EASL Clinical Practice Guidelines

What is the prevalence of C282Y homozygosity?

The prevalence of HFE gene polymorphisms in the general population

The frequency of HC-associated HFE gene polymorphisms in the general population was determined in 36 screening studies, which fulfilled the inclusion criteria (Table 3). The allelic frequency of C282Y was 6.2% in a pooled cohort of 127,613 individuals included in the individual patient meta-analysis from these 36 studies (Table 3).

Table 3
Prevalence of the common HFE polymophisms C282Y and H63D in the general population.

Authors Ref. Country – Population Individuals screened Allele frequency for
c.845 C > A (Y282) c.187 C > G (D63)
Beckman et al. (1997) [ 7] Mordvinia 85 0.0176
Finland 173 0.052
Sweden – Saamis 151 0.0199
Sweden – Saamis 206 0.0752
Merryweather-Clarke et al. (1997) [ 8] UK 368 0.060 0.12
Ireland 45 0.1 0.189
Iceland 90 0.067 0.106
Norway 94 0.074 0.112
Former USSR 154 0.010 0.104
Finland 38 0 0.118
Denmark 37 0.095 0.22
Netherlands 39 0.026 0.295
Germany 115 0.039 0.148
Ashkenazi 35 0 0.086
Italy 91 0.005 0.126
Greece 196 0.013 0.135
Turkey 70 0 0.136
Spain 78 0.032 0.263
Datz et al. (1998) [ 9] Austria 271 0.041 0.258
Burt et al. (1998) [ 10] New Zealand of European ancestry 1064 0.070 0.144
Jouanolle et al. (1998) [ 11] France – Brittany 1000 0.065
Merryweather-Clarke et al. (1999) [ 12] Scandinavia 837 0.051 0.173
Distante et al. (1999) [ 13] Norway 505 0.078 0.229
Olynyk et al. (1999) [ 14] Australia 3011 0.0757
Marshall et al. (1999) [ 15] USA – non-Hispanic whites 100 0.05 0.24
Beutler et al. (2000) [ 16] USA – whites 7620 0.064 0.154002625
Steinberg et al. (2001) [ 17] USA – non-Hispanic whites 2016 0.0637 0.153769841
Andrikovics et al. (2001) [ 18] Hungarian blood donors 996 0.034 0.014
Pozzato et al. (2001) [ 19] Italy – Celtic populations 149 0.03691 0.144295302
Byrnes et al. (2001) [ 20] Ireland 800 0.1275 0.171875
Beutler et al. (2002) [ 21] USA – non-Hispanic whites 30,672 0.0622
Guix et al. (2002) [ 22] Spain – Balearic Islands 665 0.0203 0.201503759
Deugnier et al. (2002) [ 23] France 9396 0.07636228
Cimburova et al. (2002) [ 24] Czech Republic 254 0.03937008 0.142
Van Aken et al. (2002) [ 25] Netherlands 1213 0.06141797
Phatak et al. (2002) [ 26] USA 3227 0.0507 0.1512
Jones et al. (2002) [ 27] UK 159 0.085 0.173
Candore et al. (2002) [ 28] Italy – five regions 578 0.025 0.147
Salvioni et al. (2003) [ 29] Italy – North 606 0.0470297 0.143564356
Papazoglou et al. (2003) [ 30] Greece 264 0 0.089015152
Sanchez et al. (2003) [ 31] Spain 5370 0.03156425 0.208007449
Mariani et al. (2003) [ 32] Italy – North 1132 0.032 0.134
Altes et al. (2004) [ 33] Spain – Catalonia 1043 0.0282838 0.19894535
Adams et al. (2005) [ 34] USA – whites 44,082 0.06825915 0.153157751
Barry et al. (2005) [ 35] USA – non-Hispanic whites 3532 0.057 0.14
Meier et al. (2005) [ 36] Germany 709 0.044
Matas et al. (2006) [ 37] Jewish populations – Chuetas 255 0.00784314 0.123529412
Hoppe et al. (2006) [ 38] USA – non-Hispanic whites 991 0.05499495 0.134207871
Aranda et al. (2007) [ 39] Spain – Northeastern 812 0.03140394 0.219211823
Terzic et al. (2006) [ 40] Bosnia and Herzegovina 200 0.0225 0.115
Floreani et al. (2007) [ 41] Italy – Central 502 0.0189243 0.148406375
Raszeja-Wyszomirska et al. (2008) [ 42] Poland – Northwestern 1517 0.04416612 0.154251813

From this allelic frequency for C282Y, a genotype frequency of 0.38% or 1 in 260 for C282Y homozygosity can be calculated from the Hardy–Weinberg equation. The reported frequency of C282Y homozygosity is 0.41%, which is significantly higher than the expected frequency. This probably reflects a publication or ascertainment bias.

