David Melzer

Purpose: Haemochromatosis due to HFE -C282Y homozygosity can lead to excess iron absorption and is typically associated with liver malignancy, plus widespread arthritis. Recent evidence suggests that limb fractures are more common, but little is known about vertebral effects. This study investigated the association of vertebral compression fractures, assessed with intelligent dual-energy X-ray absorptiometry (iDXA), and HFE genotype in a large community cohort. Methods: UK Biobank data from 227 European genetic ancestry C282Y homozygotes (mean 64.6 years) and 234 age, sex, and BMI-matched controls without common HFE haemochromatosis variants were included. Lateral vertebral assessment scans (iDXA, GE-Lunar) were acquired at imaging reassessment (2014-2020) and reviewed, blind to genotype, for radiological evidence of vertebral fracture. Matched logistic regression models assessed associations between C282Y homozygosity and vertebral fractures. Results: 78 vertebral fractures (16.9%) were identified within 461 participants. Male C282Y homozygotes had increased odds of vertebral fracture (n=22/89, 24.7%) compared to participants without HFE alleles (n=9/90, 10.0%); Odds Ratio [OR]: 2.95, 95%CI: 1.28–6.85, p=0.01. The association persisted after excluding individuals with a diagnosis of haemochromatosis (OR: 3.37, 95% CI: 1.41–8.10, p=0.007). No excess fracture risk was observed in female C282Y homozygotes (n=23/138, 16.7%) vs those without HFE alleles (n=24/144, 16.7%); OR: 0.99, 95%CI: 0.53-1.87, p=1.00. Conclusion: In this community-based imaging study, male HFE C282Y homozygotes had a markedly higher likelihood of vertebral fractures than those without HFE variants. These findings support further evaluation of vertebral fracture assessment in C282Y homozygous men to ensure prompt treatment to prevent future fracture if appropriate.

Supplementary Table from Hereditary Hemochromatosis Variant Associations with Incident Nonliver Malignancies: 11-Year Follow-up in UK Biobank

Background:In European ancestry populations, iron overload disorder hereditary hemochromatosis is predominantly caused by HFE p.C282Y and p.H63D mutations. Male p.C282Y homozygotes have markedly increased hepatic malignancy incidence, but risks for other cancers in male and female homozygotes are unclear.Methods:451,143 UK Biobank European ancestry participants (aged 40–70 years; 54.3% female) were followed (mean 11.6 years) via hospital admissions and national cancer registries. We estimated risks of any incident cancer (other than nonmelanoma and liver cancer) and common incident cancers [bladder, blood (with subanalyses of leukemia and lymphoma), bone, brain, breast, colorectal, kidney, lung, melanoma, esophageal, ovarian, pancreatic, prostate and stomach] in those with p.C282Y and p.H63D genotypes, compared with participants without HFE mutations.Results:Male p.C282Y homozygotes (n = 2,890, 12.1% with baseline diagnosed hereditary hemochromatosis) had increased incidence of prostate cancer [6.8% vs. 5.4% without mutations; HR = 1.32; 95% confidence interval (CI), 1.07–1.63; P = 0.01; Bonferroni adjusted P = 0.17] during follow-up. In life table estimates from ages 40 to 75 years, 14.4% of male p.C282Y homozygotes are projected to develop prostate cancer (versus 10.7% without mutations, excess 3.8%; 95% CI, 1.3–6.8). No increases in risks were found for other studied cancers in male or female p.C282Y homozygotes, or in any other p.C282Y/p.H63D genotype groups of either sex.Conclusions:In a large community sample of male p.C282Y homozygotes, there is suggestive evidence of increased prostate cancer incidence, with no evidence of excess of other studied (nonliver) cancers.Impact:Replication of results in other large community genotyped cohorts are needed to confirm if clinical monitoring for prostate cancer is necessary in p.C282Y homozygous males.

