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1.  Association of Genetic Variants in the Adiponectin Gene with Metabolic Syndrome: A Case-Control Study and a Systematic Meta-Analysis in the Chinese Population 
PLoS ONE  2013;8(4):e58412.
The prevalence of metabolic syndrome has been rising worldwide, including in China, but knowledge on specific genetic determinants of metabolic syndrome is very limited. A number of studies have reported that polymorphisms in the ADIPOQ gene are associated with metabolic syndrome in Chinese Han populations. However, data is still conflicting. The objective of this study was to examine the associations of the adiponectin genetic variants with metabolic syndrome by a case-control study and meta-analyses in Chinese.
We first investigated the association of ADIPOQ rs2241766 (+45T>G in exon 2), rs266729 (−11377C>G in promoter) and rs1501299 (+276G>T in intron 2) polymorphisms with metabolic syndrome in a Hubei Han Chinese population with 322 metabolic syndrome patients and 161 normal controls recruited from the Yichang, Hubei. Then we comprehensively reviewed the association between ADIPOQ rs2241766/rs266729/rs1501299 and metabolic syndrome in the Chinese populations via a meta-analysis. The strength of association was assessed by odds ratios (ORs) with 95% confidence intervals (CI).
The G allele frequency of rs2241766 in metabolic syndrome patients was significantly higher than those of controls group (29.8% vs 23.3%, OR = 1.40, P = 0.033). The logistic regression analysis adjusted by gender and age showed a nominally significant association for rs2241766 GG+GT genotype (P = 0.065, OR = 1.55) and rs1501299 GG genotype in recessive model (OR = 1.54, P = 0.066). However, no association was observed for rs266729 in our sample. We identified thirteen studies for rs2241766 (2,684 metabolic syndrome patients and 2,864 controls), three studies for rs266729, and eleven studies for rs1501299 (2,889 metabolic syndrome patients and 3,304 controls) in Chinese. Meta-analysis indicated significant associations for the rs2241766 G allele (OR = 1.14, 95%CI = 1.05–1.24, P = 0.003), rs266729 GG+GT genotypes (OR = 0.80, 95%CI = 0.68–0.92, P = 0.003) and rs1501299 GG+TG genotypes (OR = 1.42, 95%CI 1.16–1.75, P = 0.001).
Our results demonstrated ADIPOQ as a pleiotropic locus for metabolic syndrome and its components in the Han Chinese population.
PMCID: PMC3617191  PMID: 23593121
2.  Association of ADIPOQ gene variants with body weight, type 2 diabetes and serum adiponectin concentrations: the Finnish Diabetes Prevention Study 
BMC Medical Genetics  2011;12:5.
Adiponectin, secreted mainly by mature adipocytes, is a protein with insulin-sensitising and anti-atherogenic effects. Human adiponectin is encoded by the ADIPOQ gene on the chromosomal locus 3q27. Variations in ADIPOQ are associated with obesity, type 2 diabetes (T2DM) and related phenotypes in several populations. Our aim was to study the association of the ADIPOQ variations with body weight, serum adiponectin concentrations and conversion to T2DM in overweight subjects with impaired glucose tolerance. Moreover, we investigated whether ADIPOQ gene variants modify the effect of lifestyle changes on these traits.
Participants in the Finnish Diabetes Prevention Study were randomly assigned to a lifestyle intervention group or a control group. Those whose DNA was available (n = 507) were genotyped for ten ADIPOQ single nucleotide polymorphisms (SNPs). Associations between SNPs and baseline body weight and serum adiponectin concentrations were analysed using the univariate analysis of variance. The 4-year longitudinal weight data were analysed using linear mixed models analysis and the change in serum adiponectin from baseline to year four was analysed using Kruskal-Wallis test. In addition, the association of SNPs with the risk of developing T2DM during the follow-up of 0-11 (mean 6.34) years was analysed by Cox regression analysis.
rs266729, rs16861205, rs1501299, rs3821799 and rs6773957 associated significantly (p < 0.05) with body weight at baseline and in the longitudinal analyses. The rs266729 C allele and the rare minor alleles of rs2241766 and rs2082940 were associated with an increased adjusted hazard ratio of developing T2DM. The differences in baseline serum adiponectin concentrations were seen according to rs16861210, rs17366568, rs2241766, rs6773957 and rs2082940 and differences in the change of serum adiponectin levels from baseline to the four year examination were seen according to rs16861205, especially in subjects who were able to lose weight during the first year of intervention.
These results from the Finnish Diabetes Prevention Study support the concept that genetic variation in ADIPOQ locus contributes to variation in body size and serum adiponectin concentrations and may also modify the risk of developing T2DM.
Trial registration number NCT00518167
PMCID: PMC3032655  PMID: 21219602
3.  Genetic Variations in ADIPOQ Gene Are Associated with Chronic Obstructive Pulmonary Disease 
PLoS ONE  2012;7(11):e50848.
Adiponectin is reported to be related to the development of chronic obstructive pulmonary disease (COPD). Genetic variants in the gene encoding adiponectin (ADIPOQ) have been reported to be associated with adiponectin level in several genome–wide linkage and association studies. However, relatively little is known about the effects of ADIPOQ gene variants on COPD susceptibility. We determined the frequencies of single-nucleotide polymorphisms (SNPs) in ADIPOQ in a Chinese Han population and their possible association with COPD susceptibility.
