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 what percent of rs1800562(A;A) individuals actually develop clinical signs of hemochromatosis? At least in the UK (Caucasian) population, a 2019 survey reported that of 2890 participants homozygous for p.C282Y (0.6%, or 1 in 156), hemochromatosis was diagnosed in 21.7% of men and 9.8% of women over an average follow up (~7 years). p.C282Y homozygous men aged 40 to 70 had a higher prevalence of diagnosed hemochromatosis (OR 411.1, CI: 299-565, p<0.001), liver disease (4.30, 2.97-6.18, p<0.001), rheumatoid arthritis (2.23, 1.51-3.31, p<0.001), osteoarthritis (2.01, 1.71-2.36, p<0.001), and diabetes mellitus (1.53, 1.16-1.98, p=0.002), versus 175,000+ controls (people with no p.C282Y mutations). During the seven year follow-up, 15.7% of homozygous men developed at least one incident associated condition versus 5.0% (p<0.001) with no p.C282Y mutations; for women, it was 10.1% vs 3.4%, p<0.001). 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 one 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.

A;A

This rare genotype causes hereditary hemochromatosis. This can result in serious iron overload in males or post-menopausal females, but is easily treated. This ACMG report recommends 4 clinical actions for those carrying two C282Y copies: * Serum ferritin concentrations should be measured to establish disease status and prognosis. * MRI to estimate parenchymal iron content, including the liver and possibly the heart * When serum ferritin and liver enzyme levels are abnormal, liver biopsy can establish or exclude cirrhosis. * Consultation with a medical geneticist and/or genetic counselor. comments at this reddit thread may be useful

A;G

You are a carrier for rs1800562(A) C282Y Hereditary hemochromatosis. You are unlikely to be affected unless also a carrier of rs1799945(G) H63D, but others in your family may be. This is a treatable condition.