Resistin Single Nucleotide Polymorphisms Research Articles

Resistin G-A haplotype at SNP-420/-358 is associated with the latent sarcopenic obesity index in the toon genome study.

Resistin, which induces insulin resistance, is mainly expressed in monocytes/macrophages in humans. We reported previously that serum resistin was highest in the G-A haplotype defined by resistin single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and - 358 (rs3219175). As sarcopenic obesity is associated with insulin resistance, we aimed to examine whether serum resistin and its haplotypes were associated with sarcopenic obesity at a latent stage. We cross-sectionally analyzed 567 community-dwelling Japanese participants attending annual medical check-ups in which the sarcopenic obesity index was evaluated. The age- and gender-matched normal glucose tolerance subjects with G-A homozygotes and those with C-G homozygotes were examined via RNA-sequencing and pathway analysis (each n=3), and RT-PCR (each n=8). In multivariate logistic regression analyses, the fourth quartile (Q4) of serum resistin and G-A homozygotes were both associated with the latent sarcopenic obesity index defined by a visceral fat area of ≥ 100 cm2 and grip strength Q1 after adjustment for age and gender, with or without other confounding factors. RNA sequencing and pathway analysis showed that tumor necrosis factor (TNF) was involved in the top five pathways in the whole blood cells of G-A homozygotes compared with C-G homozygotes. RT-PCR revealed that TNF mRNA was higher in G-A homozygotes than in C-G homozygotes. The G-A haplotype was associated with the latent sarcopenic obesity index defined by grip strength in the Japanese cohort, could be mediated by TNF-α.

Association of single nucleotide polymorphisms in resistin gene with rheumatoid arthritis in a Chinese population.

Recent evidences have revealed that resistin is associated with the development of rheumatoid arthritis (RA). The aim of this study was to analyze the association of resistin gene single nucleotide polymorphisms (SNPs) with RA susceptibility. In this study, we finally analyzed three resistin SNPs (rs1862513, rs3745368, and rs3745367) in 278 RA patients and 276 normal controls recruited from Chinese population using TaqMan SNP genotyping assays. There were no significant differences for the distribution of allele and genotype frequencies of these three SNPs between RA patients and normal controls (all P>.05). The genotype effects of dominant, recessive models were also analyzed, and no significant association was detected (all P>.05). Haplotype analysis suggested that the frequency of haplotype GAA was notably lower in RA patients in comparison with normal controls (OR = 0.317, 95% CI: 0.125-0.807, P=.011). In a ward, our results indicated that resistin gene polymorphisms might affect the genetic predisposition of RA in Chinese population.

Resistin polymorphisms are associated with rheumatoid arthritis susceptibility in Chinese Han subjects.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease. To date, the specific mechanisms that drive RA disease remain unknown and provide the impetus for genetic investigations into the development of RA. Researchers hope to identify gene polymorphisms that could serve as treatment targets in patients with RA. We have previously suggested that the gene encoding the pro-inflammatory adipokine resistin (RETN) may correlate with RA development. In this report, we sought to determine whether selected RETN single nucleotide polymorphisms (SNPs) are associated with RA susceptibility and clinicopathological characteristics. Four RETN SNPs (rs3745367, rs7408174, rs1862513, and rs3219175) were assessed using TaqMan genotyping in Chinese Han patients with RA and healthy controls. We found that carriers with the C allele of the RETN SNP rs7408174 as well as those with the AG allele or who had at least one A allele of the SNP rs3219175 are at greater risk of developing RA disease compared with wild-type carriers. Moreover, RA patients with the AG allele of the RETN SNP rs3219175 had higher serum C-reactive protein expression compared with controls, and these patients had a high likelihood of being on tumor necrosis factor (TNF) inhibitor therapy. This study is the first to discuss risk factors associated with RETN SNPs in RA progression in a Chinese Han population.

Correlation between resistin gene polymorphism and clinical aspects of lung cancer.