We conducted a case–control study of 279 COPD patients and 367 age- and gender-distribution-matched control subjects. Seven tagging SNPs in ADIPOQ, including rs710445, rs16861205, rs822396, rs7627128, rs1501299, rs3821799 and rs1063537 were genotyped by SNaPshot. Association analysis of genotypes/alleles and haplotypes constructed from these loci with COPD was conducted under different genetic models.
The alleles or genotypes of rs1501299 distributed significantly differently in COPD patients and controls (allele: P = 0.002, OR = 1.43 and 95%CI = 1.14–1.79; genotype: P = 0.008). The allele A at rs1501299 was potentially associated with an increased risk of COPD in all dominant model analysis (P = 0.009; OR: 1.54; 95%CI: 1.11–2.13), recessive model analyses (P = 0.015; OR: 1.75; 95% CI: 1.11–2.75) and additive model analyses (P = 0.003; OR: 2.11; 95% CI: 1.29–3.47). In haplotype analysis, we observed haplotypes AAAAACT and GGACCTC had protective effects, while haplotypes AGAACTC, AGGCCTC, GGAACTC, GGACACT and GGGCCTC were significantly associated with the increased risk of COPD.
We conducted the first investigation of the association between the SNPs in ADIPOQ and COPD risk. Our current findings suggest that ADIPOQ may be a potential risk gene for COPD. Further studies in larger groups are warranted to confirm our results.
PMCID: PMC3508992  PMID: 23209832
4.  Association between polymorphisms in the adiponectin gene and cardiovascular disease: a meta-analysis 
BMC Medical Genetics  2012;13:40.
Previous studies have examined the associations between polymorphisms of adiponectin gene (ADIPOQ) and cardiovascular disease (CVD), but those studies have been inconclusive. The aim of this study was to access the relationship between three single nucleotide polymorphisms (SNPs), +45 T > G (rs2241766), +276 G > T (rs1501299) and -11377 C > G (rs266729) in ADIPOQ and CVD.
A comprehensive search was conducted to identify all studies on the association of ADIPOQ gene polymorphisms with CVD risk. The fixed and random effect pooled measures (i.e. odds ratio (OR) and 95% confidence interval (CI)) were calculated in the meta-analysis. Heterogeneity among studies was evaluated using Q test and the I2. Publication bias was estimated using modified Egger’s linear regression test.
Thirty-seven studies concerning the associations between the three polymorphisms of ADIPOQ gene and CVD risk were enrolled in this meta-analysis, including 6,398 cases and 10,829 controls for rs2241766, 8,392 cases and 18,730 controls for rs1501299 and 7,835 cases and 14,023 controls for rs266729. The three SNPs were significantly associated with CVD, yielding pooled ORs of 1.22 (95%CI: 1.07, 1.39; P = 0.004), 0.90 (95%CI: 0.83, 0.97; P = 0.007) and 1.09(95%CI: 1.01, 1.17; P = 0.032) for rs2241766, rs1501299 and rs266729, respectively. Rs2241766 and rs1501299 were significantly associated with coronary heart disease (CHD), yielding pooled ORs of 1.29 (95%CI: 1.09, 1.52; P = 0.004) and 0.89 (95%CI: 0.81, 0.99; P = 0.025), respectively. The pooled OR for rs266729 and CHD was 1.09 (95%CI: 0.99, 1.19; P = 0.090). Significant between-study heterogeneity was found in our meta-analysis. Evidence of publication bias was observed in the meta-analysis.
The present meta-analysis showed that the associations between rs2241766, rs1501299 and rs266729 in the ADIPOQ and CVD were significant but weak. High quality studies are still needed to confirm the associations, especially for rs2241766.
PMCID: PMC3413575  PMID: 22639977
Adiponectin; Polymorphisms; Cardiovascular disease; Meta-analysis
5.  Variants of the Adiponectin and Adiponectin Receptor 1 Genes and Breast Cancer Risk 
Cancer research  2008;68(9):3178-3184.
Breast cancer risk is higher among obese women and women with diabetes. Adiponectin is a protein exclusively secreted by adipose tissue, circulating levels of which have been associated with breast cancer risk. Whether genetic variants within the adiponectin pathway are associated with breast cancer risk is unknown. To explore the association of genetic variants of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes with breast cancer risk, we conducted a case control study of female patients with breast cancer and healthy female controls from New York City recruited between 1999 and 2004. We genotyped 733 hospital-based breast cancer cases and 839 controls for 10 haplotype-tagging single nucleotide polymorphisms (SNP) of ADIPOQ and ADIPOR1. Two ADIPOQ SNPs (rs2241766 and rs1501299), which have been associated with circulating levels of adiponectin, were associated with breast cancer risk [rs1501299*GG: odd ratios (OR), 1.80; 95% confidence interval (95% CI), 1.14–2.85; rs2241766*TG: OR, 0.61; 95% CI, 0.46–0.80]. One ADIPOR1 SNP (rs7539542), which modulates expression of adiponectin receptor 1 mRNA, was also associated with breast cancer risk (OR, 0.51; 95% CI, 0.28–0.92). Based on the known function of rs2241766 and rs1501299, we categorized individuals by adiponectin signaling status and found that, when compared with high signalers, intermediate signalers had a 4.16-fold increase in breast cancer risk (95% CI, 0.49–35.19), and low signalers had a 6.56-fold increase in breast cancer risk (95% CI, 0.78–54.89; Ptrend = 0.001). This is the first report of an association between functionally relevant variants of the adiponectin pathway and breast cancer risk. The results warrant further studies of the adiponectin pathway in breast cancer.
PMCID: PMC2685173  PMID: 18451143
6.  Adiponectin gene variants, adiponectin isoforms and cardiometabolic risk in type 2 diabetic patients 
The aim of the present study was to examine the associations of rs2241766 (+45T>G), rs1501299 (+276G>T), rs17300539 (−11391G>A) and rs182052 (−10069G>A) in the adiponectin (Ad) gene with adiponectin concentrations, and concomitantly the association of these variants with cardiometabolic risk in type 2 diabetic patients of African ancestry.
Materials and Methods
A cross‐sectional study of 200 patients was carried out. Concentrations of total, high (HMW), middle (MMW) and low (LMW) molecular weight adiponectin isoforms were measured. The four polymorphisms were genotyped.
Decreased values were noted for total Ad in overweight, dyslipidemia and coronary artery disease (CAD), for HMW in overweight and dyslipidemia, for MMW in CAD, for LMW in dyslipidemia and CAD, for the percentage HMW/total in overweight, and for MMW:HMW ratio in patients without hypertriglyceridemic waist (HTGW). Significant associations were noted between total Ad, HMW, and HMW/total Ad and rs182052 under a dominant model (P = 0.04, P = 0.03 and P = 0.04, respectively), and between MMW and rs17300539 (P = 0.006). No significant difference in adiponectin concentrations was noted according to rs2241766 and rs1501299 genotypes. Patients carrying the rs2241766 G allele (TG+GG) had an increased risk of HTGW (odds ratio [OR] 3.1; P = 0.04) and of CAD (OR 3.3; P = 0.01). The odds of having low total adiponectin concentrations (<25th percentile: 3.49 ng/mL) for carrying the rs182052A allele (AA+GA) was: OR 0.40; P = 0.009. The single‐nucleotide polymorphism associated with adiponectin levels was not concomitantly associated with cardiometabolic risk factors.
Adiponectin concentrations and ADIPOQ variants are implicated in the pathophysiological process leading to cardiovascular diseases, but the genetic effects seem to be independent of adiponectin concentrations in our Afro–Caribbean diabetic patients.
PMCID: PMC4023583  PMID: 24843760
Adiponectin; Cardiometabolic risk; Diabetes
7.  Association of ADIPOQ +45T>G polymorphism with body fat mass and blood levels of soluble adiponectin and inflammation markers in a Mexican-Mestizo population 
Obesity is a disease with genetic susceptibility characterized by an increase in storage and irregular distribution of body fat. In obese patients, the decrease in the Adiponectin gene (ADIPOQ) expression has been associated with a systemic low-grade inflammatory state. Our aim was to investigate the relationship between ADIPOQ +45T>G gene simple nucleotide polymorphism (SNP rs2241766) with serum adiponectin (sAdiponectin), distribution of body fat storage, and inflammation markers.
Subjects and methods
In this cross-sectional study, 242 individuals from Western Mexico characterized as Mexican-Mestizo and classified by body mass index (BMI), were included. Anthropometrics, body composition, body fat distribution, and inflammation markers were measured by routine methods. Genotypes were characterized using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique and sAdiponectin by the ELISA method. A P-value <0.05 was considered the statistically significant threshold.
sAdiponectin is associated with BMI (P < 0.001) and the genotypes (P < 0.001 to 0.0046) GG (8169 ± 1162 ng/mL), TG (5189 ± 501 ng/mL), and TT (3741 ± 323 ng/mL), but the SNP ADIPOQ +45T>G is not associated with BMI. However, the detailed analysis showed association of this SNP with a pattern of fat distribution and correlations (P < 0.05) with inflammation markers and distribution of body fat storage (Pearson’s r = −0.169 to −0.465) were found.
In this study, we have suggested that the ADIPOQ +45G allele could be associated with distribution of body fat storage in obesity. On the other hand, as no association was observed between ADIPOQ +45T>G gene polymorphism and obesity, it cannot be concluded that the ADIPOQ +45G allele is responsible for the increase of adiponectin levels.
PMCID: PMC3484511  PMID: 23118546
ADIPOQ gene polymorphism; levels of inflammation markers; body fat distribution; obesity; Mexican-Mestizo population
8.  Association of Adiponectin Gene (ADIPOQ) rs2241766 Polymorphism with Obesity in Adults: A Meta-Analysis 
PLoS ONE  2014;9(4):e95270.
Adiponectin plays an important role in regulating glucose levels and fatty acid oxidation. Multiple studies have assessed the association between rs2241766 polymorphism in the adiponectin (ADIPOQ) gene and obesity susceptibility. However, the results are inconsistent and inconclusive. The aim of this meta-analysis was to investigate this association in adults.
Several electronic databases were searched for relevant literature published up to November 2013. Statistical analyses were performed using software Review Manager (Version 5.02) and STATA (Version 10.0). The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with a random-effects model or a fixed-effect model depending on heterogeneity among studies. Q tests and Egger’s tests were performed to assess heterogeneity and publication bias. Sensitivity analysis was conducted to confirm the reliability and stability of the meta-analysis.
