Genome-wide association analysis identifies TYW3/CRYZ and NDST4 loci associated with circulating resistin levels.
ABSTRACT Resistin is a polypeptide hormone that was reported to be associated with insulin resistance, inflammation and risk of type 2 diabetes and cardiovascular disease. We conducted a genome-wide association (GWA) study on circulating resistin levels in individuals of European ancestry drawn from the two independent studies: the Nurses' Health Study (n = 1590) and the Health, Aging and Body Composition Study (n = 1658). Single-nucleotide polymorphisms (SNPs) identified in the GWA analysis were replicated in an independent cohort of Europeans: the Gargano Family Study (n = 659). We confirmed the association with a previously known locus, the RETN gene (19p13.2), and identified two novel loci near the TYW3/CRYZ gene (1p31) and the NDST4 gene (4q25), associated with resistin levels at a genome-wide significant level, best represented by SNP rs3931020 (P = 6.37 × 10(-12)) and SNP rs13144478 (P = 6.19 × 10(-18)), respectively. Gene expression quantitative trait loci analyses showed a significant cis association between the SNP rs3931020 and CRYZ gene expression levels (P = 3.68 × 10(-7)). We also found that both of these two SNPs were significantly associated with resistin gene (RETN) mRNA levels in white blood cells from 68 subjects with type 2 diabetes (both P = 0.02). In addition, the resistin-rising allele of the TYW3/CRYZ SNP rs3931020, but not the NDST4 SNP rs13144478, showed a consistent association with increased coronary heart disease risk [odds ratio = 1.18 (95% CI, 1.03-1.34); P = 0.01]. Our results suggest that genetic variants in TYW3/CRYZ and NDST4 loci may be involved in the regulation of circulating resistin levels. More studies are needed to verify the associations of the SNP rs13144478 with NDST4 gene expression and resistin-related disease.
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ABSTRACT: Plasma resistin level is a potential molecular link between obesity and diabetes. Causal role of resistin, type 2 diabetes mellitus (T2DM) and genetic variants have not been thoroughly investigated Therefore, we conducted a genome-wide association study (GWAS) to identify quantitative trait loci associated with resistin levels and investigated whether these variants were prospectively associated with the development of metabolic syndrome (MetS) and T2DM in an independent community-based cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS). We genotyped 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 SNP chips and searched for QTLs of resistin in the 1(st) stage GWAS and confirmed the finding in another 559 YOH subjects. Logistic regression was used to examine the Mendelian randomization effects between genotypes of confirmed QTLs and metabolic outcomes in 3400 subjects of CVDFACTS. Two SNPs (rs3745367 and rs1423096) were significantly associated with resistin levels (p = 5.52x10(-15) and p = 2.54 × 10(-20) ) and replicated in another 559 YOH subjects (p = 1.29x10(-3) and p = 1.13 × 10(-7) ), respectively. The SNP rs1423096 was further associated with the levels of HDL-C (p = 0.006), the risk of MetS (OR = 2.21, p = 0.0034), and T2DM (OR = 1.62, p = 0.0063) in the CVDFACTS. People with the haplotypes A-G and G-G determined by rs3745367 and rs1423096 showed a significantly increased T2DM risk (p = 0.0068 and p = 0.0035 respectively) compared with those with A-A haplotype. We have found that rs3745367 and rs1423096 on the RETN gene were significantly associated with resistin levels. However, rs1423096, downstream of RETN, seems to be associated with MetS and T2DM risk more so than rs3745367. The established genotype-disease association points to a causal association resistin and T2DM. This article is protected by copyright. All rights reserved.Diabetes/Metabolism Research and Reviews 10/2013; · 3.59 Impact Factor
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ABSTRACT: Excess body weight is associated with various types of malignancies. Resistin, originally described as an adipocyte-specific hormone modulating insulin resistance in rodents, may exhibit proliferative, antiapoptotic, proinflammatory, proangiogenic and metastatic properties. Accumulating evidence supports a role of resistin as a risk factor and potential diagnostic and prognostic biomarker in cancer. In this report, the current knowledge about resistin's properties and pathophysiological implications in cancer in the context of dysregulated adipose tissue in obesity is summarized; clinical translations, preventive and therapeutic considerations, and future perspectives in the field of resistin research are discussed. At the same time, several enigmatic issues involving resistin receptor and signaling pathways remain to be clarified in order to unmask its ontological role in cancer pathophysiology.Biomarkers in Medicine 01/2014; 8(1):107-18. · 3.22 Impact Factor