Harvest F. Gu

New susceptibility loci associated with kidney disease in Type 1 diabetes

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Human neuropeptide Y signal peptide gain-of-function polymorphism is associated with increased body mass index: Possible mode of function

Neuropeptide Y (NPY) has been implicated in the control of food intake and energy balance based on many observations in animals. We have studied single nucleotide polymorphisms (SNPs) within the regulatory and coding sequences of the human NPY gene. One variant (1128 T>C), which causes an amino acid change from leucine to proline at codon 7 in the signal peptide of NPY, was associated with increased body mass index (BMI) in two separate Swedish populations of normal and overweight individuals. In vitro transcription and translation studies indicated the unlikelihood that this signal peptide variation affects the site of cleavage and targeting or uptake of NPY into the endoplasmic reticulum (ER). However, the mutant, and to a lesser extent the wild-type, signal peptide by themselves markedly potentiated NPY-induced food intake, as well as hypothalamic NPY receptor signaling. Our findings in humans strongly indicate that the NPY signaling system is implicated in body weight regulation and suggest a new and unexpected functional role of a signal peptide.

A single nucleotide polymorphism alters the sequence of SP1 binding site in the adiponectin promoter region and is associated with diabetic nephropathy among type 1 diabetic patients in the Genetics of Kidneys in Diabetes Study.

OBJECTIVE The adiponectin promoter single nucleotide polymorphism (SNP) -11391G/A is found to be associated with nephropathy in type 1 diabetic (T1D) patients among Danish, but not French, Finnish, and Swedish populations. In the present study, we identified the binding sites for transcriptional factors in the adiponectin promoter region and also evaluated the association between adiponectin promoter polymorphisms and diabetic nephropathy (DN) in T1D patients. MATERIALS AND METHODS Three adiponectin promoter SNPs, including -11377C/G, -11391G/A, and -11426A/G, were genotyped with dynamic allele-specific hybridization. The subjects included 1177 American T1D patients (622 females/555 males) with or without DN. All patients are of European descent and selected from the Genetics of Kidneys in Diabetes (GoKinD) study. RESULTS We identified four binding sites of transcriptional stimulatory protein (SP1) in the adiponectin putative promoter and found that the G allele of SNP -11377C/G altered the sequence for one of the SP1 binding sites. This polymorphism was significantly associated with DN in female T1D patients (P=.022, OR=1.352, 95% CI=1.044-1.752). Further analyses indicated the common diplotype (haplotypic genotype) H1/H1, constructed with SNPs -11377C/G and -11391G/A, was significantly associated with DN in females (P=.013), while the association of another diplotype H1/H2 with DN in females was of borderline significance (P=.071). CONCLUSIONS The present study thus provides the first evidence that SNP -11377C/G alters the sequence in one of the SP1 binding sites in the adiponectin promoter region. This polymorphism, together with another promoter SNP -11391G/A, may confer susceptibility to the development of DN in T1D patients among the GoKinD population.

Associations of variants in FTO and Near MC4R with obesity traits in South Asian Indians

Recent genome‐wide association studies show that loci in FTO and melanocortin 4 receptor (MC4R) associate with obesity‐related traits. Outside Western populations the associations between these variants have not always been consistent and in Indians it has been suggested that FTO relates to diabetes without an obvious intermediary obesity phenotype. We investigated the association between genetic variants in FTO (rs9939609) and near MC4R (rs17782313) with obesity‐ and type 2 diabetes (T2DM)‐related traits in a longitudinal birth cohort of 2,151 healthy individuals from the Vellore birth cohort in South India. The FTO locus displayed significant associations with several conventional obesity‐related anthropometric traits. The per allele increase is about 1% for BMI, waist circumference (WC), hip circumference (HC), and waist—hip ratio. Consistent associations were observed for adipose tissue‐specific measurements such as skinfold thickness reinforcing the association with obesity‐related traits. Obesity associations for the MC4R locus were weak or nonsignificant but a signal for height (P < 0.001) was observed. The effect on obesity‐related traits for FTO was seen in adulthood, but not at younger ages. The loci also showed nominal associations with increased blood glucose but these associations were lost on BMI adjustment. The effect of FTO on obesity‐related traits was driven by an urban environmental influence. We conclude that rs9939609 variant in the FTO locus is associated with measures of adiposity and metabolic consequences in South Indians with an enhanced effect associated with urban living. The detection of these associations in Indians is challenging because conventional anthropometric obesity measures work poorly in the Indian “thin‐fat” phenotype.

