Accessibility issues or difficulties with this website?
Call 919-962-2073 or email hchsadministration@unc.edu.

Genome-wide association study of iron traits and relation to diabetes in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL): potential genomic intersection of iron and glucose regulation?

TitleGenome-wide association study of iron traits and relation to diabetes in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL): potential genomic intersection of iron and glucose regulation?
Publication TypePublication
Year2017
AuthorsRaffield LM, Louie T, Sofer T, Jain D, Ipp E, Taylor KD, Papanicolaou GJ, Avilés-Santa L, Lange LA, Laurie CC, Conomos MP, Thornton TA, Chen Y-DIda, Qi Q, Cotler S, Thyagarajan B, Schneiderman N, Rotter JI, Reiner AP, Lin HJ
JournalHum Mol Genet
Volume26
Issue10
Pagination1966-1978
Date Published2017 05 15
ISSN1460-2083
KeywordsAdult, Anemia, Iron-Deficiency, Antigens, CD, Blood Glucose, Diabetes Mellitus, Fasting, Female, Ferritins, Genetic Association Studies, Genetic Variation, genome-wide association study, Genomics, glucose, Hemochromatosis, Hispanic Americans, Hospitals, Community, Humans, insulin, Iron, Male, Membrane Proteins, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Receptors, Transferrin, Risk Factors, Serine Endopeptidases, Transferrin
Abstract

Genetic variants contribute to normal variation of iron-related traits and may also cause clinical syndromes of iron deficiency or excess. Iron overload and deficiency can adversely affect human health. For example, elevated iron storage is associated with increased diabetes risk, although mechanisms are still being investigated. We conducted the first genome-wide association study of serum iron, total iron binding capacity (TIBC), transferrin saturation, and ferritin in a Hispanic/Latino cohort, the Hispanic Community Health Study/Study of Latinos (>12 000 participants) and also assessed the generalization of previously known loci to this population. We then evaluated whether iron-associated variants were associated with diabetes and glycemic traits. We found evidence for a novel association between TIBC and a variant near the gene for protein phosphatase 1, regulatory subunit 3B (PPP1R3B; rs4841132, β = -0.116, P = 7.44 × 10-8). The effect strengthened when iron deficient individuals were excluded (β = -0.121, P = 4.78 × 10-9). Ten of sixteen variants previously associated with iron traits generalized to HCHS/SOL, including variants at the transferrin (TF), hemochromatosis (HFE), fatty acid desaturase 2 (FADS2)/myelin regulatory factor (MYRF), transmembrane protease, serine 6 (TMPRSS6), transferrin receptor (TFR2), N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2), ABO blood group (ABO), and GRB2 associated binding protein 3 (GAB3) loci. In examining iron variant associations with glucose homeostasis, an iron-raising variant of TMPRSS6 was associated with lower HbA1c levels (P = 8.66 × 10-10). This association was attenuated upon adjustment for iron measures. In contrast, the iron-raising allele of PPP1R3B was associated with higher levels of fasting glucose (P = 7.70 × 10-7) and fasting insulin (P = 4.79 × 10-6), but these associations were not attenuated upon adjustment for TIBC-so iron is not likely a mediator. These results provide new genetic information on iron traits and their connection with glucose homeostasis.

DOI10.1093/hmg/ddx082
Alternate JournalHum Mol Genet
PubMed ID28334935
PubMed Central IDPMC6075359
Grant ListHHSN268201300005C / HL / NHLBI NIH HHS / United States
P01 GM099568 / GM / NIGMS NIH HHS / United States
R01 HL129132 / HL / NHLBI NIH HHS / United States
N01HC65236 / HL / NHLBI NIH HHS / United States
N01HC65235 / HL / NHLBI NIH HHS / United States
N01HC65234 / HL / NHLBI NIH HHS / United States
T32 HL129982 / HL / NHLBI NIH HHS / United States
K01 HL129892 / HL / NHLBI NIH HHS / United States
N01HC65233 / HL / NHLBI NIH HHS / United States
N01HC65237 / HL / NHLBI NIH HHS / United States
MS#: 
0411
ECI: 
Yes
Manuscript Status: 
Published