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Genetic determinants for body iron store and type 2 diabetes risk in US men and women.

ABSTRACT: High body iron store has been associated with an increased risk of type 2 diabetes (T2D); it remains unknown whether the genetic variants related to body iron status affect T2D risk. We aimed at comprehensively investigating the associations between the genetic variants related to body iron status and the T2D risk.Six common SNPs related to body iron status from recent genome-wide association (GWA) studies were determined in the Nurses' Health Study (NHS; 1,467 diabetic cases and 1,754 controls) and the Health Professionals Follow-up Study (HPFS; 1,124, diabetic cases and 1,298 controls). Plasma levels of ferritin, soluble transferrin receptor (sTfR), and transferrin were measured in NHS. Significant associations were observed for loci in TPMRSS6 with sTfR (P?=?3.47×10(-6)), TF with transferrin (P?=?0.0002 to 1.72×10(-10)); and HFE with ferritin (P?=?0.017 to 1.6×10(-8)), sTfR (P?=?0.007 to 7.9×10(-6)), and transferrin (P?=?0.006 to 0.0007). The six SNPs together explained 5.7%, 2.7%, and 13.3% of the variation in plasma levels of ferritin, sTfR, and transferrin. After adjustment for the conventional risk factors, the T allele of SNP rs855791 in the TPMRSS6 gene was significantly associated with a 19% decreased risk of T2D (OR?=?0.81; 95% CI?=?0.66-0.98; P?=?0.03) in men. Multiple tests attenuated this significant association to null. No associations were observed in women. SNPs at HFE and TF were not associated with diabetes risk in either sex. Dietary iron intake did not modify the associations of the newly identified loci with diabetes risk.The newly identified iron-related SNP rs855791 in TPMRSS6 was nominally associated with a decreased risk of T2D in men but not in women. The apparent differences by gender warrant further study.

SUBMITTER: He M

PROVIDER: S-EPMC3397952 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Genetic determinants for body iron store and type 2 diabetes risk in US men and women.

He Meian M Workalemahu Tsegaselassie T Manson JoAnn E JE Hu Frank B FB Qi Lu L

PloS one 20120716 7

<h4>Background</h4>High body iron store has been associated with an increased risk of type 2 diabetes (T2D); it remains unknown whether the genetic variants related to body iron status affect T2D risk. We aimed at comprehensively investigating the associations between the genetic variants related to body iron status and the T2D risk.<h4>Methodology/principal findings</h4>Six common SNPs related to body iron status from recent genome-wide association (GWA) studies were determined in the Nurses' H ...[more]

PMID: 22815867

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Project description:BackgroundCirculating sex hormone-binding globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain.MethodsWe performed a nested case-control study of postmenopausal women in the Women's Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). Plasma levels of sex hormone-binding globulin were measured; two polymorphisms of the gene encoding sex hormone-binding globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians' Health Study II (170 with newly diagnosed type 2 diabetes and 170 controls).ResultsAmong women, higher plasma levels of sex hormone-binding globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher sex hormone-binding globulin levels (P=0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P=0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated sex hormone-binding globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of sex hormone-binding globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that sex hormone-binding globulin may have a causal role in the risk of type 2 diabetes.ConclusionsLow circulating levels of sex hormone-binding globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination.

Dataset Information

Genetic determinants for body iron store and type 2 diabetes risk in US men and women.

Publications

Genetic determinants for body iron store and type 2 diabetes risk in US men and women.

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