Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients

C.A. Mccune, David Ravine, K. Carter, H.A. Jackson, D. Hutton, J. Hedderich, M. Krawczak, M. Worwood

    Research output: Contribution to journalArticle

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    Abstract

    Background and aims: Although most cases of hereditary haemochromatosis are associated with homozygosity for the C282Y mutation of the HFE gene, clinical penetrance varies and other genes may modify disease expression. If so, relatives from clinically affected families, by inheriting such genes, may accumulate more iron. To seek evidence for this, we compared iron status and morbidity in unselected first degree relatives of two groups of index cases from South Wales, namely asymptomatic C282Y homozygotes identified by genetic screening of blood donors (n = 56) and C282Y homozygous haemochromatosis patients presenting clinically (n = 60).Methods: All participating relatives had a structured interview, clinical assessment, and laboratory investigations. Health related quality of life was measured (SF-36 version 2).Results: In total, 92% of 180 eligible first degree relatives were interviewed in the "screened" family group and 85% of 143 eligible relatives in the "patient" group. Of 59 relatives homozygous for C282Y, 76% of men and 32% of women had the "iron phenotype" (raised transferrin saturation and serum ferritin). Logistic regression modelling of the iron phenotype risk showed that 42% of the initial model deviance could be explained by homozygosity for C282Y, another 6% by lifestyle factors, and 6% by being male. Family group membership was not a significant risk factor. Morbidity and SF-36 scores did not differ significantly either between C282Y homozygotes and relatives lacking C282Y, or between C282Y homozygotes from the "screened" and "patient" groups. Serious morbidity (including cirrhosis) was low in both groups of relatives.Conclusions: HFE C282Y homozygosity has a high penetrance for iron accumulation but a low clinical penetrance. Lack of excess morbidity among C282Y homozygous relatives of index cases who presented clinically suggests that residual unknown genetic or environmental factors do not greatly influence clinical outcome among C282Y homozygotes.
    Original languageEnglish
    Pages (from-to)554-562
    JournalGut
    Volume55
    Issue number4
    DOIs
    Publication statusPublished - 2006

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    Homozygote
    Population Genetics
    Genetic Testing
    Iron
    Morbidity
    Penetrance
    Hemochromatosis
    Genes
    Phenotype
    Wales
    Transferrin
    Ferritins
    Blood Donors
    Life Style
    Fibrosis
    Logistic Models
    Quality of Life
    Interviews

    Cite this

    Mccune, C.A. ; Ravine, David ; Carter, K. ; Jackson, H.A. ; Hutton, D. ; Hedderich, J. ; Krawczak, M. ; Worwood, M. / Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients. In: Gut. 2006 ; Vol. 55, No. 4. pp. 554-562.
    @article{a9b43366f4364e3c8e10b7459ecac01f,
    title = "Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients",
    abstract = "Background and aims: Although most cases of hereditary haemochromatosis are associated with homozygosity for the C282Y mutation of the HFE gene, clinical penetrance varies and other genes may modify disease expression. If so, relatives from clinically affected families, by inheriting such genes, may accumulate more iron. To seek evidence for this, we compared iron status and morbidity in unselected first degree relatives of two groups of index cases from South Wales, namely asymptomatic C282Y homozygotes identified by genetic screening of blood donors (n = 56) and C282Y homozygous haemochromatosis patients presenting clinically (n = 60).Methods: All participating relatives had a structured interview, clinical assessment, and laboratory investigations. Health related quality of life was measured (SF-36 version 2).Results: In total, 92{\%} of 180 eligible first degree relatives were interviewed in the {"}screened{"} family group and 85{\%} of 143 eligible relatives in the {"}patient{"} group. Of 59 relatives homozygous for C282Y, 76{\%} of men and 32{\%} of women had the {"}iron phenotype{"} (raised transferrin saturation and serum ferritin). Logistic regression modelling of the iron phenotype risk showed that 42{\%} of the initial model deviance could be explained by homozygosity for C282Y, another 6{\%} by lifestyle factors, and 6{\%} by being male. Family group membership was not a significant risk factor. Morbidity and SF-36 scores did not differ significantly either between C282Y homozygotes and relatives lacking C282Y, or between C282Y homozygotes from the {"}screened{"} and {"}patient{"} groups. Serious morbidity (including cirrhosis) was low in both groups of relatives.Conclusions: HFE C282Y homozygosity has a high penetrance for iron accumulation but a low clinical penetrance. Lack of excess morbidity among C282Y homozygous relatives of index cases who presented clinically suggests that residual unknown genetic or environmental factors do not greatly influence clinical outcome among C282Y homozygotes.",
    author = "C.A. Mccune and David Ravine and K. Carter and H.A. Jackson and D. Hutton and J. Hedderich and M. Krawczak and M. Worwood",
    year = "2006",
    doi = "10.1136/gut.2005.070342",
    language = "English",
    volume = "55",
    pages = "554--562",
    journal = "Gut: an international journal of gastroenterology & hepatology",
    issn = "0017-5749",
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    Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients. / Mccune, C.A.; Ravine, David; Carter, K.; Jackson, H.A.; Hutton, D.; Hedderich, J.; Krawczak, M.; Worwood, M.

