The H63D variant in the HFE gene predisposes to arthralgia, chondrocalcinosis and osteoarthritis

Abstract

Objectives: To investigate the relation between the HFE C282Y and H63D variants with arthralgia and joint pathology in the population-based Rotterdam Study. Methods: From a cohort of 7983 people aged 55 years and over, 2095 randomly drawn subjects were genotyped for C282Y and H63D variants. We compared the frequency of arthralgia, and the presence of chondrocalcinosis, osteophytes, joint space narrowing and radiographic osteoarthritis in hand, hip and knee joints, and Heberden's nodes in carriers of HFE variants with that in non-carriers. Results: Overall, there was a significantly higher frequency of arthralgia (odds ratio 1.6; 95% CI 1.0 to 2.6), oligoarthralgia (2.3; 1.2 to 4.4) and Heberden's nodes (2.0; 1.1 to 3.8) in H63D homozygotes compared with non-carriers. In subjects aged 65 years or younger, H63D homozygotes had significantly more often polyarthralgia (3.1; 1.3 to 7.4), chondrocalcinosis in hip or knee joints (4.7; 1.2 to 18.5), and more hand joints with osteophytes (6.1¡1.0 vs 4.4¡0.3), space narrowing (2.8¡0.5 vs 1.0¡0.1), radiographic osteoarthritis (4.4¡0.7 vs 2.0¡0.2) and Heberden's nodes (3.1; 1.3 to 12.8) than non-carriers. We found no relation of arthralgia or joint pathology to C282Y, but compound heterozygotes had a significantly higher frequency of arthralgia (2.9; 1.0 to 9.3), chondrocalcinosis in hip joints (6.5; 1.8 to 22.3), and an increased number of osteophytes in knee (6.9¡1.2, n = 5 vs 2.4¡0.1) joints at a later age (.65 years). Conclusions:The HFE H63D variant may explain, at least in part, the prevalence of arthralgia in multiple joints sites, chondrocalcinosis, and hand osteoarthritis in the general population.A rthropathy affects up to 85% of patients with type I hereditary haemochromatosis, [1][2][3][4][5][6] seriously influencing their quality of life.7 Hand, hip and knee joints are most often affected. [8][9][10][11] In patients with haemochromatosis, arthropathy may originate from a progressive degenerative arthritis initially presenting in hand joints, 9 10 but it can also originate from an inflammatory mediated condition like chondrocalcinosis, 9 10 12 or it may resemble rheumatoid arthritis, 8 9 accompanied by Heberden's nodes. 13 The main radiographic findings in haemochromatosis arthropathy are calcium crystal depositions, osteophytes and joint space narrowing. 10The HFE C282Y and H63D variants are the most common genetic factors involved in hereditary haemochromatosis. 5 14-16 Eleven per cent of Caucasians are carriers of C282Y, and 23% of the total population worldwide are carriers of H63D. 15 The risk of haemochromatosis is increased for C282Y homozygotes (4383-fold) or compound heterozygotes, that is carriers of both H63D and C282Y (32-fold).15 Also, H63D homozygotes are estimated to have a sixfold increased risk of haemochromatosis, although their iron levels may be modestly increased. 17Findings on the relation between HFE variants and arthropathy are neither consistent nor conclusive. Some studies found no relationship between C282Y and self-reported arthrop...

The association between ANKH promoter polymorphism and chondrocalcinosis is independent of age and osteoarthritis: results of a case–control study

“…Similar findings have been reported previously [20]. The lack of association between homozygosity for minor allele at rs1800562 and CC may be due to a channeling bias (that is, patients with hemochromatosis are excluded from these studies).…”

Increased Risk of Arthropathies and Joint Replacement Surgery in Patients With Genetic Hemochromatosis: A Study of 3,531 Patients and Their 11,794 First‐Degree Relatives

“…Only 2 population‐based cohort studies on arthropathy in individuals with heterozygous mutation for the C282Y mutation have been conducted. No association was found, but the number of heterozygous individuals identified was <200 in both studies (15, 46). In longitudinal and observational studies on heterozygosity for the C282Y mutation in individuals with existing arthritis of unknown origin, some studies (13, 14, 16, 17), but not all (18–23), suggest an association.…”

“…Studies aimed at identifying an association between C282Y heterozygosity and arthropathy show mixed results (13–23). Interestingly, individuals with OA found to be heterozygous for the C282Y mutation show higher synovial ferritin than controls (24).…”

Musculoskeletal Complications of Hereditary Hemochromatosis: A Case-Control Study

“…Some studies found that arthritis or presence of abnormal second and third MCP joints was more common in C282Y homozygotes than in controls 17,18 ; others found that the prevalence of joint pain or arthritis was similar in C282Y homozygotes and controls 19,20,21,22,23 . Moreover, a recent metaanalysis of 66,000 cases and 226,000 controls found the hemochromatosis genotypes (C282Y/C282Y or C282/H63D) not associated with arthritis 24 .…”