A total of 2,819 obese and 3,024 controls in 18 case-control studies were included in the meta-analysis. The results indicated that compared with TT genotype, the ADIPOQ-rs2241766 GG genotype was associated with an increased risk for obesity (OR = 1.39, 95% CI: 1.11–1.73, P for heterogeneity = 0.520, I2 = 0%) in overall studies. Whereas, GT genotype was associated with a borderland increased risk for obesity (OR = 1.13, 95% CI: 0.94–1.36, P for heterogeneity = 0.006, I2 = 51%). The susceptibility of obesity was increased based on genotypes of TT
The results of this meta-analysis suggest that the ADIPOQ-rs2241766 G/T polymorphism might be associated with obesity in Chinese studies but not in non-Chinese studies in adults. Better-designed studies that consider confounding factors and assess larger sample sizes with a focus on ADIPOQ-rs2241766G/T polymorphisms and obesity are required in the future.
PMCID: PMC3989273  PMID: 24740426
The Scientific World Journal  2014;2014:650393.
Diabetes is a serious global health problem. Large-scale genome-wide association studies identified loci for type 2 diabetes mellitus (T2DM), including adiponectin (ADIPOQ) gene and transcription factor 7-like 2 (TCF7L2), but few studies clarified the effect of genetic polymorphisms of ADIPOQ and TCF7L2 on risk of T2DM. We attempted to elucidate association between T2DM and polymorphic variations of both in Taiwan's Chinese Han population, with our retrospective case-control study genotyping single nucleotide polymorphisms (SNPs) in ADIPOQ and TCF7L2 genes both in 149 T2DM patients and in 139 healthy controls from Taiwan. Statistical analysis gauged association of these polymorphisms with risk of T2DM to show ADIPOQ rs1501299 polymorphism variations strongly correlated with T2DM risk (P = 0.042), with rs2241766 polymorphism being not associated with T2DM (P = 0.967). However, both polymorphisms rs7903146 and rs12255372 of TCF7L2 were rarely detected in Taiwanese people. This study avers that ADIPOQ rs1501299 polymorphism contributes to risk of T2DM in the Taiwanese population.
PMCID: PMC4121223  PMID: 25121131
PLoS ONE  2013;8(6):e67275.
As insulin resistance (IR) is an established risk factor for colorectal cancer (CRC), we explored the association between each of the IR-related gene polymorphisms of adiponectin (ADIPOQ) rs2241766, uncoupling protein 2 (UCP2) rs659366, and fatty acid-binding protein (FABP2) rs1799883 and CRC risk. Genotyping of blood samples and collection of lifestyle and dietary habits were performed for 400 case-control pairs. Unconditional logistic regression (ULR) was applied to assess the effects of the three single nucleotide polymorphisms (SNP), environmental factors. Both ULR and generalized multifactor dimensionality reduction (GMDR) were used to test the gene-gene and gene-environment interactions on CRC risk. Subjects carrying the ADIPOQ rs2241766 TG+GG genotype had a higher CRC risk than those carrying the TT genotype (OR = 1.429, 95% CI 1.069–1.909). The additive and multiplicative interactions between ADIPOQ rs2241766 and FABP2 rs1799883 on CRC were found by ULR (RERI = 0.764, 95%CI 0.218∼1.311, AP = 0.514, 95%CI 0.165∼0.864, S = −1.745, 95%CI is unachievable, and Pmulti = 0.017, respectively). Furthermore, the high order gene-gene interaction of the three SNPs were found by GMDR (P = 0.0107). A significant dosage effect with an increasing number of risk genotypes was observed as the risk of CRC increased (Ptrend = 0.037). In GMDR, the gene-environment interaction among the three SNPs and red meat consumption on CRC risk was significant (P = 0.0107). Compared with subjects with low red meat consumption and null risk genotypes, those with high-red meat consumption and three risk genotypes had 3.439-fold CRC risk (95% CI 1.410–8.385). In conclusion, the results showed that the ADIPOQ rs2241766 TG+GG genotype increased CRC risk. Given the complexity of the carcinogen for CRC, ADIPOQ rs2241766, UCP2 rs659366, FABP2 rs1799883 and red meat consumption potentially worked together in affecting CRC risk.
PMCID: PMC3695067  PMID: 23826253
Oncology Letters  2011;3(1):176-180.
In order to evaluate the contribution of polymorphisms of the adiponectin gene, ADIPOQ, to the risk of colon cancer, we conducted a case-control study of 60 colon cancer patients and 60 age, gender and ethnicity-matched controls in the Saudi population. We tested the hypothesis by analyzing the genotypes for two single nucleotide polymorphisms (SNPs), rs1501299 (G276T) and rs2241766 (T45G), in the ADIPOQ gene. In addition, the study was also designed to assess whether the two SNPs contribute to circulating adiponectin levels. We observed an increased risk of colon cancer associated with the 276T allele. The odds ratio (OR) was 2.64 [95% confidence interval (CI), 0.49–14.6]. The G allele at the T45G polymorphism was associated with a lower risk of colon cancer (OR=0.41; 95% CI, 0.19–0.86). Our results suggest that the risk of developing colon cancer may be partially explained by genetic polymorphisms in the ADIPOQ gene.