    In: Gut, Vol. 55, No. 4, 2006, p. 554-562.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients

    AU - Mccune, C.A.

    AU - Ravine, David

    AU - Carter, K.

    AU - Jackson, H.A.

    AU - Hutton, D.

    AU - Hedderich, J.

    AU - Krawczak, M.

    AU - Worwood, M.

    PY - 2006

    Y1 - 2006

    N2 - Background and aims: Although most cases of hereditary haemochromatosis are associated with homozygosity for the C282Y mutation of the HFE gene, clinical penetrance varies and other genes may modify disease expression. If so, relatives from clinically affected families, by inheriting such genes, may accumulate more iron. To seek evidence for this, we compared iron status and morbidity in unselected first degree relatives of two groups of index cases from South Wales, namely asymptomatic C282Y homozygotes identified by genetic screening of blood donors (n = 56) and C282Y homozygous haemochromatosis patients presenting clinically (n = 60).Methods: All participating relatives had a structured interview, clinical assessment, and laboratory investigations. Health related quality of life was measured (SF-36 version 2).Results: In total, 92% of 180 eligible first degree relatives were interviewed in the "screened" family group and 85% of 143 eligible relatives in the "patient" group. Of 59 relatives homozygous for C282Y, 76% of men and 32% of women had the "iron phenotype" (raised transferrin saturation and serum ferritin). Logistic regression modelling of the iron phenotype risk showed that 42% of the initial model deviance could be explained by homozygosity for C282Y, another 6% by lifestyle factors, and 6% by being male. Family group membership was not a significant risk factor. Morbidity and SF-36 scores did not differ significantly either between C282Y homozygotes and relatives lacking C282Y, or between C282Y homozygotes from the "screened" and "patient" groups. Serious morbidity (including cirrhosis) was low in both groups of relatives.Conclusions: HFE C282Y homozygosity has a high penetrance for iron accumulation but a low clinical penetrance. Lack of excess morbidity among C282Y homozygous relatives of index cases who presented clinically suggests that residual unknown genetic or environmental factors do not greatly influence clinical outcome among C282Y homozygotes.

    AB - Background and aims: Although most cases of hereditary haemochromatosis are associated with homozygosity for the C282Y mutation of the HFE gene, clinical penetrance varies and other genes may modify disease expression. If so, relatives from clinically affected families, by inheriting such genes, may accumulate more iron. To seek evidence for this, we compared iron status and morbidity in unselected first degree relatives of two groups of index cases from South Wales, namely asymptomatic C282Y homozygotes identified by genetic screening of blood donors (n = 56) and C282Y homozygous haemochromatosis patients presenting clinically (n = 60).Methods: All participating relatives had a structured interview, clinical assessment, and laboratory investigations. Health related quality of life was measured (SF-36 version 2).Results: In total, 92% of 180 eligible first degree relatives were interviewed in the "screened" family group and 85% of 143 eligible relatives in the "patient" group. Of 59 relatives homozygous for C282Y, 76% of men and 32% of women had the "iron phenotype" (raised transferrin saturation and serum ferritin). Logistic regression modelling of the iron phenotype risk showed that 42% of the initial model deviance could be explained by homozygosity for C282Y, another 6% by lifestyle factors, and 6% by being male. Family group membership was not a significant risk factor. Morbidity and SF-36 scores did not differ significantly either between C282Y homozygotes and relatives lacking C282Y, or between C282Y homozygotes from the "screened" and "patient" groups. Serious morbidity (including cirrhosis) was low in both groups of relatives.Conclusions: HFE C282Y homozygosity has a high penetrance for iron accumulation but a low clinical penetrance. Lack of excess morbidity among C282Y homozygous relatives of index cases who presented clinically suggests that residual unknown genetic or environmental factors do not greatly influence clinical outcome among C282Y homozygotes.

    U2 - 10.1136/gut.2005.070342

    DO - 10.1136/gut.2005.070342

    M3 - Article

    VL - 55

    SP - 554

    EP - 562

    JO - Gut: an international journal of gastroenterology & hepatology

    JF - Gut: an international journal of gastroenterology & hepatology

    SN - 0017-5749

    IS - 4

    ER -