Diet and genetic factors associated with iron status in middle-aged women

Background: Gene mutations associated with iron overload have been identified. How food and nutrient intakes affect iron status in persons who may be at risk of iron overload because their genetic status is unknown. Objective: The objective was to determine the relation between food and nutrient intakes,HFE genotype, and iron status. Foods and nutrients associated with iron stores, with adjustment for gene mutations associated with hemochromatosis, were explored. Design: A prospective cohort of women aged 35–69 y (the UK Women’s Cohort Study) provided information on diet through a questionnaire and food diary; 6779 women in the cohort provided cheek cell samples, blood samples, or both, which were genotyped for C282Y and H63D mutations, and 2489 women also had their iron status assessed. Relations between serum ferritin and iron intake were investigated by using multiple linear regression, with adjustment for potential confounders. Results: The strongest dietary association with serum ferritin concentration was a positive association with heme iron and not with nonheme or total iron. Weaker positive associations were seen with red and white meat, and negative associations were seen with total energy and white and brown whole-meal bread, independent of genotype and other potential confounders. The effect of genotype on ferritin concentrations primarily occurred after menopause, at which time a strong interaction between genotype and heme iron intake was observed. Other factors associated with serum ferritin concentrations were age, body mass index, blood donation, menopausal status, andHFE genotype. Conclusions: Postmenopausal women eating a diet rich in heme iron and who were C282Y homozygotes had the highest serum ferritin concentrations

Inherited variants in the MC1R gene and survival from cutaneous melanoma: a BioGenoMEL study

Inherited MC1R variants modulate MITF transcription factor signaling, which in turn affects tumor cell proliferation, apoptosis, and DNA repair. The aim of this BioGenoMEL collaborative study in 10 melanoma cohorts was to test the hypothesis that inherited variants thereby moderate survival expectation. A survival analysis in the largest cohort (Leeds) was carried out adjusting for factors known to impact on survival. The results were then compared with data from nine smaller cohorts. The absence of any consensus MC1R alleles was associated with a significantly lower risk of death in the Leeds set (HR, 0.64; 95% CI, 0.46–0.89) and overall in the 10 data sets (HR, 0.78; 95% CI, 0.65–0.94) with some support from the nine smaller data sets considered together (HR, 0.83; 95% CI, 0.67–1.04). The data are suggestive of a survival benefit for inherited MC1R variants in melanoma patients

Risk factors for melanoma by anatomical site: an evaluation of aetiological heterogeneity

Background: Melanoma aetiology has been proposed to have two pathways, which are determined by naevi and type of sun exposure and related to the anatomical site where melanoma develops. Objectives: We examined associations with melanoma by anatomical site for a comprehensive set of risk factors including pigmentary and naevus phenotypes, ultraviolet radiation exposure and polygenic risk. Methods: We analysed harmonized data from 2617 people with incident first invasive melanoma and 975 healthy controls recruited through two population-based case–control studies in Australia and the UK. Questionnaire data were collected by interview using a single protocol, and pathway-specific polygenic risk scores were derived from DNA samples. We estimated adjusted odds ratios using unconditional logistic regression that compared melanoma cases at each anatomical site with all controls. Results: When cases were compared with control participants, there were stronger associations for many naevi vs. no naevi for melanomas on the trunk, and upper and lower limbs than on the head and neck (P-heterogeneity < 0·001). Very fair skin (vs. olive/brown skin) was more weakly related to melanoma on the trunk than to melanomas at other sites (P-heterogeneity = 0·04). There was no significant difference by anatomical site for polygenic risk. Increased weekday sun exposure was positively associated with melanoma on the head and neck but not on other sites. Conclusions: We found evidence of aetiological heterogeneity for melanoma, supporting the dual pathway hypothesis. These findings enhance understanding of risk factors for melanoma and can guide prevention and skin examination education and practices.</p

Assessing the incremental contribution of common genomic variants to melanoma risk prediction in two population-based studies

It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n=1,035) and the UK (n=1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, centre and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under receiver operating characteristic curve (AUC) by 2.3% (p=0.003) for Australia and by 2.8% (p=0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile