion S, Galimberti S, Piperno A, Pelucchi S

Language: English
References: 30
Page: 451-456
PDF size: 204.30 Kb.


ABSTRACT

Background and Aim. HFE-related Hemochromatosis (HH) is characterized by marked phenotype heterogeneity, probably due to the combined action of acquired and genetic factors. Among them, GNPAT rs11558492 was proposed as genetic modifier of iron status, but results are still controversial. To shed light on these discrepancies, we genotyped 298 Italian p.C282Y homozygotes and 169 healthy controls. Material and methods. Allele and genotype frequencies were analysed and compared with those reported in Exome Variant Server (EVS). To explore the role of rs11558492 as a potential modifier of iron status, serum ferritin (SF), liver iron concentration (LIC) and iron removed (IR) were studied according to allele and genotype frequencies. In addition, the effect of the SNP on liver fibrosis was examined comparing patients with absent/mild-moderate fibrosis to those with severe fibrosis-cirrhosis. Results. GNPAT rs11558492 minor allele (G) frequency (MAF) was 20.3% in HFE-HH, 17.2% in controls and 20.6% in EVS database. Genotype frequencies were 64% and 69.2% (AA), 31.2% and 27.2% (AG), 4.8% and 3.6% (GG) in HFE-HH and controls, respectively. No significant differences were found comparing genotype and allele frequencies even selecting subgroups of only-males with extreme phenotypes and low alcohol intake. SF, IR and LIC levels did not significantly differ according to rs11558492 genotypes. Also, MAF did not differ between patients with absent/mild fibrosis and severe fibrosis/cirrhosis. Conclusions. Our findings indicate that GNPAT rs11558492 is not a major modifier of iron status and is not associated with liver fibrosis in HFE-HH patients.


REFERENCES

  1. Powell LW, Seckington RC, Deugnier Y. Haemochromatosis. Lancet 2016; 388: 706-16.

  2. Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, McLaren CE, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008; 358: 221-30.

  3. Rochette J, Le Gac G, Lassoued K, Férec C, Robson KJ. Factors influencing disease phenotype and pene- trance in HFE haemochromatosis. Hum Genet 2010; 128: 233-48.

  4. Piperno A. Molecular diagnosis of hemochromatosis. Expert Opin Med Diagn 2013; 7: 161-77.

  5. Powell EE, Ali A, Clouston AD, Dixon JL, Lincoln DJ, Purdie DM, Fletcher LM, et al. Steatosis is a cofactor in liver injury in hemochromatosis. Gastroenterology 2005; 129: 1937-43.

  6. Adams PC, Agnew S. Alcoholism in hereditary hemochromatosis revisited: prevalence and clinical consequences among homozygous siblings. Hepatology 1996; 23: 724-7.

  7. Deugnier Y, Brissot P, Loréal O. Iron and the liver: update 2008. J Hepatol 2008; 48(Suppl. 1): S113-123.

  8. Piperno A, Mariani R, Arosio C, Vergani A, Bosio S, Fargion S, Sampietro M, et al. Haemochromatosis in patients with beta-thalassaemia trait. Br J Haematol 2000; 111: 908-14.

  9. Lainé F, Jouannolle AM, Morcet J, Brigand A, Pouchard M, Lafraise B, Mosser J, et al. Phenotypic expression in detected C282Y homozygous women depends on body mass index. J Hepatol 2005; 43: 1055-9.

  10. Fleming RE, Feng Q, Britton RS. Knockout mouse models of iron homeostasis. Annu Rev Nutr 2011; 31: 117-37.

  11. de Tayrac M, Roth MP, Jouanolle AM, Coppin H, le Gac G, Piperno A, Férec C, et al. Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis. J Hepatol 2015; 62: 664-72.

  12. Tanaka T, Roy CN, Yao W, Matteini A, Semba RD, Arking D, Walston JD, et al. A genome-wide association analysis of serum iron concentrations. Blood 2010; 115: 94-6.