Association of +45G15G(T/G) and +276(G/T) polymorphisms in the ADIPOQ gene with polycystic ovary syndrome among Han Chinese women.

OBJECTIVE Polycystic ovary syndrome (PCOS) is frequently associated with insulin resistance (IR) and consequently with increased risk of metabolic disorders. Adiponectin is the most abundant adipocytokine and may play a role in the regulation of insulin sensitivity and IR in PCOS. The aim of the present study was to evaluate the genetic influence of the adiponectin (ADIPOQ) gene polymorphisms in the development of PCOS among Han Chinese women. METHODS Two single nucleotide polymorphisms (SNPs),+45G15G(T/G) and +276(G/T), in the ADIPOQ gene were genotyped in 120 patients with PCOS and 120 healthy control subjects. All of them were Han Chinese women. RESULTS Both SNPs were found to be significantly associated with PCOS (P=0.021, odds ratios=1.629, 95% confidence intervals: 1.074-2.469 and P=0.015, 1.576, 1.091-2.279 respectively). In SNP +276(G/T), the allele G was found to be significantly associated with increased fasting insulin levels, homeostasis model assessment to assess IR index, and area under the curve glucose levels, but decreased glucose and insulin ratio in the PCOS patients. Furthermore, the patients carrying genotypes G/G and G/T had significantly decreased levels of serum adiponectin (6.16+/-3.18 plus 5.93+/-3.23 vs 8.96+/-3.21 microg/ml, P=0.030) compared with the patients with genotype T/T. CONCLUSIONS The present study provides evidence that SNPs +45G15G(T/G) and +276(G/T) in the ADIPOQ gene are associated with PCOS in Han Chinese women. SNP +276(G/T) may contribute to an impact of insulin levels and IR, which are implicated in the susceptibility for PCOS.

Genetic influences of the intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in development of Type 1 diabetes and diabetic nephropathy.

Aim  The intercellular adhesion molecule‐1 (ICAM‐1) gene is located on chromosome 19p13, which is linked to Type 1 diabetes (T1D). ICAM‐1 expression is related to development of T1D and diabetic nephropathy. The present study aims to evaluate the genetic influence of ICAM‐1 gene polymorphisms on the development of T1D and diabetic nephropathy.

Single nucleotide polymorphisms in the proximal promoter region of apolipoprotein M gene (apoM) confer the susceptibility to development of type 2 diabetes in Han Chinese

Dyslipidemia correlating to insulin resistance is one of the key features in type 2 diabetes (T2D). Recent studies have demonstrated that apolipoprotein M (apoM) is important for the formation of preβ‐high‐density lipoprotein (HDL) and cholesterol (CHO) efflux in macrophages to HDL. In the present study, we investigated the potential association of apoM genetic variation with the development of T2D.

Consumption of whole grain reduces risk of deteriorating glucose tolerance, including progression to prediabetes

