Editing Hereditary haemochromatosis (section)

== Genetics ==
The regulation of dietary iron absorption is complex and understanding is incomplete. One of the better-characterized genes responsible for hereditary haemochromatosis is [[HFE gene|''HFE'']]<ref name="pmid18752323">{{cite journal |vauthors=Olynyk JK, Trinder D, Ramm GA, Britton RS, Bacon BR |title=Hereditary hemochromatosis in the post-HFE era |journal=Hepatology |volume=48 |issue=3 |pages=991–1001 |date=September 2008 |pmid=18752323 |doi=10.1002/hep.22507 |pmc=2548289 }}</ref> on [[chromosome 6]], which codes for a transmembrane protein involved in the induction of hepcidin expression upon high iron load. The ''HFE'' gene has three often observed genetic variants:<ref>{{cite web |url=https://www.mayoclinic.org/diseases-conditions/hemochromatosis/symptoms-causes/syc-20351443 |title=Hemochromatosis |work=Mayo Foundation for Medical Education and Research (MFMER) |access-date=30 November 2020 |archive-date=31 May 2013 |archive-url=https://web.archive.org/web/20130531022317/http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=tests-and-diagnosis |url-status=live }}</ref><ref name="pmid26931183">{{cite journal | vauthors = den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, Roux AF, Smith T, Antonarakis SE, Taschner PE | author-link3=Donna R. Maglott| title = HGVS Recommendations for the Description of Sequence Variants: 2016 Update | journal = Human Mutation | volume = 37 | issue = 6 | pages = 564–9 | date = June 2016 | pmid = 26931183 | doi = 10.1002/humu.22981 | s2cid = 205923146 | doi-access = free | hdl = 2381/37207 | hdl-access = free }}</ref>
* rs1799945, c.187C>G, p.His63Asp (H63D);
* rs1800562, c.845G>A, p.&nbsp;Cys282Tyr (C282Y);
* rs1800730, c.193A>T, p.Ser65Cys (S65C).

The worldwide prevalence rates for H63D, C282Y and S65C (minor allele frequencies) are 10%, 3% and 1% respectively.<ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/snp/rs1799945#frequency_tab|title=Reference SNP (rs) Report rs1799945 Allele Frequency|publisher=National Center for Biotechnology Information|access-date=30 November 2020|archive-date=10 September 2019|archive-url=https://web.archive.org/web/20190910122853/https://www.ncbi.nlm.nih.gov/snp/rs1799945#frequency_tab|url-status=live}}</ref><ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/snp/rs1800562#frequency_tab|title=Reference SNP (rs) Report rs1800562 Allele Frequency|publisher=National Center for Biotechnology Information|access-date=30 November 2020|archive-date=9 March 2021|archive-url=https://web.archive.org/web/20210309103747/http://www.ncbi.nlm.nih.gov/snp/rs1800562#frequency_tab|url-status=live}}</ref><ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/snp/rs1800730#frequency_tab|title=Reference SNP (rs) Report rs1800730 Allele Frequency|publisher=National Center for Biotechnology Information|access-date=30 November 2020|archive-date=13 September 2019|archive-url=https://web.archive.org/web/20190913040805/https://www.ncbi.nlm.nih.gov/snp/rs1800730#frequency_tab|url-status=live}}</ref>

