Rs1800562

rs1800562 represents a SNP that accounts for ~85% of all cases of hemochromatosis, a disorder whose symptoms include cirrhosis of the liver, diabetes, hypermelanotic pigmentation of the skin, and heart failure. OMIM indicates that liver cancer is responsible for about one-third of deaths of rs1800562(A;A) homozygotes, and since hemochromatosis is a relatively easily treated disorder if diagnosed, this is a form of preventable cancer.

The rs1800562(A) allele is known as the C282Y or Cys282Tyr mutation, and it is found at a frequency of around 5-10% in many Caucasian populations, leading to an incidence of (A;A) homozygotes around 1 in 200. Early identification of rs1800562(A;A) homozygotes can prevent complications of hemochromatosis; however, the percentage of all (A;A) homozygotes who actually develop clinical signs of hemochromatosis may be relatively low, may depend on sex (see below), and appears to be influenced by other SNPs yet to all be discovered as well as (unidentified) environmental factors, possibly including the amount of iron in the diet.

In rs1800562(A;A) patients who do develop hemochromatosis, a SNP has been identified which increases the risk of cardiomyopathy (a form of heart disease). rs4880(T;T) homozygotes are at ~10 fold increased risk for dilated- or non-dilated cardiopathy based on a study of 217 patients.

rs235756, a SNP in the BMP2 gene, is another SNP that may influence the development of hemochromatosis in rs1800562(A;A) individuals, at least if serum transferrin levels are a good indication. Transferrin levels increased with increasing copies of the rs235756(T) allele.

So which rs1800562(A;A) individuals actually develop clinical signs of hemochromatosis? In a recent study of ~200 rs1800562(A;A) homozygotes, ~30% of the males had iron-overload related diseases versus 1% of the females. Male C282Y homozygotes with a serum ferritin level of 1,000 mcg per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who lacked a rs1800562(A) allele.

Women who are rs1800562(A) homozygotes are less affected by hemochromatosis due to elimination of excess iron during menstruation, but may become affected after menopause.

Carriers of rs1800562(A) may be affected by a mild form of hemochromatosis if also a carrier of rs1799945(G) H63D.

According to Coriell, in Caucasian populations:
 * (A;A) - 0.4% of individuals, carrying 2 copies of the risk variant (33-57% of such males will have quite elevated iron levels; 3-16% if female)
 * (G;A) - 12% carry 1 copy of the risk variant and 1 copy of the non-risk variant
 * (G;G) - 87.6% carry (only) the non-risk variant

Was the C282Y mutation an Irish Gaelic mutation that the Vikings helped disseminate? Conclusion: The C282Y frequency shows a west to east decline from Ireland through the north of Europe. Vikings may have been involved in the spread of C282Y, but the mutation is probably older and may have been spread in Europe by earlier seafarers.