Natural history of HFE simple heterozygosity for C282Y and H63D: A prospective 12-year study

Background and Aim - The risk of hemochromatosis-related morbidity for HFE simple heterozygosity for either the C282Y or H63D substitutions in the HFE protein was assessed using a prospective community-based cohort study. Methods - HFE genotypes were measured for 31 192 persons of northern European descent, aged between 40 and 69 years when recruited to the Melbourne Collaborative Cohort Study, and subjects were followed for an average of 12 years. For a random sample of 1438 participants stratified according to HFE genotype, two sets of biochemical iron indices performed 12 years apart and, at follow-up only, the presence/absence of six disease features associated with hereditary hemochromatosis were obtained. Summary data for 257 (139 female) C282Y simple heterozygotes and 123 (74 female) H63D simple heterozygotes were compared with 330 (181 female) controls with neither HFE mutation. Results - At baseline, mean transferrin saturation (TS) (95% confidence interval) and prevalence of TS > 55% were 35.14% (33.25, 37.04) and 3/112 (3%), 33.03% (29.9, 36.15) and 0/39 (0%), and 29.67% (27.93, 31.4) and 3/135 (2%) for C282Y, H63D and wild-type male participants, respectively. At follow-up, mean TS levels remained similar to baseline levels for both men and women irrespective of simple heterozygosity for either mutation. No HFE C282Y or H63D simple heterozygotes had documented iron overload (based on hepatic iron measures or serum ferritin greater than 1000 mg/L at baseline with documented therapeutic venesection). Conclusion - No documented iron overload was observed for HFE simple heterozygotes for either C282Y or H63D, and morbidity for both HFE simple heterozygote groups was similar to that of HFE wild-type participants

Blood donor behaviour, motivations and the need for a systematic cross-cultural perspective: the example of moral outrage and health and non-health based philanthropy across seven countries

Background: Blood donation is a prosocial altruistic act that is motived by the mechanisms that underlie altruism (e.g., warm-glow, reciprocity, fairness/trust). Because there is consistent evidence that altruism and its mechanisms show cross-cultural variability, in the present paper we make the case for a cross-cultural perspective in blood donor research. Methods: We analyse a subset of variables from a larger study, with samples drawn from seven countries (England, Malta, the Netherlands, Australia, USA, Hungary, Italy: average N per country = 282). This subset of variables focuses on health (organ donor registration) and non-health (volunteering, donating money) philanthropy, family traditions of helping, and moral outrage as predictors of blood donor status. Results: We show two cross-cultural universals: 1) organ donor registration in opt-in countries is positively associated with blood donor status and 2) non-health philanthropy is generally unrelated to blood donor status. We also show two country specific effects: 1) a family tradition for helping is associated with blood donor status in Italy only and 2) moral outrage is a predictor only in the USA. Conclusions: We contend that these findings provide proof of principle why a cross-cultural perspective on blood donor behaviour is needed

A comparison of self-reported puberty using the pubertal development scale and the sexual maturation scale in a school-based epidemiologic survey

Purpose: To examine concordance between two self-reported measures of puberty: Sexual Maturatiom Scale (SMS) and Pubertal Developl1!ent Scale (PDS) and their acceptability to adolescents. Methods: Participants of a school-based study in grades 5, 7 and 9 were classified into one of 5 pubertal stages using each method. Results: 2864 students (age 9-16 years) participated. Agreement was moderate for males (K 0.42, 95% CI 0.39,0.45) and females (K 0.57, 95% CI 0.53, 0.61). Concordance within one stage was excellent (females 97%, males 89%), with discrepancies due to females being classified one stage later on the PDS (26%) and males one stage earlier (32%). There were more missing data for the SMS (13%) than the PDS (4%).<br /

Bivariate mixture models for the joint distribution of repeated serum ferritin and transferrin saturation measured 12 years apart in a cohort of healthy middle-aged Australians

Homozygosity for the p.C282Y substitution in the HFE protein encoded by the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. McLaren et al. used bivariate mixture modeling to analyze the joint population distribution of transferrin saturation (TS) and serum ferritin concentration (SF) measured for participants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. They identified four components (C1, C2, C3, and C4) with successively increasing means for TS and SF. They demonstrated that bivariate mixture modeling in TS and SF reflect the genetic locus of HFE and may isolate p.C282Y homozygotes from the general population. In the current study we used data from the another large cohort, the Australian HealthIron study of genetic and environmental modifiers of hereditary hemochromatosis, to validate the component analysis approach, to examine stability of component proportions over time and to determine if TS and SF values from an individual move between components at baseline and follow-up. Because sampling fractions from each p.C282Y / p.H63D genotype stratum are not equal, we used frequency weights based on the inverse of the probability of selection for invitation to participate. In the weighted female analytic cohorts, C4 captured most of C282Y homozygotes, and C2 was the largest component. We identified four components from the weighted male analytic cohort and C4 captured most of p.C282Y homozygotes. The bivariate mixture modeling approach suggested that the model is transferable from one white population to another, although estimated means within components may differ

A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis

There is emerging evidence that there are genetic modifiers of iron indices for HFE gene mutation carriers at risk of hereditary hemochromatosis. A random sample, stratified by HFE genotype, of 863 from a cohort of 31 192 people of northern European descent provided blood samples for genotyping of 476 single nucleotide polymorphisms (SNPs) in 44 genes involved in iron metabolism. Single SNP association testing, using linear regression models adjusted for sex, menopause and HFE genotype, was conducted for four continuously distributed outcomes: serum ferritin (log transformed), transferrin saturation, serum transferrin, and serum iron. The SNP rs884409 in CYBRD1 is a novel modifier specific to HFE C282Y homozygotes. Median unadjusted serum ferritin concentration decreased from 1194 microg/l (N = 27) to 387 microg/l (N = 16) for male C282Y homozygotes and from 357 microg/l (N = 42) to 69 microg/l (N = 12) for females, comparing those with no copies to those with one copy of rs884409. Functional testing of this CYBRD1 promoter polymorphism using a heterologous expression assay resulted in a 30% decrease in basal promoter activity relative to the common genotype (P = 0.004). This putative genetic modifier of iron overload expression accounts for 11% (95% CI 0.4%, 22.6%) of the variance in serum ferritin levels of C282Y homozygotes