  13. Benyamin B, McRae AF, Zhu G, Gordon S, Henders AK, Palotie A, Peltonen L, et al. Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. Am J Hum Genet 2009; 84: 60-5.

  14. Pelucchi S, Mariani R, Calza S, Fracanzani AL, Modignani GL, Bertola F, Busti F, et al. CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients. Haematologica 2012; 97: 1818-25.

  15. McLaren CE, Garner CP, Constantine CC, McLachlan S, Vulpe CD, Snively BM, Gordeuk VR, et al. Genome-wide association study identifies genetic loci associated with iron deficiency. PLoS One 2011; 6: e17390.

  16. Chambers JC, Zhang W, Li Y, Sehmi J, Wass MN, Zabaneh D, Hoggart C, et al. Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat Genet 2009; 41: 1170-2.

  17. McLaren CE, Emond MJ, Subramaniam VN, Phatak PD, Barton JC, Adams PC, Goh JB, et al. Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload. Hepatology 2015; 62: 429-39.

  18. Bardou-Jacquet E, de Tayrac M, Mosser J, Deugnier Y. GNPAT Variant associated with severe iron overload in HFE hemochromatosis. Hepatology 2015; 62: 1917-18.

  19. Ryan E, Russell J, Ryan JD, Crowe J, Stewart S. GNPAT variant is not associated with severe iron overload in Irish C282Y homozygotes. Hepatology 2016; 63: 2055-6.

  20. Besson-Fournier C, Martinez M, Vinel JP, Aguilar-Martinez P, Coppin H, Roth MP. Further support for the association of GNPAT variant rs11558492 with severe iron overload in hemochromatosis. Hepatology 2016; 63: 2054-5.

  21. Hsiao SC, Lee CT, Pei SN. GNPAT variant is associated with iron phenotype in healthy Taiwanese women: A population without the HFE C282Y mutation. Hepatology 2016; 63: 2057-8.

  22. Rametta R, Dongiovanni P, Fargion S, Valenti L. GNPAT p.D519G variant and iron metabolism during oral iron tolerance test. Hepatology 2016.

  23. Pelucchi S, Galimberti S, Greni F, Rametta R, Mariani R, Pelloni I, Girelli D, et al. Proprotein convertase 7 rs236918 is associated with liver fibrosis in Italian patients with HFE-related Hemochromatosis. J Gastroenterol Hepatol 2016.

  24. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696-9.

  25. Piperno A, Arosio C, Fargion S, Roetto A, Nicoli C, Girelli D, Sbaiz L, et al. The ancestral hemochromatosis haplotype is associated with a severe phenotype expression in Italian patients. Hepatology 1996; 24: 43-6.

  26. Galimberti S, Trombini P, Bernasconi DP, Redaelli I, Pelucchi S, Bovo G, Di Gennaro F, et al. Simultaneous liver iron and fat measures by magnetic resonance imaging in patients with hyperferritinemia. Scand J Gastroenterol 2015; 50: 429-38.

  27. Salvioni A, Mariani R, Oberkanins C, Moritz A, Mauri V, Pelucchi S, Riva A, et al. Prevalence of C282Y and E168X HFE mutations in an Italian population of Northern European ancestry. Haematologica 2003; 88: 250-5.

  28. Levstik A, Stuart A, Adams PC. GNPAT variant (D519G) is not associated with an elevated serum ferritin or iron removed by phlebotomy in patients referred for C282Y-linked hemochromatosis. Ann Hepatol 2016; 15: 907-10.

  29. Piazza A, Cappello N, Olivetti E, Rendine S. A genetic history of Italy. Ann Hum Genet 1988; 52: 203-13.

  30. Stickel F, Buch S, Zoller H, Hultcrantz R, Gallati S, Österreicher C, Finkenstedt A, et al. Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis. Hum Mol Genet 2014; 23: 3883-90.




2020     |     www.medigraphic.com