Significant variations in frequencies of the C282Y allele between different geographic regions across Europe have been reported with frequencies ranging from 12.5% in Ireland to 0% in Southern Europe (Fig. 1).


Fig. 1 Frequency of the C282Y allele in different European regions. (For detailed information see Table 3.)
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In addition to C282Y, which is also known as the 'major' HFE-associated polymorphism, H63D, considered to be the 'minor' HFE polymorphism, has been found more frequently in HC patients than in the control population. The frequency of the H63D polymorphism shows less geographic variation, with an average allelic frequency of 14.0% from pooled data (23,733 of 170,066 alleles). An additional HFE polymorphism is S65C, which can be associated with excess iron when inherited in trans with C282Y on the other parental allele. The allelic frequency of this polymorphism is ∼0.5% and appears to be higher in Brittany, France.

The prevalence of homozygosity for C282Y in the HFE gene in clinically recognized hemochromatosis

The prevalence of C282Y homozygosity in clinically recognized individuals with iron overload was assessed in a meta-analysis including 32 studies with a total of 2802 hemochromatosis patients of European ancestry (Table 4). This analysis of pooled data shows that 80.6% (2260 of 2802) of HC patients are homozygous for the C282Y polymorphism in the HFE gene. Compound heterozygosity for C282Y and H63D was found in 5.3% of HC patients (114 of 2117, Table 4). In the control groups, which were reported in 21 of the 32 studies, the frequency of C282Y homozygosity was 0.6% (30 of 4913 control individuals) and compound heterozygosity was present in 1.3% (43 of 3190 of the control population).

Table 4
Prevalence of C282Y homozygosity and C282Y/H63D compound heterozygosity in clinically recognized hemochromatosis.

Authors Ref. Study population Prevalence of HLA/HFE among clinical hemochromatosis cases
No. of cases C282Y homozygote C282Y/H63D compound heterozygote Wild type both alleles
Feder et al. (1996) [ 1] USA – Multicenter 187 148 21
Jazwinska et al. (1996) [ 43] Australia 112 112 0
Jouanolle et al. (1996) [ 44] France 65 65 3 0
Beutler et al. (1996) [ 45] USA – European origin 147 121
Borot et al. (1997) [ 46] France – Toulouse 94 68 4 18
Carella et al. (1997) [ 47] Italy – Northern 75 48 5
Datz et al. (1998) [ 9] Austria 40 31
Willis et al. (1997) [ 48] UK – Eastern England 18 18
The UK Haemochromatosis Consortium (1997) [ 49] UK – Consortium 115 105 5
Press et al. (1998) [ 50] USA – Portland 37 12
Cardoso et al. (1998) [ 51] Sweden 87 80 3 1
Sanchez et al. (1998) [ 52] Spain 31 27 2 1
Ryan et al. (1998) [ 53] Ireland 60 56 1 2
Nielsen et al. (1998) [ 54] Germany – Northern 92 87 4
Murphy et al. (1998) [ 55] Ireland 30 27
Mura et al. (1999) [ 56] France – Brittany 711 570 40 35
Brissot et al. (1999) [ 57] France – Northwest 217 209 4 2
Bacon et al. (1999) [ 58] USA 66 60 2
Brandhagen et al. (2000) [ 60] USA – Liver transplant recipients 5 4
Rivard et al. (2000) [ 60] Canada – Quebec 32 14 3 8
Papanikolaou et al. (2000) [ 61] Greece 10 3 5
Guix et al. (2000) [ 62] Spain – Balearic Islands 14 13
Brandhagen et al. (2000) [ 63] USA 82 70 2
Sham et al. (2000) [ 64] USA – Minnesota 123 74 15 6
Van Vlierberghe et al. (2000) [ 65] Belgium – Flemish 49 46 2 1
Bell et al. (2000) [ 66] Norway 120 92 3
Hellerbrand et al. (2001) [ 67] Germany – Southern 36 26 3 2
de Juan et al. (2001) [ 68] Spain – Basque population 35 20 4 2
Guix et al. (2002) [ 22] Spain – Balearic Islands 30 27 2 0
De Marco et al. (2004) [ 69] Italy – Southern 46 9 10 11
Bauduer et al. (2005) [ 70] France – Basque population 15 8 2
Cukjati et al. (2007) [ 71] Slovenia 21 10 2 2