Lung cancer is one of the most common cancers and is associated with a poor survival rate in the Chinese Han population. Analysis of genetic variants could lead to improvements in prognosis following lung cancer treatment. Resistin (RETN) is an important mediator of metabolic diseases and tumor progression. In this study, we explored the effects of RETN single nucleotide polymorphisms (SNPs) on the susceptibility and clinicopathological characteristics of patients with lung cancer. Four RETN SNPs (rs7408174, rs1862513, rs3745367, and rs3219175) were analyzed using TaqMan SNP genotyping in 371 patients with lung cancer and 451 cancer-free controls. The results showed that the RETN SNP rs3219175 with AG or at least 1 A allele was associated with a higher risk of lung cancer than wild-type (GG) carriers. Moreover, the RETN SNP rs3219175 with AG or AG + AA alleles was associated with a higher risk of distant metastasis than that in patients carrying GG alleles. We also used genotype-tissue expression datasets to compare the correlation of the RETN SNP rs3219175 in lung tissue and whole blood. In conclusion, our study demonstrated, for the first time, that RETN polymorphisms were correlated with lung cancer progression in the Chinese Han population.

Adiponectin promoter polymorphisms are predictors of lipid profile improvement after bariatric surgery.

Our aim was to investigate if single nucleotide polymorphisms (SNPs) located in the 5′ regions of leptin (LEP, -2548 G > A, rs7799039), resistin (RETN, -420 C > G, rs1862513) and adiponectin (ADIPOQ, -11391 G > A, rs17300539 and -11377 C > G, rs266729) genes were related to changes in body mass index (BMI) and metabolic variables after bariatric surgery in 60 extremely obese individuals. At baseline, ADIPOQ -11391 A-allele carriers showed higher plasma adiponectin and lower total cholesterol levels when compared to G/G homozygotes. Approximately 32 months post-surgery, a mean reduction of 35% in BMI and an important improvement in metabolic profiles were observed. In addition, for the ADIPOQ -11377 polymorphism, a higher decrease in lipid profile was associated to the C/C genotype. Moreover, individuals bearing the A-C haplotype for the two ADIPOQ SNPs were more prone to show a reduction in low-density lipoprotein levels after bariatric surgery (-43.0% A-C carriers vs. -18.1% G-G carriers, p = 0.019). We did not find any association of leptin and resistin SNPs with the clinical parameters analyzed. In summary, our results indicate that the A-C haplotype is a predictor of better lipid profile post-surgery and the studied SNPs in ADIPOQ gene are associated to changes in metabolic variables in obese individuals.

Resistin reinforces interferon λ-3 to eliminate hepatitis C virus with fine-tuning from RETN single-nucleotide polymorphisms.

The effect of resistin (RETN) on the response to anti-HCV therapy remains unclear. A prospective cohort study was performed using 655 consecutive HCV patients, of whom 513 had completed a course of interferon-based therapy. Multivariate and GEE analyses revealed four RETN single-nucleotide polymorphisms (SNPs), rs34861192, rs3219175, rs3745367 and rs1423096, to be synergistically associated with resistin levels. After adjusting for co-factors such as interferon λ-3 (IFNL3)-rs12979860, the resistin level and the hyper-resistinemic genotype at the 4 RETN SNPs were positively and negatively associated with a sustained virological response (SVR), respectively. RETN-rs3745367 was in linkage disequilibrium with IFNL3-rs12979860. Compared to non-SVR patients, SVR patients had higher levels of pre-therapy resistin, primarily originating from intrahepatic lymphocytes, stellate cells, Kupffer cells, hepatic progenitor cells and hepatocytes. This difference diminished over the course of therapy, as only SVR patients exhibited a 24-week post-therapy decrease in resistin. Both resistin and IFNL3 mRNAs were upregulated, but only resistin mRNA was upregulated by recombinant resistin in peripheral blood mononuclear cells with and without hyper-resistinemic genotypes of the 4 RETN SNPs, respectively. Fine-tuned by RETN SNPs, intrahepatic, multi-cellular resistin reinforced IFNL3 in eliminating HCV via immunomodulation to counteract pro-inflammation. These results encourage the development of novel resistin-targeted anti-viral agents.