The C282Y allele is a [[Transition (genetics)|transition]] [[point mutation]] from [[guanine]] to [[adenine]] at nucleotide 845 in ''HFE'', resulting in a [[missense mutation]] that replaces the [[cysteine]] residue at position 282 with a [[tyrosine]] amino acid.<ref name="pmid8696333">{{cite journal |journal=Nature Genetics |title=A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis |volume=13 |issue=4 |pages=399–408 |year=1996 |pmid=8696333 |doi=10.1038/ng0896-399 |vauthors=Feder JN, Gnirke A, Thomas W, etal |s2cid=26239768}}</ref> Heterozygotes for either allele can manifest clinical iron overload, if they have two of any alleles. This makes them compound heterozygous for haemochromatosis and puts them greatly at risk of storing excess iron in the body.<ref name="pmid20107990">{{cite journal |vauthors=Aranda N, Viteri FE, Montserrat C, Arija V |title=Effects of C282Y, H63D, and S65C HFE gene mutations, diet, and life-style factors on iron status in a general Mediterranean population from Tarragona, Spain |journal=Ann Hematol |volume=89 |issue=8 |pages=767–73 |date=August 2010 |pmid=20107990 |pmc=2887936 |doi=10.1007/s00277-010-0901-9 |url=}}</ref><ref name="pmid20714725">{{cite journal |vauthors=Spínola C, Brehm A, Spínola H |title=Prevalence of H63D, S65C, and C282Y hereditary hemochromatosis gene variants in Madeira Island (Portugal) |journal=Ann Hematol |volume=90 |issue=1 |pages=29–32 |date=January 2011 |pmid=20714725 |doi=10.1007/s00277-010-1034-x |s2cid=20788219 |url=https://hal.science/hal-00566727/document |access-date=2 February 2024 |archive-date=2 February 2024 |archive-url=https://web.archive.org/web/20240202143137/https://hal.science/hal-00566727/document |url-status=live }}</ref><ref name="pmid31529915">{{cite journal |vauthors=Axelrod EV, Mironov KO, Dunaeva EA, Shipulin GA |title=[The comparison of three molecular genetic techniques for identifying major mutations in gene HFE related to development of inherent hemochromatosis.] |language=Russian |journal=Klin Lab Diagn |volume=61 |issue=5 |pages=316–320 |date=2016 |pmid=31529915 |doi=10.18821/0869-2084-2016-61-5-316-320 |doi-broken-date=1 November 2024 |url=}}</ref><ref name="pmid21796974">{{cite journal |vauthors=Madani HA, Afify RA, Abd El-Aal AA, Salama N, Ramy N |title=Role of HFE gene mutations on developing iron overload in beta-thalassaemia carriers in Egypt |journal=East Mediterr Health J |volume=17 |issue=6 |pages=546–51 |date=June 2011 |pmid=21796974 |doi= 10.26719/2011.17.6.546|url=|doi-access=free }}</ref> [[Homozygosity]] for the C282Y genetic variant is the most common genotype responsible for clinical iron accumulation, though [[heterozygosity]] for C282Y/H63D variants, so-called [[compound heterozygotes]], results in clinically evident iron overload.<ref name="pmid35699322">{{cite journal |vauthors=Hsu CC, Senussi NH, Fertrin KY, Kowdley KV |title=Iron overload disorders |journal=Hepatol Commun|date=June 2022 |volume=6 |issue=8 |pages=1842–1854 |pmid=35699322 |doi=10.1002/hep4.2012|pmc=9315134 |s2cid=249644289 }}</ref> Considerable debate exists regarding the [[penetrance]]—the probability of clinical expression of the trait given the genotype— for clinical disease in homozygotes.<ref name="pmid23820649">{{cite journal |vauthors=Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H |title=Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease |journal=Hum Genet |volume=132 |issue=10 |pages=1077–130 |date=October 2013 |pmid=23820649 |pmc=3778950 |doi=10.1007/s00439-013-1331-2 |url=}}</ref> Most males homozygous for ''HFE'' C282Y show at least one manifestation of iron-storage disease by middle age.<ref>{{cite book
|title=Oxford Textbook of Medicine
|volume=1
|author=David A. Warrell |author2=Edward J. Benz Jr. |author3=Timothy M. Cox |author4=John D. Firth
|publisher=Oxford University Press
|year=2003
|isbn=978-0-19-262922-7
|quote=Most patients with the disease develop symptoms at, or above, the age of 40 years. [...] Most middle-aged male C282Y homozygous appear to express at least one clinical manifestation of iron-storage disease.
|page=92
|url=https://books.google.com/books?id=_s65U1n9Lf8C&q=C282Y+homozygous&pg=RA1-PA92
}}</ref> Individuals with the relevant genetic variants may never develop iron overload. Phenotypic expression is present in 70% of C282Y homozygotes with less than 10% going on to experience severe iron overload and organ damage.<ref name=":0">{{Cite journal |last1=Bacon |first1=Bruce R. |last2=Adams |first2=Paul C. |last3=Kowdley|first3=Kris V. |last4=Powell |first4=Lawrie W. |last5=Tavill |first5=Anthony S. |date=July 2011 |title=Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases |journal=Hepatology |volume=54 |issue=1 |pages=328–343 |doi=10.1002/hep.24330 |pmc=3149125 |pmid=21452290}}</ref>