Background and Aims: The HFE p.C282Y+/+ (homozygous) genotype and central adiposity both increase liver disease and diabetes risks, but the combined effects are unclear. We estimated waist-to-hip ratio (WHR) associations with incident clinical outcomes in routine care in p.C282Y+/+ participants in the UK Biobank community cohort. Approach and Results: Baseline WHR data available in 1297 male and 1602 female p.C282Y+/+ with 13.3-year mean follow-up for diagnoses. Spline regressions and Cox proportional hazard models were adjusted for age and genetic principal components. Cumulative incidence was from age 40 to 80 years. In p.C282Y+/+ males, there were positive linear WHR relationships for hospital inpatient–diagnosed liver fibrosis/cirrhosis (p = 2.4 × 10⁻⁵), liver cancer (p = 0.007), non-alcoholic fatty liver disease (p = 7.7 × 10⁻¹¹), and type 2 diabetes (p = 5.1 × 10⁻¹⁶). The hazard ratio for high WHR in p.C282Y+/+ males (≥0.96; 33.9%) was 4.13 for liver fibrosis/cirrhosis (95% CI: 2.04–8.39, p = 8.4 × 10⁻⁵ vs. normal WHR); cumulative age 80 incidence 15.0% (95% CI: 9.8%–22.6%) versus 3.9% (95% CI: 1.9%–7.6%); for liver cancer, cumulative incidence was 9.2% (95% CI: 5.7%–14.6%) versus 3.6% (95% CI: 1.9%–6.6%). Hemochromatosis was diagnosed in 23 (96%) of the 24 high WHR p.C282Y+/+ males with incident fibrosis/cirrhosis. High WHR (≥0.85; 30.0%) p.C282Y+/+ females had raised hazards for liver fibrosis/cirrhosis (hazard ratio = 9.17, 95% CI: 2.51–33.50, p = 3.8 × 10⁻⁷) and Non-alcoholic fatty liver disease (hazard ratio = 5.17, 95% CI: 2.48–10.78, p = 1.2 × 10⁻⁵). Fibrosis/cirrhosis associations were similar in the subset with additional primary care diagnoses. Conclusions: In p.C282Y+/+ males and females, increasing WHR is associated with substantially higher risks of liver complications. Interventions to reduce central adiposity to improve these outcomes should be tested.

Iron overload is implicated in mitochondrial dysfunction. Some iron and mitochondria-related measures show sex differences. It is unclear whether mitochondrial DNA copy number (mtDNAcn) from blood associated with iron depositions in the brain or liver and whether the relationship differs by sex. In this population-based study, we find that among community-dwelling adults, lower mtDNAcn assessed in blood is associated with higher brain iron in basal ganglia and hippocampus and more liver fat, and not with brain volumes or liver iron. Interestingly, the association between mtDNAcn and brain iron in basal ganglia is prominent in men. Our observations lead to the hypothesis that mechanisms connecting mitochondrial dysfunction and iron overload may differ between brain and liver and differ by sex.

The solute carrier organic anion transporter family member 1B1 (SLCO1B1) encodes the organic anion-transporting polypeptide 1B1 (OATP1B1 protein) that transports statins to liver cells. Common genetic variants in SLCO1B1, such as *5, cause altered systemic exposure to statins and therefore affect statin outcomes, with potential pharmacogenetic applications; yet, evidence is inconclusive. We studied common and rare SLCO1B1 variants in up to 64,000 patients from UK Biobank prescribed simvastatin or atorvastatin, combining whole-exome sequencing data with up to 25-year routine clinical records. We studied 51 predicted gain/loss-of-function variants affecting OATP1B1. Both SLCO1B1*5 alone and the SLCO1B1*15 haplotype increased LDL during treatment (beta*5 = 0.08 mmol/L, p = 6 × 10⁻⁸; beta*15 = 0.03 mmol/L, p = 3 × 10⁻⁴), as did the likelihood of discontinuing statin prescriptions (hazard ratio*5 = 1.12, p = 0.04; HR*15 = 1.05, p = 0.04). SLCO1B1*15 and SLCO1B1*20 increased the risk of General Practice (GP)-diagnosed muscle symptoms (HR*15 = 1.22, p = 0.003; HR*20 = 1.25, p = 0.01). We estimated that genotype-guided prescribing could potentially prevent 18% and 10% of GP-diagnosed muscle symptoms experienced by statin patients, with *15 and *20, respectively. The remaining common variants were not individually significant. Rare variants in SLCO1B1 increased LDL in statin users by up to 1.05 mmol/L, but replication is needed. We conclude that genotype-guided treatment could reduce GP-diagnosed muscle symptoms in statin patients; incorporating further SLCO1B1 variants into clinical prediction scores could improve LDL control and decrease adverse events, including discontinuation.