Hence, 19.4% of clinically characterized HC patients have the disease in the absence of C282Y homozygosity. Although compound heterozygosity (H63D/C282Y) appears to be disease associated, in such individuals with suspected iron overload, cofactors should be considered as a cause [[72], [73], [74]].

The prevalence of HFE genotypes in selected patient groups

Fatigue

To date, there are only cross-sectional or case-control studies investigating the prevalence of C282Y homozygosity in patients with fatigue or chronic fatigue syndrome [[75], [76], [77]]. None of the three studies found the prevalence of C282Y homozygosity to be increased.

Arthralgia

Most available studies investigated the prevalence of C282Y mutations in patients with inflammatory arthritis [[78], [79], [80]]; there are few studies in patients with non-inflammatory arthralgia or chondrocalcinosis [[75], [81]]. In the majority of studies of patients with undifferentiated osteoarthritis the prevalence of C282Y homozygosity did not exceed that of the control population [[3], [80]]. In patients with osteoarthritis in the 2nd and 3rd metacarpophalangeal joints, higher allele frequencies of the HFE-polymorphisms (C282Y and H63D) were found, although this was not accompanied by an increased frequency of C282Y homozygotes [[82], [83]]. A higher prevalence of C282Y homozygosity was only found in patients with well-characterized chondrocalcinosis [81].

Diabetes

Association of the C282Y polymorphism with diabetes mellitus has been mainly evaluated in patients with type 2 diabetes mellitus in cross-sectional and case-control studies [[84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95]]. Apart from one exception, no association between type 2 diabetes and C282Y homozygosity was found [75]. A higher prevalence of the C282Y allele was found in proliferative diabetic retinopathy and nephropathy complicating type 2 diabetes [96], although the frequency of C282Y homozygosity was not increased. The prevalence of C282Y homozygotes in patients with type 1 diabetes mellitus has been addressed in only one study where a significantly higher rate of C282Y homozygotes was detected (odds ratio 4.6; prevalence 1.26%) [97].

Liver disease

There are a limited number of studies reporting C282Y-homozygosity in unselected patients with liver disease [[98], [99], [100]]. Three to 5.3% of patients were C282Y-homozygous, which is about 10-fold higher than the reported prevalence in the general population. The prevalence of C282Y homozygosity increased to 7.7% if patients were selected on the basis of a transferrin saturation of >45% [98].

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a recognized complication of HFE-HC. Nevertheless few studies have analyzed the frequency of C282Y homozygosity in patients with HCC and these are limited with respect to their size [[101], [102], [103], [104], [105], [106]]. The etiology of HCC differed significantly between the studies. Patients with clinical HC were specifically excluded in one study [103]. Subgroup analysis for gender specific prevalence and different etiologies were statistically underpowered. However, three studies in HCC reported a frequency of C282Y-homozygotes of 5.5–10% [[101], [102], [106]] and three further studies found an increased prevalence of C282Y heterozygosity [[103], [105], [107]]. Only one study [104] did not find an association between HCC and the C282Y-polymorphism.

Hair loss, hyperpigmentation, amenorrhea, loss of libido

There were no hits according to the search criteria.

Porphyria cutanea tarda

The prevalence of C282Y homozygosity among patients with porphyria cutanea tarda (PCT) was found to be increased significantly compared with control populations, ranging from 9% to 17% in several studies [[108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124]]. No association between PCT and the C282Y polymorphism was found in Italian patients [125]. The association between PCT and the common HFE gene polymorphisms C282Y and H63D is illustrated by a recent meta-analysis, where the odds ratios for PCT were 48 (24–95) in C282Y homozygotes, and 8.1 (3.9–17) in C282Y/H63D compound heterozygotes [126].