The [[HFE H63D gene mutation|H63D variant]] is just a [[gene polymorphism]], and if there are no other changes, it may not have clinical significance.<ref name="pmid10383365">{{cite journal | vauthors = Bacon BR, Olynyk JK, Brunt EM, Britton RS, Wolff RK | title = HFE genotype in patients with hemochromatosis and other liver diseases | journal = Annals of Internal Medicine | volume = 130 | issue = 12 | pages = 953–62 | date = June 1999 | pmid = 10383365 | doi = 10.7326/0003-4819-130-12-199906150-00002| s2cid = 9764782 }}</ref><ref name="pmid11874997">{{cite journal | vauthors = Gochee PA, Powell LW, Cullen DJ, Du Sart D, Rossi E, Olynyk JK | title = A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation | journal = Gastroenterology | volume = 122 | issue = 3 | pages = 646–51 | date = March 2002 | pmid = 11874997 | doi = 10.1016/s0016-5085(02)80116-0| doi-access = free }}</ref><ref name="pmid11529872">{{cite journal | vauthors = Jackson HA, Carter K, Darke C, Guttridge MG, Ravine D, Hutton RD, Napier JA, Worwood M | title = HFE mutations, iron deficiency and overload in 10,500 blood donors | journal = British Journal of Haematology | volume = 114 | issue = 2 | pages = 474–84 | date = August 2001 | pmid = 11529872 | doi = 10.1046/j.1365-2141.2001.02949.x| s2cid = 4800162 | doi-access = free }}</ref> In a 2014 study, H63D homozygosity was associated with an elevated mean [[ferritin]] level, but only 6.7% had documented iron overload at follow-up.<ref name="pmid24729993">{{cite journal | vauthors = Kelley M, Joshi N, Xie Y, Borgaonkar M | title = Iron overload is rare in patients homozygous for the H63D mutation | journal = Canadian Journal of Gastroenterology & Hepatology | volume = 28 | issue = 4 | pages = 198–202 | date = April 2014 | pmid = 24729993 | pmc = 4071918 | doi = 10.1155/2014/468521| doi-access = free }}</ref> As about the people with one copy of the H63D alteration (heterozygous carriers), this genotype is very unlikely to cause a clinical presentation, there is no predictable risk of iron overload.<ref>{{cite web |url=http://live.nhsggc.org.uk/about-us/professional-support-sites/west-of-scotland-genetic-services/clinical-genetics/haemochromatosis/heterozygous-for-ph63d/ |title=Heterozygous for p.H63D |access-date=16 October 2020 |archive-date=17 October 2020 |archive-url=https://web.archive.org/web/20201017171337/http://live.nhsggc.org.uk/about-us/professional-support-sites/west-of-scotland-genetic-services/clinical-genetics/haemochromatosis/heterozygous-for-ph63d/ }}</ref> Besides that, two 2020 studies revealed that the frequency of homozygous or heterozygous H63D variant is significantly higher in elite endurance athletes comparing to ethnically matched controls, and is associated with high V̇O<sub>2max</sub> in male athletes.<ref name="pmid31970519">{{cite journal | vauthors = Semenova EA, Miyamoto-Mikami E, Akimov EB, Al-Khelaifi F, Murakami H, Zempo H, Kostryukova ES, Kulemin NA, Larin AK, Borisov OV, Miyachi M, Popov DV, Boulygina EA, Takaragawa M, Kumagai H, Naito H, Pushkarev VP, Dyatlov DA, Lekontsev EV, Pushkareva YE, Andryushchenko LB, Elrayess MA, Generozov EV, Fuku N, Ahmetov II | title = The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis | journal = European Journal of Applied Physiology | volume = 120 | issue = 3 | pages = 665–673 | date = March 2020 | pmid = 31970519 | pmc = 7042188 | doi = 10.1007/s00421-020-04306-8 | url = }}</ref><ref name="pmid33433155">{{cite journal | vauthors = Thakkar D, Sicova M, Guest N, Garcia-Bailo B, El-Sohemy A | title = HFE Genotype and Endurance Performance in Competitive Male Athletes | journal = Medicine and Science in Sports and Exercise | volume =  53| issue = 7| pages = 1385–1390| date = December 2020 | pmid = 33433155 | doi = 10.1249/MSS.0000000000002595 | s2cid = 231585184 | url = }}</ref>

Each patient with the susceptible genotype accumulates iron at different rates depending on iron intake, the exact nature of the genetic variant, and the presence of other insults to the liver, such as alcohol and viral disease. As such, the degree to which the liver and other organs are affected is highly variable and is dependent on these factors and co-morbidities, as well as age at which they are studied for manifestations of disease.<ref name=Olynwk_1999/> Penetrance differs between populations.

Disease-causing genetic variants of the ''HFE'' [[gene]] account for 90% of the cases of non-transfusion iron overload.{{medical citation needed|date=July 2020}}

This gene is closely [[genetic linkage|linked]] to the [[Human leukocyte antigen|HLA-A3]] [[Locus (genetics)|locus]].{{citation needed|date=October 2020}}