Relevance Study on Cerebral Infarction and Resistin Gene Polymorphism in Chinese Han Population.

Recent research on genome-wide associations has implicated that the serum resistin level and its gene polymorphism are associated with cerebral infarction (CI) morbidity and prognosis, and could thereby regulate CI. This study aimed to investigate the association between the resistin single nucleotide polymorphism (SNP) and the susceptibility to CI in the Chinese Han population. A total of 550 CI patients and 313 healthy controls were genotyped. Nine SNPs of the resistin gene previously shown were sequenced and assessed for an association with CI. The numbers of GG genotype carriers of rs3219175 and rs3486119 in the CI group were significantly higher than those in the control group among the middle-aged group (aged 45-65), at 76% vs 67.9% (P=0.025) and 75.5% vs 67.9% (P=0.031). rs3219175 and rs34861192 were associated with CI in the dominant and superdominant models according to the genetic model analysis (P<0.05). Meanwhile, there was strong linkage disequilibrium among the rs34124816, rs3219175, rs34861192, rs1862513, rs3745367, 180C/G and rs3745369 sites. In a haplotype analysis, the occurrence rate of the haplotype AGGCAGC was 1.97 times (P<0.05) higher in the patient group than in the control group. In addition, the numbers of GG genotype carriers of rs3219175 and rs3486119 in the middle-aged male CI patients and the middle-aged small artery occlusion (SAO) CI patients were higher than those in the control group (P<0.05). In the Chinese Han middle-aged population, the GG gene type carriers of the resistin gene sites rs3219175 and rs34861192 had a high risk for CI onset, especially in middle-aged male patients and SAO CI in all middle-aged patients.

Clinical Implications of Tumor Necrosis Factor-Alpha, Interleukin-6 and Resistin in Coronary Artery Disease

Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) are involved in the progression of coronary artery disease (CAD). The cytokines’ levels are associated with the severity of CAD. We have recently reported on the association of resistin, a relatively novel cytokine with the pathogenesis of cardiovascular disease (CVD). Although the inflammatory cytokines’ impact on atherosclerosis is widely accepted, yet some controversy exists regarding the involvement of these factors in atherogenesis. The current review highlights the potential association of TNF-alpha, IL-6 and resistin SNPs (single nucleotide polymorphisms) with CAD. Molecular genetics data along with the intracellular signaling cascade mechanisms may have important clinical implications in the treatment of CAD.

Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians

Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the -420C>G putative gain-of-function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans. We examined the association of three resistin polymorphisms, -852A>G, -420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C-reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851). Resistin levels were higher, dose-dependently, with the -420G allele (CC 5.9 +/- 2.7 ng/ml, GC 6.5 +/- 4.0 ng/ml and GG 7.2 +/- 4.8 ng/ml, trend P = 0.04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1.07 (1.00-1.15), P < 0.05)]. The -852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor-receptor 2 (sol-TNFR2) levels in fully adjusted models [1.06 (95% CI 1.01-1.11), P = 0.01)]. The estimated resistin haplotype (GGT) was associated with sol-TNFR2 (P = 0.04) and the AGT haplotype was related to CRP (P = 0.04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores. Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5' variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.

Genetic variation in adipokine genes and risk of colorectal cancer

Obesity has been related to an increased risk of colorectal cancer (CRC). Adipokines produced by the adipose tissue are directly linked to obesity and may thus contribute to the pathogenesis of CRC. We hypothesized that potentially functional polymorphisms in the adipokine genes leptin (LEP), leptin receptor (LEPR), resistin (RETN), and adiponectin (ADIPOQ) may be associated with CRC. We studied the association of four putatively functional single nucleotide polymorphisms (SNPs) with CRC risk using a hospital-based study design with 702 cases and 752 controls from the Czech Republic. We used likelihood ratio tests to select the best model to represent the relationship between genotypes and risk of CRC. Age-adjusted odds ratios (ORs) under the best model were calculated for each SNP. Previous genotyping data on insulin (INS)-related genes were used to explore interactions between genes in obesity- and diabetes-related pathways by using two independent methods, logistic regression, and multifactor-dimensionality reduction. A trend to associate between the RETN SNP rs1862513 (C-420G) and CRC risk was observed (per allele OR 1.18, 95% confidence interval (0.99-1.40). Statistically, significant interactions were observed between the INS SNP rs3842754 (+1127INSPstI) genotypes and both the LEPR SNP rs1137101 (Q223R) and the ADIPOQ SNP rs266729 (C-11374G) genotypes. Our results suggest that variants in the adipokine genes may affect CRC risk in combination with variants in diabetes-related genes.

