Mutations in the Hereditary Hemochromatosis Gene Are Not Associated With the Increased Body Iron Stores Observed in Overweight and Obese Women With Polycystic Ovary Syndrome Free

We recently reported (1) that serum ferritin levels are increased in overweight and obese women with polycystic ovary syndrome (PCOS) independently of inflammation. This finding suggested increased body iron stores in these women, raising the possibility that genes related to iron metabolism are altered in PCOS.

Classic hereditary hemochromatosis is an autosomal recessive disorder caused by mutations in the HFE gene, resulting in increased intestinal iron absorption and iron accumulation in several organs. In the study by Sanchez et al. (2), >80% of the Spanish patients with hereditary hemochromatosis were homozygous for the HFE C282Y mutation or compound heterozygotes for the HFE C282Y and H63D mutations.

Although hereditary hemochromatosis has low penetrance in young women, we studied the HFE genotypes of 78 PCOS patients and 43 control subjects characterized in our previous report of increased body iron stores in PCOS (1). Genotyping was conducted by PCR/restriction fragment–length polymorphism methods using the PmlI and BclI restriction enzymes for the C282Y and H63D mutations, respectively. The ethics committee of the Hospital Ramón y Cajal approved the study, and informed consent was obtained from all participants.

We did not find homozygosity for the C282Y substitution in HFE in any PCOS patient or control subject. Three patients with PCOS but no control subjects were compound heterozygotes for the C282Y and H63D mutations (χ² = 1.696, P = 0.552), but their serum ferritin levels were 14, 82, and 113 pmol/l (normal range 11–325), ruling out a condition of iron overload.

Forty-eight of the patients (61.5%) and 24 of the control subjects (55.8%) had one or more mutated alleles of the C282Y and H63D genotype alleles, whereas all other women were homozygous for wild-type alleles of both HFE mutations (χ² = 0.377, P = 0.539). The HFE mutations studied here did not influence serum ferritin levels when considering PCOS patients and control subjects as a whole (C282C [n = 110] 109 ± 94 pmol/l vs. C282Y [n = 11]110 ± 115 pmol/l [F = 0.122, P = 0.728]; H63H [n = 57] 108 ± 98 pmol/l vs. H63D and D63D [n = 64] 110 ± 94 pmol/l [F = 0.499, P = 0.481]; and interaction between both genotypes [F= 0.834, P = 0.363]) or separately (data not shown).

Finally, a multivariate stepwise linear regression analysis model retained BMI (β = 0.263, P = 0.003) and PCOS status (β = 0.238, P = 0.007) as predictive variables of serum ferritin levels (R² = 0.127, F = 8.557, P < 0.001), whereas carrier status for C282Y and/or H63D mutations, as well as having oligo/amenorrhea compared with having regular cycles, were excluded as predictors.

In summary, PCOS is not associated with the C282Y and H63D mutations in HFE, and these mutations did not influence serum ferritin levels in our series. As discussed earlier (1), other mechanisms are possibly related to the increase in body iron stores observed in overweight and obese PCOS patients.