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J Diabetes. 2018 Jun;10(6):524-533. doi: 10.1111/1753-0407.12648. Epub 2018 Apr 6.

Genetic variants in sex hormone pathways and the risk of type 2 diabetes among African American, Hispanic American, and European American postmenopausal women in the US.

Author information

1
Metabolic Epidemiology Section, Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
2
Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
3
Department of Epidemiology, Brown University, Providence, Rhode Island, USA.
4
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
5
Department of Biostatistics, University of Washington, Seattle, Washington, USA.
6
Genetic Analysis Platform, Broad Institute, Cambridge, Massachusetts, USA.
7
Office of Population Genomics, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
8
HealthPartners Institute, Minneapolis, Minnesota, USA.
9
Department of Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
10
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, Winston-Salem, North Carolina, USA.
11
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
12
Department of Epidemiology and Center for Global Cardiometabolic Health, Brown University, Providence, Rhode Island, USA.
13
Division of Endocrinology, Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

Abstract

BACKGROUND:

Sex hormones are implicated in the development of diabetes. However, whether genetic variations in sex hormone pathways (SHPs) contribute to the risk of type 2 diabetes mellitus (T2DM) remains to be determined. This study investigated associations between genetic variations in all candidate genes in SHPs and T2DM risk among a cohort of women participating in the Women's Health Initiative (WHI).

METHODS:

Single nucleotide polymorphisms (SNPs) located within 30 kb upstream and downstream of SHP genes were comprehensively examined in 8180 African American, 3498 Hispanic American, and 3147 European American women in the WHI. In addition, whether significant SNPs would be replicated in independent populations was examined.

RESULTS:

After adjusting for age, region, and ancestry estimates and correcting for multiple testing, seven SNPs were significantly associated with the risk of T2DM among Hispanic American women were identified in the progesterone receptor (PGR) gene, with rs948516 showing the greatest significance (odds ratio 0.67; 95% confidence interval 0.57-0.78; P = 8.8 × 10-7 ; false discovery rate, Q = 7.8 × 10-4 ). These findings were not replicated in other ethnic groups in the WHI or in sex-combined analyses in replication studies.

CONCLUSION:

Significant signals were identified implicating the PGR gene in T2DM development in Hispanic American women in the WHI, which are consistent with genome-wide association studies findings linking PGR to glucose homeostasis. Nevertheless, the PGR SNPs-T2DM association was not statistically significant in other ethnic populations. Further studies, especially sex-specific analyses, are needed to confirm the findings and clarify the role of SHPs in T2DM.

KEYWORDS:

diabetes risk; sex hormone pathways; single nucleotide polymorphisms; 单核苷酸多态性; 性激素途径; 糖尿病风险

PMID:
29417738
PMCID:
PMC5980699
[Available on 2019-06-01]
DOI:
10.1111/1753-0407.12648
[Indexed for MEDLINE]

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