title: A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis.
abstract: 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.
authors: Centre for MEGA Epidemiology, School of Population Health, University of Melbourne, Carlton, Victoria, Australia.
authors: Clare C
authors: CC
authors: Constantine
authors: Greg J
authors: GJ
authors: Anderson
authors: Chris D
authors: CD
authors: Vulpe
authors: Christine E
authors: CE
authors: McLaren
authors: Melanie
authors: M
authors: Bahlo
authors: Heng Lin
authors: HL
authors: Yeap
authors: Dorota M
authors: DM
authors: Gertig
authors: Nicholas J
authors: NJ
authors: Osborne
authors: Nadine A
authors: NA
authors: Bertalli
authors: Kenneth B
authors: KB
authors: Beckman
authors: Victoria
authors: V
authors: Chen
authors: Pavel
authors: P
authors: Matak
authors: Andrew T
authors: AT
authors: McKie
authors: Martin B
authors: MB
authors: Delatycki
authors: John K
authors: JK
authors: Olynyk
authors: Dallas R
authors: DR
authors: English
authors: Melissa C
authors: MC
authors: Southey
authors: Graham G
authors: GG
authors: Giles
authors: John L
authors: JL
authors: Hopper
authors: Katrina J
authors: KJ
authors: Allen
authors: Lyle C
authors: LC
authors: Gurrin
mesh_terms: D000328:Adult; D000368:Aged; D003573:Cytochrome b Group / Q000235:genetics*; D005260:Female; D005293:Ferritins / Q000097:blood*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006432:Hemochromatosis / Q000097:blood / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D010088:Oxidoreductases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D014168:Transferrin / Q000378:metabolism
chemical_list: D003573:Cytochrome b Group; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D005293:Ferritins; D007501:Iron; D010088:Oxidoreductases; C422926:CYBRD1 protein, human