PMCID: PMC3362502  PMID: 22740876
adiponectin; colon cancer; single nucleotide polymorphisms; polymerase chain reaction; restriction fragment length polymorphism
Lumbar disc degeneration (LDD) is a widespread public health problem that may lead to disability and loss of productivity. Adiponectin is an adipokine secreted by adipose tissue and has been shown to be involved in cartilage homeostasis. In the present study, the association between the rs266729 (−11377C/G) and rs2241766 (45T/G) single nucleotide polymorphisms (SNPs) in the adiponectin gene (ADIPOQ) and LDD was investigated. In addition, the correlation between the plasma adiponectin level and LDD was examined. A total of 289 subjects, 168 patients with LDD and 122 healthy individuals, were recruited in the study. All subjects were genotyped for rs266729 and rs2241766 SNPs using polymerase chain reaction-restriction fragment length polymorphism. Circulating levels of adiponectin protein were measured using the ELISA technique. A strong association was found between adiponectin level and LDD (P<0.01), where high levels of adiponectin were found in patients compared with healthy controls. The increase in adiponectin level was not affected by gender. However, no significant differences were found in the genotype distribution or allelic frequency of the two examined polymorphisms between patients with LDD and healthy controls (P>0.05). In conclusion, adiponectin appears to be elevated in patients with LDD. The rs266729 and rs2241766 SNPs in the ADIPOQ gene are not associated with LDD.
PMCID: PMC4151636  PMID: 25187851
adiponectin; ADIPOQ; lumbar disc; degeneration; polymorphism
PLoS ONE  2011;6(5):e19999.
Cardiovascular risk increases with the presence of both metabolic syndrome (MetS) and hypertension (HTN). Although the adiponectin (ADIPOQ) gene has been reported to be involved in MetS, its association with HTN remained undetermined. This study aimed to investigate the association of ADIPOQ gene with the phenotypes of HTN and MetS.
A total of 962 participants from 302 families from the Taiwan young-onset hypertension genetic study were enrolled. Plasma adiponectin were measured, and association analysis was conducted by using GEE regression-based method. Another study, of 1448 unrelated participants, was conducted to replicate the association between ADIPOQ gene and variable phenotypes of MetS with or without HTN.
Among 962 subjects from family samples, the lowest plasma adiponectin value was observed in MetS with HTN component (9.3±0.47 µg/ml) compared with hypertensives (13.4±0.74 µg /ml) or MetS without HTN (11.9±0.60 µg/ml, P<0.05). The SNP rs1501299 (G276T) in ADIPOQ gene was found associated with the presence of HTN in MetS (odds ratio for GG+GT vs. TT = 2.46; 95% CI: 1.14-5.3, p = 0.02), but not rs2241766 (T45G). No association of ADIPOQ gene with HTN alone or MetS without HTN was observed. The significant association of the SNP rs1501299 (G276T) with the phenotype of presence of HTN in MetS was confirmed (odds ratio for GG+GT vs. TT = 2.15; 95% CI: 1.1–4.3) in the replication study.
ADIPOQ genetic variants were selectively and specifically associated with the concomitant presence of MetS and HTN, suggesting potential genetic linkage between MetS and HTN.
PMCID: PMC3103519  PMID: 21637762
BMC Medical Genetics  2013;14:15.
Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals.
Sixty-four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling.
Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained <5% of the variance in serum adiponectin concentration. None of the ADIPOR1/R2 tagSNPs were associated with serum adiponectin. There was no association between any of the genetic variants and insulin resistance or metabolic syndrome. A multi-SNP genotypic risk score for ADIPOQ alleles revealed an association with 3 independent SNPs, rs12637534, rs16861209, rs17366568 and type 2 diabetes after adjusting for adiponectin levels (OR=0.86, 95% CI=(0.75, 0.99), P=0.0134).
Genetic variation in ADIPOQ, but not its receptors, was associated with altered serum adiponectin. However, genetic variation in ADIPOQ and its receptors does not appear to contribute to the risk of insulin resistance or metabolic syndrome but did for type 2 diabetes in a European-Australian population.
PMCID: PMC3598639  PMID: 23351195
Adiponectin; ADIPOQ; ADIPOR; Type 2 diabetes; Insulin resistance and Metabolic syndrome
Objective The adiponectin gene (ADIPOQ) has been suggested to be associated with the pathogenesis of colorectal cancer (CRC). However, the results have been inconsistent. In this study, we performed a meta-analysis to investigate the association between adiponectin polymorphisms and CRC risk.
Methods All eligible case-control studies published up to March 2013 were identified by searching PubMed, Web of Science and CNKI. Effect sizes of odds ratio (OR) and 95% confidence interval (95% CI) were calculated by using a fixed- or random-effect model.
Results A total of 9 case-control studies were included, Of those studies, there were eight studies (2024 cases and 2777 controls) for rs1501299G/T polymorphism, five studies (1401 cases and 1691 controls) for rs2241766T/G polymorphism, five studies (2945 cases and 3361 controls) for rs266729C/G polymorphism, three studies (1221 cases and 1579 controls) for rs822395A/C polymorphism and three studies (1222 cases and 1575 controls) for rs822396A/G polymorphism. Overall, a significant association was observed for rs2241766T/G polymorphism under heterozygote comparison (TG vs. TT: OR=1.22, 95%CI: 1.05-1.43); while there was no significant association for rs2241766 polymorphism under other genetic models, and for other four polymorphisms under all genetic models. Besides, when stratified analyses by ethnicity, no significant association between five polymorphisms and CRC risk were observed under all genetic models among Asian, Caucasian and African-American.
Conclusions This meta-analysis indicated that adiponectin rs2241766T/G rather than rs1501299G/T, rs266729C/G, rs822395A/C and rs822396A/G polymorphism was associated with the risk of colorectal cancer.
