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?
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.
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Laura M
LM
Raffield
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Tin
T
Louie
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Tamar
T
Sofer
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Deepti
D
Jain
Department of Medicine and Division of Endocrinology, Harbor-UCLA Medical Center, Torrance, CA 90502, USA and the David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Eli
E
Ipp
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, and the David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Kent D
KD
Taylor
Division of Cardiovascular Sciences, NHLBI, NIH, Bethesda, MD 20892, USA.
George J
GJ
Papanicolaou
Division of Cardiovascular Sciences, NHLBI, NIH, Bethesda, MD 20892, USA.
Larissa
L
Avilés-Santa
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Leslie A
LA
Lange
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Cathy C
CC
Laurie
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Matthew P
MP
Conomos
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Timothy A
TA
Thornton
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, and the David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.|Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, and the David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Yii-Der Ida
YI
Chen
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Qibin
Q
Qi
Department of Medicine, Division of Hepatology, Loyola University Medical Center, Maywood, IL 60153, USA.
Scott
S
Cotler
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Bharat
B
Thyagarajan
Department of Psychology and Behavioral Medicine, University of Miami, FL 33124, USA.
Neil
N
Schneiderman
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, and the David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.|Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, and the David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Jerome I
JI
Rotter
Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
Alex P
AP
Reiner
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, and the David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Henry J
HJ
Lin
D000328:Adult; D018798:Anemia, Iron-Deficiency / Q000097:blood; D015703:Antigens, CD; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D005215:Fasting; D005260:Female; D005293:Ferritins / Q000032:analysis / Q000097:blood / Q000378:metabolism; D056726:Genetic Association Studies / Q000379:methods; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D023281:Genomics; D005947:Glucose / Q000235:genetics* / Q000378:metabolism*; D006432:Hemochromatosis / Q000235:genetics; D006630:Hispanic or Latino / Q000235:genetics; D006764:Hospitals, Community / Q000379:methods; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007501:Iron / Q000097:blood / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011990:Receptors, Transferrin / Q000235:genetics; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D014168:Transferrin / Q000032:analysis / Q000378:metabolism
D015703:Antigens, CD; D001786:Blood Glucose; C068126:CD71 antigen; D007328:Insulin; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D014168:Transferrin; D005293:Ferritins; D007501:Iron; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human; D005947:Glucose