Objectives: HFE haemochromatosis genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.H63D variant cumulative incidence of multiple clinical outcomes in a large community cohort. Design: Prospective cohort study. Setting: 22 assessment centres across England, Scotland, and Wales in the UK Biobank (2006–2010). Participants: 451 270 participants genetically similar to the 1000 Genomes European reference population, with a mean of 13.3-year follow-up through hospital inpatient, cancer registries and death certificate data. Main outcome measures: Cox proportional HRs of incident clinical outcomes and mortality in those with HFE p.C282Y/p.H63D mutations compared with those with no variants, stratified by sex and adjusted for age, assessment centre and genetic stratification. Cumulative incidences were estimated from age 40 years to 80 years. Results: 12.1% of p.C282Y+/+ males had baseline (mean age 57 years) haemochromatosis diagnoses, with a cumulative incidence of 56.4% at age 80 years. 33.1% died vs 25.4% without HFE variants (HR 1.29, 95% CI: 1.12 to 1.48, p=4.7×10 ^-4 ); 27.9% vs 17.1% had joint replacements, 20.3% vs 8.3% had liver disease, and there were excess delirium, dementia, and Parkinson’s disease but not depression. Associations, including excess mortality, were similar in the group undiagnosed with haemochromatosis. 3.4% of women with p.C282Y+/+ had baseline haemochromatosis diagnoses, with a cumulative incidence of 40.5% at age 80 years. There were excess incident liver disease (8.9% vs 6.8%; HR 1.62, 95% CI: 1.27 to 2.05, p=7.8×10 ^-5 ), joint replacements and delirium, with similar results in the undiagnosed. p.C282Y/p.H63D and p.H63D+/+ men or women had no statistically significant excess fatigue or depression at baseline and no excess incident outcomes. Conclusions: Male and female p.C282Y homozygotes experienced greater excess morbidity than previously documented, including those undiagnosed with haemochromatosis in the community. As haemochromatosis diagnosis rates were low at baseline despite treatment being considered effective, trials of screening to identify people with p.C282Y homozygosity early appear justified.