PMCID: PMC3714387  PMID: 23869187
Adiponectin; Polymorphism; Colorectal cancer; Meta-analysis.
PLoS Genetics  2008;4(5):e1000084.
Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r2 = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10−16). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10−19), nephritis (MAF = 34.3%, OR = 1.80, p<10−11), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10−13). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10−4 in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.
Author Summary
Systemic lupus erythematosus is a chronic disabling autoimmune disease, most commonly striking women in their thirties or forties. It can cause a wide variety of clinical manifestations, including kidney disease, arthritis, and skin disorders. Prognosis varies greatly depending on these clinical features, with kidney disease and related characteristics leading to greater morbidity and mortality. It is also complex genetically; while lupus runs in families, genes increase one’s risk for lupus but do not fully determine the outcome. It is thought that the interactions of multiple genes and/or interactions between genes and environmental factors may cause lupus, but the causes and disease pathways of this very heterogeneous disease are not well understood. By examining relationships between subtypes of lupus and specific genes, we hope to better understand how lupus is triggered and by what biological pathways it progresses. We show in this work that the STAT4 gene, very recently identified as a lupus risk gene, predisposes specifically to severe manifestations of lupus, including kidney disease.
PMCID: PMC2377340  PMID: 18516230
Adiponectin is an adipocyte-derived protein that is down-regulated in obesity-linked disorders. Variants of the adiponectin gene (ADIPOQ) have been shown to affect adiponectin level. We have now examined the relation of polymorphisms of ADIPOQ to adiponectin concentration and to metabolic disorders in the Kita-Nagoya Genomic Epidemiology study, a population-based study of elderly Japanese. The genomic region including ADIPOQ was genotyped for 30 single nucleotide polymorphisms in 500 subjects of a screening population with the use of a fluorescence- or colorimetry-based allele-specific DNA primer–probe assay system. Four polymorphisms were then selected for genotyping in an additional 2797 subjects. Serum adiponectin level was negatively associated with metabolic abnormalities after adjustment for age and sex. The minor alleles of the rs1656930, Ile164Thr, and rs9882205 polymorphisms were associated with a low serum adiponectin level. Whereas the minor alleles of rs1656930 and rs9882205 were common (minor allele frequency of 6.2 and 38.5%, respectively), that of Ile164Thr was rare (0.9%). The minor allele of rs1656930 was positively associated with systolic blood pressure and the prevalence of hypertension. The association of rs1656930 with adiponectin level was replicated in an independent population. A subject with the 164Thr/Thr genotype had an extremely low serum adiponectin level (0.6 μg/ml) and the phenotype of metabolic syndrome. Our results suggest that a common variant of ADIPOQ, the minor allele of rs1656930, is associated with hypoadiponectinemia and hypertension. Screening for a common genetic background underlying low adiponectin levels might provide important information for assessment and management of metabolic disorders.
PMCID: PMC3062002  PMID: 21150884
adiponectin; polymorphism; metabolic disorder; hypertension; epidemiology
Adipocytokines are produced by visceral fat, and levels may be associated with breast cancer risk. We investigated whether single nucleotide polymorphisms (SNPs) in adipocytokine genes adiponectin (ADIPOQ), leptin (LEP), and the leptin receptor (LEPR) were associated with basal-like or luminal A breast cancer subtypes. 104 candidate and tag SNPs were genotyped in 1776 of 2022 controls and 1972 (200 basal-like, 679 luminal A) of 2311 cases from the Carolina Breast Cancer Study (CBCS), a population-based case–control study of whites and African Americans. Breast cancer molecular subtypes were determined by immunohistochemistry. Genotype odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Haplotype ORs and 95% CIs were estimated using Hapstat. Interactions with waist-hip ratio were evaluated using a multiplicative interaction term. Ancestry was estimated from 144 ancestry informative markers (AIMs), and included in models to control for population stratification. Candidate SNPs LEPR K109R (rs1137100) and LEPR Q223R (rs1137101) were positively associated with luminal A breast cancer, whereas ADIPOQ +45 T/G (rs2241766), ADIPOQ +276 G/T (rs1501299), and LEPR K656N (rs8129183) were not associated with either subtype. Few patterns were observed among tag SNPs, with the exception of 3 LEPR SNPs (rs17412175, rs9436746, and rs9436748) that were in moderate LD and inversely associated with basal-like breast cancer. However, no SNP associations were statistically significant after adjustment for multiple comparisons. Haplotypes in LEP and LEPR were associated with both basal-like and luminal A subtypes. There was no evidence of interaction with waist-hip ratio. Data suggest associations between LEPR candidate SNPs and luminal A breast cancer in the CBCS and LEPR intron 2 tag SNPs and basal-like breast cancer. Replication in additional studies where breast cancer subtypes have been defined is necessary to confirm these potential associations.
PMCID: PMC3355661  PMID: 21516303
Adiponectin; Leptin; Leptin receptor; Breast cancer; Subtypes; Single nucleotide polymorphism
Studies have linked prostate cancer risk with insulin resistance and obesity. Circulating levels of adiponectin, a protein involved in insulin resistance and obesity, have been associated with prostate cancer risk. We studied the association of prostate cancer risk with haplotype tagging single nucleotide polymorphisms (SNPs) of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) chosen based on their functional relevance or association with other types of cancer.
