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.