BACKGROUND High whole-grain intake has been reportedly associated with reduced risk of developing type 2 diabetes (T2D), which is an effect possibly subject to genetic effect modification. Confirmation in prospective studies and investigations on the impact on prediabetes is needed. OBJECTIVES In a prospective population-based study, we investigated whether a higher intake of whole grain protects against the development of prediabetes and T2D and tested for modulation by polymorphisms of the TCF7L2 gene. DESIGN We examined the 8-10-y incidence of prediabetes (impaired glucose tolerance, impaired fasting glucose, or the combination of both) and T2D in relation to the intake of whole grain. Baseline data were available for 3180 women and 2297 men aged 35-56 y. RESULTS A higher intake of whole grain (>59.1 compared with <30.6 g/d) was associated with a 34% lower risk to deteriorate in glucose tolerance (to prediabetes or T2D; women and men combined). The association remained after adjustments for age, family history of diabetes, BMI, physical activity, smoking, education, and blood pressure (OR: 0.78; 95% CI: 0.63, 0.96). Risk reduction was significant in men (OR: 0.65; 95% CI: 0.49, 0.85) but not in women. Associations were significant for prediabetes per se (all, OR: 0.73; 95% CI: 0.56, 0.94; men, OR: 0.57; 95% CI: 0.40, 0.80). The intake of whole grain correlated inversely with insulin resistance (HOMA-IR). The impact of whole-grain intake was undetectable in men who harbored diabetogenic polymorphisms of the TCF7L2 gene. CONCLUSIONS A higher intake of whole grain is associated with decreased risk of deteriorating glucose tolerance including progression from normal glucose tolerance to prediabetes by mechanisms likely tied to effects on insulin sensitivity. Effect modifications by TCF7L2 genetic polymorphisms are supported.

Biomarkers of adiponectin: plasma protein variation and genomic DNA polymorphisms.

Adiponectin is secreted by white adipose tissue and exists as the most abundant adipokine in the human plasma. Recent research has indicated that plasma adiponectin levels are inversely correlated with body mass index (BMI) and insulin resistance. Reduction of plasma adiponectin levels is commonly observed in the patients with type 2 diabetes (T2D) and/or in those who are obese in comparison with healthy control individuals. The adiponectin (AdipoQ) gene has a moderate linkage disequilibrium (LD), but two small LD blocks are observed, respectively, in the promoter region and the boundary of exon 2-intron 2. Genetic association studies have demonstrated that single nucleotide polymorphisms (SNPs) +45G15G(T/G) in exon 2 and +276G/T in intron 2 of the AdipoQ gene confer the risk susceptibility to the development of T2D, obesity and diabetic nephropathy (DN). The SNPs in the promoter region, including –11426A/G, –11377C/G and –11391G/A, are found to be associated with T2Dand DN. Recent research has indicated that the promoter polymorphisms interfere with the AdipoQ promoter activity. The haplotypes constructed by the promoter polymorphisms and SNP +276G/T in intron 2 are associated with circulating adiponectin levels. This review summarises genetic and pathophysiological relevancies of adiponectin and discusses about the biomarkers of adiponectin plasma protein variation and genomic DNA polymorphisms.

Labisia pumila extract regulates body weight and adipokines in ovariectomized rats

OBJECTIVE We investigated the effects of a standardized water extract of Labisia pumila var. alata (LPva), and compared to estrogen replacement (ERT), on body weight gain, uterus weight, adipose tissue mRNA and protein levels of adipokines in ovariectomized (OVX) rats. METHODS Eight-week-old OVX Sprague-Dawley rats were administered orally with either 10 mg/kg/day (LPva10), 20 mg/kg/day (LPva20) or 50 mg/kg/day (LPva50) of LPva for 30 days. Sham-operated (Sham) and estrogen-treated OVX rats (ERT, 0.625 mg/kg/day) served as controls. Plasma adipokines were measured, and mRNA expressions of the adipokines were determined in the adipose tissues. RESULTS ERT- and LPva50-treated OVX rats showed significantly less (p<0.05) weight gain compared to untreated OVX rats. Ovariectomy caused plasma leptin levels to decrease significantly (p<0.05), but when treated with LPva or ERT, plasma leptin increased significantly to levels higher or comparable to that seen in the Sham group. The mRNA expression of leptin was higher in the LPva-treated animals than in all other groups. In contrast, the elevated plasma resistin concentrations in OVX rats were significantly reduced in rats given ERT (p<0.05) and LPva extracts (p<0.05). There was no difference in adiponectin levels in all groups. The uterus to body weight ratio of untreated OVX rats was significantly low compared to Sham (p<0.05), but showed dose-dependent increase upon treatment with LPva. CONCLUSION The present study provides first evidence that LPva exerts uterotrophic effect and regulates body weight gain by modulating secretion of leptin and resistin, and expression of the adipokines in adipose tissues.