DNA samples from 465 cases and 441 healthy volunteers from New York City were genotyped for ADIPOQ rs266729, rs822395, rs822396, rs1501299 and rs2241766 SNPs and ADIPOR1 rs12733285, rs1342387, rs7539542, rs2232853 and rs10920531 SNPs. We performed both single and multiple SNP analyses.
We found that rs12733285, rs7539452, rs266729, rs822395, rs822396 and rs1501299 were significantly associated with prostate cancer risk. Haplotype analysis confirmed these results and identified five ADIPOQ 4-SNP haplotypes and one ADIPOR1 2-SNP haplotype tightly associated with prostate cancer risk. Importantly two ADIPOQ SNPs, rs266729 and rs1501299 have been previously associated with colon and breast cancer risk, respectively, in the same direction as in this study.
These findings suggest that variants of the adiponectin pathway may be associated with susceptibility to various forms of common cancers and warrant validation studies.
PMCID: PMC3134585  PMID: 21397927
We explored potential associations of two single nucleotide polymorphisms (SNPs) in the adiponectin gene (ADIPOQ; +45T>G, rs2241766 and +276G>T, rs1501299) with circulating total and high-molecular weight (HMW) adiponectin, insulin resistance (IR), and markers of obesity in a healthy Greek female population.
Design and methods
The two SNPs were genotyped in 349 women without diabetes (mean age: 47.0±12.1 years, mean body mass index: 28.9±5.6 kg/m2). Total and HMW adiponectin concentrations, body composition variables, IR parameters, and plasma lipid levels were determined.
In single SNP analysis adjusting for several potential confounders, SNP +276G>T was associated with higher fasting insulin levels (P = 0.01) and higher homeostasis model assessment index for IR (HOMA-IR; P = 0.009), and SNP +45T>G was associated with lower insulin levels and HOMA-IR (P = 0.05 and P = 0.07 respectively). No association with total or HMW adiponectin, plasma lipid levels, and body composition variables was observed; however, haplotype analysis revealed that subjects homozygous for the most common +45T/+276G haplotype had lower total adiponectin levels than did noncarriers of this haplotype (P = 0.02). The observed differences in HOMA-IR were very significant among women with a higher body fat (BF) percentage (≥ the population median of 41%; all P ≤ 0.005), but not among leaner individuals (P for interactions 0.01–0.07), thus suggesting that ADIPOQ effects on insulin sensitivity may depend upon BF status.
Our data suggest a significant role of ADIPOQ variants at positions +45 and +276 in the development of IR in healthy Greek women possibly through an interaction with BF.
PMCID: PMC2896503  PMID: 19755407
World Journal of Gastroenterology : WJG  2014;20(46):17456-17462.
AIM: To examine whether diabetes-related genetic variants are associated with pancreatic cancer risk.
METHODS: We genotyped 7 single-nucleotide polymorphisms (SNPs) in PPARG2 (rs1801282), ADIPOQ (rs1501299), ADRB3 (rs4994), KCNQ1 (rs2237895), KCNJ11 (rs5219), TCF7L2 (rs7903146), and CDKAL1 (rs2206734), and examined their associations with pancreatic cancer risk in a multi-institute case-control study including 360 cases and 400 controls in Japan. A self-administered questionnaire was used to collect detailed information on lifestyle factors. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between these diabetes-associated variants and pancreatic cancer risk.
RESULTS: With the exception of rs1501299 in the ADIPOQ gene (P = 0.09), no apparent differences in genotype frequencies were observed between cases and controls. Rs1501299 in the ADPIOQ gene was positively associated with pancreatic cancer risk; compared with individuals with the AA genotype, the age- and sex-adjusted OR was 1.79 (95%CI: 0.98-3.25) among those with the AC genotype and 1.86 (95%CI: 1.03-3.38) among those with the CC genotype. The ORs remained similar after additional adjustment for body mass index and cigarette smoking. In contrast, rs2237895 in the KCNQ1 gene was inversely related to pancreatic cancer risk, with a multivariable-adjusted OR of 0.62 (0.37-1.04) among individuals with the CC genotype compared with the AA genotype. No significant associations were noted for other 5 SNPs.
CONCLUSION: Our case-control study indicates that rs1501299 in the ADIPOQ gene may be associated with pancreatic cancer risk. These findings should be replicated in additional studies.
PMCID: PMC4265605  PMID: 25516658
Single-nucleotide polymorphisms; Pancreatic cancer; Risk; Case-control study; Odds ratio
Adiponectin is a protein derived from adipose tissue suspected to play an important role in prostate carcinogenesis. Variants in the adiponectin gene (ADIPOQ) and its type I receptor (ADIPOR1) have been recently linked to risk of both breast and colorectal cancer. Therefore, we set out to examine the relationship between polymorphisms in these genes, obesity and prostate cancer in study of African American men.
Ten single nucleotide polymorphisms (SNPs) in ADIPOQ and ADIPOR1 were genotyped in DNA samples from 131 African American prostate cancer cases and 344 controls participating in the Flint Men's Health Study. Logistic regression was then used to estimate their association with prostate cancer and obesity.
While no significant associations were detected between any of the tested SNPs and prostate cancer, the rs1501299 SNP in ADIPOQ was significantly associated with body mass (p=0.03).
Genetic variation in ADIPOQ and ADIPOR1 did not predict risk of prostate cancer in this study of African American men. However, the rs1501299 SNP in ADIPOQ was associated with obesity. Further investigation is warranted to determine if racial differences exist in the influence of the adiponectin pathway on prostate cancer risk.