A Pilot Study Suggests that the G/G Genotype of Resistin Single Nucleotide Polymorphism at -420 May Be an Independent Predictor of a Reduction in Fasting Plasma Glucose and Insulin Resistance by Pioglitazone in Type 2 Diabetes

The aim of this study was to determine the relation between the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 (rs1862513) and glycemic control by pioglitazone in type 2 diabetes. In Study 1, 121 type 2 diabetic patients were treated with pioglitazone (15 or 30 mg/day) for 12 weeks, in addition to previous medication. In Study 2, 63 patients who had been treated with pioglitazone for 12 weeks were examined retrospectively. In Study 1, multiple regression analysis revealed that the G/G but not C/G genotype was correlated with a reduction in fasting plasma glucose (FPG) and homeostasis model assessment of insulin resistance (HOMA-IR) compared to C/C. When adjusted for age, gender, and BMI, the G/G genotype was an independent factor for the reduction of FPG (P=0.020) and HOMA-IR (P =0.012). When studies 1 and 2 were combined by adjusting the studies, age, gender, and BMI, the reduction of HbA1c was correlated with the G/G genotype (beta=-0.511, P=0.044). Therefore, this pilot study suggests that the G/G genotype of resistin SNP -420 may be an independent predictor of the reduction of fasting plasma glucose and HOMA-IR by pioglitazone.

Serum resistin is reduced by glucose and meal loading in healthy human subjects

Resistin is an adipokine that induces insulin resistance in mice; serum concentrations are decreased by fasting and increased by feeding. Adiponectin, another adipokine, improves insulin sensitivity. The aims of this study were to determine the effects of glucose and meal loading on serum resistin and total and high–molecular weight (HMW) adiponectin in humans and to explore potential determinants of fasting serum resistin and of changes in resistin. Serum resistin and total and HMW adiponectin were measured by enzyme-linked immunosorbent assay in young, lean, nondiabetic subjects during 75-g oral glucose tolerance test (OGTT) and meal tolerance test (MTT). Resistin single nucleotide polymorphism (SNP) −420 was typed. Serum resistin was decreased at 60 and 120 minutes during OGTT compared with baseline (n = 36, 1-way repeated-measures analysis of variance, P < .0001; Scheffe, P = .0457 and P < .0001, respectively). Serum resistin was also reduced at 240 minutes during MTT (n = 33, 1-way repeated measures analysis of variance, P < .0001; Scheffe, P = .0002). Multiple regression analysis adjusted for age, sex, and body mass index revealed that the reductions in serum resistin were dependent on baseline resistin levels. Subjects with greater baseline concentrations of resistin experienced more pronounced declines in resistin (OGTT, unstandardized regression coefficient ( β) = −0.19, P = .0005; MTT, β = −0.63, P < .0001). Serum total and HMW adiponectin was unchanged. Fasting serum resistin was positively correlated with the G allele number of SNP −420 ( β = 7.70, P = .01) and white blood cell count ( β = 0.007, P = .0001) adjusted for age, sex, and body mass index. Therefore, in young, lean, nondiabetic humans, serum resistin was reduced by glucose and meal loading; the reduction in resistin was greater in subjects with higher fasting resistin. Fasting resistin was correlated with SNP −420 and white blood cell count.