Objectives: HFE haemochromatosis genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.H63D variant cumulative incidence of multiple clinical outcomes in a large community cohort. Design: Prospective cohort study. Setting: 22 assessment centres across England, Scotland, and Wales in the UK Biobank (2006-2010). Participants: 451,270 participants genetically similar to the 1000-Genomes European reference population, with a mean 13.3-year follow-up through hospital inpatient, cancer registries and death certificate data. Main outcome measures: Cox proportional hazard ratios of incident clinical outcomes and mortality in those with HFE p.C282Y-p.H63D mutations compared to those with no variants, stratified by sex and adjusted for age, assessment centre and genetic stratification. Cumulative incidences were estimated from age 40 to 80 years. Results: 12.1% of p.C282Y+/+ males had baseline (mean age 57) haemochromatosis diagnoses, with age 80 cumulative incidence of 56.4%. 33.1% died vs. 25.4% without HFE variants (Hazard Ratio [HR] 1.29, 95% CI: 1.12-1.48, p=4.7*10 ^-4 ); 27.9% vs 17.1% had joint replacements, 20.3% vs 8.3% had liver disease, and there was excess delirium, dementia, and Parkinson’s disease, but not depression. Associations, including excess mortality, were similar in the group undiagnosed with haemochromatosis. 3.4% of p.C282Y+/+ females had baseline haemochromatosis diagnoses, with cumulative age 80 incidence of 40.5%. There was excess incident liver disease (8.9% vs 6.8%; HR 1.62, 95% CI: 1.27-2.05, p=7.8*10 ^-5 ), joint replacements and delirium, with similar results in the undiagnosed. p.C282Y/p.H63D and p.H63D+/+ men or women had no statistically significant excess fatigue or depression at baseline and no excess incident outcomes. Conclusions: Male and female p.C282Y homozygotes experienced greater excess morbidity than previously documented, including those undiagnosed with haemochromatosis in the community. As haemochromatosis diagnosis rates were low at baseline despite treatment being considered effective, trials of screening to identify people with p.C282Y homozygosity early appear justified. Strengths and limitations of this study: We analyzed largescale data on community volunteers from the UK Biobank, one of the world’s largest HFE genotyped cohorts. We have analyzed incident disease outcomes during an extended follow-up period of mean 13.3 years. We have provided the first clinical outcome data to age 80 years in those with haemochromatosis genotypes, including those undiagnosed with haemochromatosis at baseline, expanding the life-course evidence on HFE penetrance. UK Biobank participants were somewhat healthier than the general population, but HFE allele frequencies were similar to previous UK studies. Incident outcomes were from hospital inpatient and cancer registry follow-up, so did not rely on potentially biased patient self-reporting, but community diagnosed conditions may be underestimated.

The iron overload disorder hemochromatosis is primarily caused by the homozygous HFE p.C282Y variant, but the scale of excess related musculoskeletal morbidity is uncertain. We estimated hemochromatosis‐genotype associations with clinically diagnosed musculoskeletal outcomes and joint replacement surgeries in the UK Biobank community cohort. A total of 451,143 European ancestry participants (40 to 70 years at baseline) were followed in hospital records (mean 11.5‐years). Cox proportional hazards models estimated HFE p.C282Y and p.H63D associations with incident outcomes. Male p.C282Y homozygotes (n = 1294) had increased incidence of osteoarthritis (n = 52, hazard ratio [HR]: 2.12 [95% confidence interval, CI: 1.61 to 2.80]; p = 8.8 × 10⁻⁸), hip replacement (n = 88, HR: 1.84 [95% CI: 1.49 to 2.27]; p = 1.6 × 10⁻⁸), knee replacement (n = 61, HR: 1.54 [95% CI: 1.20 to 1.98]; p = 8.4 × 10⁻⁴), and ankle and shoulder replacement, compared to males with no HFE mutations. Cumulative incidence analysis, using Kaplan–Meier lifetable probabilities demonstrated 10.4% of male homozygotes were projected to develop osteoarthritis and 15.5% to have hip replacements by age 75, versus 5.0% and 8.7% respectively without mutations. Male p.C282Y homozygotes also had increased incidence of femoral fractures (n = 15, HR: 1.72 [95% CI: 1.03 to 2.87]; p = 0.04) and osteoporosis (n = 21, HR: 1.71 [95% CI: 1.11 to 2.64]; p = 0.02), although the latter association was limited to those with liver fibrosis/cirrhosis diagnoses. Female p.C282Y homozygotes had increased incidence of osteoarthritis only (n = 57, HR: 1.46, [95% CI: 1.12 to 1.89]; p = 0.01). Male p.C282Y/p.H63D compound heterozygotes experienced a modest increased risk of hip replacements (n = 234, HR: 1.17 [95% CI: 1.02 to 1.33], p = 0.02), but this did not pass multiple testing corrections. In this large community cohort, the p.C282Y homozygote genotype was associated with substantial excess musculoskeletal morbidity in males. Wider HFE genotype testing may be justified, including in orthopedic clinics serving higher HFE variant prevalence populations. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.