PMCID: PMC2978765  PMID: 20697428
adipokines; body mass index; genetic susceptibility; single nucleotide polymorphism; racial differences
Mædica  2012;7(4):271-276.
Background: Previous reports associated ADIPOQ 276G>T polymorphism with plasma adiponectin levels and diabetes. Our objective was to study this polymorphism in type 2 diabetes (T2D) Romanian patients and to assess its influence on plasma adiponectin levels; possible link to prevalence of T2D was also addressed.
Design: Case control study
Material and Methods: Consecutive T2D patients, age and sex matched controls were genotyped for the 276 ADIPOQ locus. Medical history, laboratory evaluation, plasma adiponectin were assessed.
Outcomes: 105 T2D patients and 48 controls were included. Adiponectin was higher in controls (17.04±3.02 µg/ml) than in T2D patients (10.32±1.16 µg/ml), difference failed to reach significance (p=0.06). Genotype distribution wasn't different between T2D patients and controls. 44 (41.90%) of T2D patients had GG genotype, 51 (48.57%) GT and 10 (9.52%) TT genotype. Adiponectin was higher (19.03±3.46 µg/ml) in diabetic TT allele carriers than in GT (9.96±1.76 µg/ml) or GG patients (8.71±1.60 µg/ml) p=0.003. In controls, 28 (58.33 %) subjects were carriers of the GG genotype, 16 (33.33%) had GT genotype and 4 (8.33%) had TT genotype. There weren't significant differences in the studied parameters between different genotypes in the control group. Logistic regression disclosed age p=0.0001 (OR 1.086; CI 1.041/1.133), waist circumference p=0.00049 (OR 1.084; CI 1.036/1.135), adiponectinemia p=0.036 (OR 0.963; CI 0.929/0.998) but not genotype as predictors for the presence of diabetes.
Conclusion: Presence of the TT allele at the 276 locus of the ADIPOQ gene is associated with higher plasma adiponectin levels in type 2 diabetes patients. Plasma adiponectin, and not genotype at the 276 locus is predictive for the presence of T2D.
PMCID: PMC3593275  PMID: 23483234
adiponectin; gene polymorphism; type 2 diabetes
PLoS ONE  2013;8(8):e72551.
Systemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs) in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies.
Methodology/Principal Findings
The 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027). The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041). Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G) risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46–11.2 P<0.05).
Associations of polymorphisms in STAT4 and SPP1 with childhood-onset SLE were confirmed in a Japanese population. Although these are preliminary results for a limited number of cases, TNFAIP3 rs2230926G may be an important predictor of disease onset in males. We also replicated findings that the cumulative number of risk alleles was significantly increased in childhood-onset SLE.
PMCID: PMC3758304  PMID: 24023622
An NZB-derived genetic locus (Sle2c2) that suppresses autoantibody production in a mouse model of induced systemic lupus erythematosus contains a polymorphism in the gene encoding the G-CSF receptor. This study was designed to test the hypothesis that the Sle2c2 suppression is associated with an impaired G-CSF receptor function that can be overcome by exogenous G-CSF.
Leukocytes from B6.Sle2c2 and B6 congenic mice, which carry a different allele of the G-CSF receptor, were compared for their responses to G-CSF. Autoantibody production was induced with the chronic graft-versus-host-disease (cGVHD) model by adoptive transfer of B6.bm12 splenocytes. Different treatment regimens varying the amount and frequency of G-CSF (Neulasta®) or carrier control were tested on cGVHD outcomes. Autoantibody production, immune cell activation, and reactive oxygen species (ROS) production were compared between the two strains with the various treatments. In addition, the effect of G-CSF treatment was examined on the production autoantibodies in the B6.Sle1.Sle2.Sle3 (B6.TC) spontaneous model of lupus.
B6.Sle2c2 and B6 leukocytes responded differently to G-CSF. G-CSF binding by B6.Sle2c2 leukocytes was reduced as compared to B6, which was associated with a reduced expansion in response to in vivo G-CSF treatment. G-CSF in vivo treatment also failed to mobilize bone-marrow B6.Sle2c2 neutrophils as it did for B6 neutrophils. In contrast, the expression of G-CSF responsive genes indicated a higher G-CSF receptor signaling in B6.Sle2c2 cells. G-CSF treatment restored the ability of B6.Sle2c2 mice to produce autoantibodies in a dose-dependent manner upon cGVHD induction, which correlated with restored CD4+ T cells activation, as well as dendritic cell and granulocyte expansion. Steady-state ROS production was higher in B6.Sle2c2 than in B6 mice. cGVHD induction resulted in a larger increase in ROS production in B6 than in B6.Sle2c2 mice, and this difference was eliminated with G-CSF treatment. Finally, a low dose G-CSF treatment accelerated the production of anti-dsDNA IgG in young B6.TC mice.
The different in vivo and in vitro responses of B6.Sle2c2 leukocytes are consistent with the mutation in the G-CSFR having functional consequences. The elimination of Sle2c2 suppression of autoantibody production by exogenous G-CSF indicates that Sle2c2 corresponds to a loss of function of G-CSF receptor. This result was corroborated by the increased anti-dsDNA IgG production in G-CSF-treated B6.TC mice, which also carry the Sle2c2 locus. Overall, these results suggest that the G-CSF pathway regulates the production of autoantibodies in murine models of lupus.
PMCID: PMC3672747  PMID: 23566364

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