The prevalence of C282Y homozygosity in individuals with biochemical iron abnormalities

There is considerable variation in the cut-off of ferritin and transferrin saturation used for genetic screening of hereditary hemochromatosis (HH).

Serum ferritin

The prevalence of elevated ferritin varies between 4% and 41% in healthy populations depending on the cut-off and the screening setting (Table 5) [[10], [13], [14], [23], [84]]. The positive predictive value of an elevated ferritin for detection of C282Y-homozygotes was 1.6–17.6% (Table 5). The frequency of a ferritin concentration above 1000 μg/L was 0.2–1.3% in non-selected populations [[34], [133]].

Table 5
Prevalence of C282Y homozygosity in patients with elevated serum ferritin and transferrin saturation.

Authors Ref. Study population Prevalence of C282Y homozygotes among patients with elevated serum ferritin Prevalence of C282Y homozygotes among patients with elevated transferrin saturation (TS) Comments
Prevalence of elevated serum ferritin Prevalence of C282Y Prevalence of TS elevation Prevalence of C282Y
Deugnier et al. [ 23] Cross-sectional, n = 9396 em 76 of 981 (7.5%) 21 of 76 (17.6%) 70 of 993 (7%) 26 of 70 (18%) Health care, young patients; ferritin available for a subgroup only
Olynyk et al. [ 14] Cross-sectional, n = 3011 fn 405 of 3011 (13.5%) 8 of 405 (2%) 202 of 3011 (6.7%) 15 of 202 (7.4%) Patient selection included persistently elevated TS (45% or higher) or homozygosity for the C282Y mutation
Burt et al. [ 10] Cross-sectional, n = 1064 gl 42 of 1040 (4.0%) 2 of 42 (4.8%) 46 of 1040 (4.4%) 5 of 46 (10.9%) Voters
Distante et al. [ 13] Cross-sectional, n = 505 hl 23 of 505 (4.6%) 2 of 23 (8.7%) 25 of 505 pts (5%) 2 of 25 (8%) Health care
McDonnell et al. [ 127] Cross-sectional, n = 1450 io No data No data 60 of 1640 (3.7%) 13 of 60 (21.7%) HMO employees; only data for TS
Delatycki et al. [ 128] Cross-sectional, n = 11,307 No data No data No data No data 2 of 47 pts (biopsy in 6 pts) had precirrhotic fibrosis
Adams et al. [ 129] Cross-sectional, n = 5211 p No data No data 60 of 5211 (1.2%) 4 of 60 (6.7%) Blood donors
150 of 5211 (2.9%) 9 of 150 (6%)
278 of 5211 (5.3%) 12 of 278 (4.3%)
Adams et al. [ 34] Cross-sectional, n = 99,711 aq No data No data No data No data HEIRS study
Beutler et al. [ 16] Cross-sectional, n = 9650 br No data No data 67% of males, 39% of females
80% of males, 50% of females
Barton et al. [ 130] Cross-sectional, n = 43,453 caucasian ar 9299 whites (21.4%) 147 of 9299 (1.6%) 2976 of 43,453 (6.8%) 166 of 2976 (5.6%)
Asberg et al. [ 131] Cross-sectional, n = 65,238 m No data No data 2.7% of males, 2.5% of females 269 of 1698 (15.8%)
Gordeuk et al. [ 132] Cross-sectional, n = 101,168 ar 2253 of 101,168 (2.2%) 2253 of 101,168 (2.2%) 155 of 2253 (6.9%) Primary care combination of TS and ferritin
Ferritin [μg/L] cutoffs: a>300 males and postmenopausal females, >200 females, b>250 males and >200 females, c>300 males and females, d>250 males and >200 females, e>280 males >130 females, f>300 males and females, g>428 males >302 females, h>200 males and females, i95% percentile Transferrin saturation [%] cutoff: k>55: males >45: females, l>50, m>55: males and >50: females, n>45, o>55: males, >60: females, p>54 or >49 or >45, q>55: males >45: females, r>50 overall >45 overall.
Transferrin saturation

Elevated transferrin saturation was found in 1.2–7% of screened individuals in unselected populations [[10], [13], [14], [23], [129], [130], [131]] (Table 5). The positive predictive value of elevated transferrin saturation for the detection of C282Y-homozygotes was 4.3–21.7% (Table 5).