Frequency of the G/G Genotype of Resistin Single Nucleotide Polymorphism at −420 Appears to Be Increased in Younger-Onset Type 2 Diabetes

Resistin is an adipocyte-secreted cytokine associated with insulin resistance in mice. We previously reported that the G/G genotype of a resistin single nucleotide polymorphism (SNP) at -420 increases type 2 diabetes susceptibility by enhancing its promoter activity. The aim of the present study was to determine the relevance of SNP -120 in a large number of subjects. We examined 2,610 type 2 diabetic case and 2,502 control subjects. The relation between SNP -420 and the age of type 2 diabetes onset was further analyzed by adding 237 type 2 diabetic subjects with age of onset <or=40 years. When analyzed without considering subject age, the SNP -420 genotype was not associated with type 2 diabetes. Since we reported that the onset of type 2 diabetes was earlier in G/G genotype, we analyzed the data using a trend test for age intervals of 10 years. The frequency of G/G genotype differed among age grades in type 2 diabetes (P = 0.037) and appeared to be higher in younger grades. In type 2 diabetes, G/G genotype was more frequent in subjects aged <40 years than in those aged >or=40 years (G/G vs. C/C, P = 0.003). In a total of 2,430 type 2 diabetic subjects with age of onset <60 years, the trend test showed that the G/G genotype had an increasing linear trend as the age grade of type 2 diabetes onset became younger (P = 0.0379). In control subjects, the frequency of C/G genotype showed an increasing linear trend with increasing age (P = 0.010). The G/G genotype frequency of resistin SNP -420 appears to be increased in younger-onset type 2 diabetic subjects.

Resistin Polymorphisms Are Associated with Muscle, Bone, and Fat Phenotypes in White Men and Women

The biological function of resistin (RST) is unknown, although it may have roles in obesity, diabetes, and insulin resistance. The objective of this study was to examine the effects of single nucleotide polymorphisms (SNPs) in the human RST gene on muscle, bone, and adipose tissue phenotypes and in response to resistance training (RT). Subjects were white and consisted of strength (n = 482) and size (n = 409) cohorts who had not performed RT in the previous year. Subjects completed 12 weeks of structured, unilateral upper arm RT aimed at increasing the size and strength of the non-dominant arm, using their dominant arm as an untrained control. Strength measurements were taken pre- and post-12-week RT and consisted of elbow flexor isometric strength and one-repetition maximum during a biceps curl using free weights. Whole muscle, subcutaneous fat, and cortical bone volumes were measured by magnetic resonance imaging. Six RST SNPs were identified. Analysis of covariance was used to test for effects of the SNPs on pre- and post-muscle strength and whole muscle, fat, and bone volumes independent of gender, age, and body weight. Five RST SNPs (-537 A>C, -420 C>G, 398 C>T, 540 G>A, 980 C>G) were associated with measured phenotypes among subjects when stratified by BMI (<25, >/ or = 25 kg/m(2)). Several gender-specific associations were observed between RST SNPs and phenotypes among individuals with a BMI > or = 25. Conversely, only two associations were observed among individuals with a BMI < 25. These data support previous identified associations of RST with adipose tissue and demonstrate additional associations with bone and skeletal muscle that warrant further investigation.

Resistin SNP-420 determines its monocyte mRNA and serum levels inducing type 2 diabetes

Resistin, secreted from adipocytes, causes insulin resistance in rodents. Its roles and main source in humans remain unknown. The G/G genotype of resistin single nucleotide polymorphism, SNP-420, induces type 2 diabetes mellitus (T2DM) by increasing promoter activity. We elucidated factors correlated with serum resistin and effects of SNP-420 on monocyte resistin mRNA. In 198 T2DM and 157 controls, fasting serum resistin was higher in T2DM. Multiple regression analysis revealed that SNP-420 genotype was the strongest determinant of serum resistin. In T2DM, 1-year duration of T2DM and 1% HbA1c was also correlated with 0.19 and 0.54 ng/ml serum resistin, respectively. Logistic regression analysis revealed that serum resistin was an independent factor for T2DM. In 23 healthy volunteers, monocyte resistin mRNA was positively correlated with its simultaneous serum levels and was higher in G/G genotype. Thus, SNP-420 determines monocyte mRNA and serum levels of resistin, which could induce T2DM.