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Common variants in the LAMA5 gene associate with fasting plasma glucose and serum triglyceride levels in a cohort of pre- and early pubertal children.

ABSTRACT: Laminins are glycoproteins found in basement membranes where they play a vital role in tissue architecture and cell behavior. Previously, we reported the association of two polymorphisms (rs659822 and rs944895) in the laminin alpha5 (LAMA5) gene with anthropometric traits, fasting lipid profile, and glucose levels in pre-menopausal women and elderly subjects. Furthermore, studies in mice showed that Lama5 is involved in organogenesis and placental function during pregnancy. The objective of this study was to investigate whether rs659822 and/or rs944895 are associated with inter-individual variability in birth weight as well as anthropometric traits and metabolic phenotypes in children. Two hundred and eighty nine healthy children aged 7-12 yr of European, Hispanic, and African-American ancestry were studied. Co-dominant models adjusted for genetic admixture, age, gender, and stages of puberty were used to test for the association of the polymorphisms with each trait. Our analysis showed significant associations of rs659822 with fasting plasma glucose levels (P = 0.0004) and of rs944895 with fasting serum triglycerides (P = 0.004) after Bonferroni correction for multiple testing. Our results corroborate our previous findings that genetic variants in LAMA5 contribute to variation in metabolic phenotypes and provide evidence that this may occur early in life.

SUBMITTER: De Luca M

PROVIDER: S-EPMC5020947 | biostudies-other | 2012 Dec

REPOSITORIES: biostudies-other

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Common variants in the LAMA5 gene associate with fasting plasma glucose and serum triglyceride levels in a cohort of pre-and early pubertal children.

Project description:Laminins are large glycoproteins found in basement membranes where they play a vital role in tissue architecture and cell behavior. Previously, we reported the association of two LAMA5 polymorphisms (rs659822 and rs944895) with anthropometric traits, fasting lipid profile, and plasma glucose levels in pre-menopausal women and elderly subjects. Furthermore, earlier work in mice showed that Lama5 is involved in organogenesis and placental function during pregnancy. The objective of this study was to investigate whether LAMA5 rs659822 or rs944895 are associated with inter-individual variability in birth weight as well as anthropometric, fasting lipid profile, and fasting glucose levels in children. Two hundred and eighty nine healthy children aged 7-12 years of European, Hispanic, and African-American ancestry were studied. Co-dominant models adjusted for genetic admixture, age, gender, and stages of puberty were used to test for the association of the polymorphisms with each trait. Our analysis showed significant associations of rs659822 with fasting plasma glucose levels (p = 0.0004) and of rs944895 with fasting serum triglycerides (p = 0.004) after Bonferroni correction for multiple testing. Our results corroborate our previous findings that genetic variants in LAMA5 contribute to variation in metabolic phenotypes and provide evidence that this may occur early in life.

| S-EPMC3527014 | biostudies-literature

Variants in MTNR1B influence fasting glucose levels.

Project description:To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.

| S-EPMC2682768 | biostudies-literature

Common genetic variants associate with serum phosphorus concentration.

Project description:Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.

| S-EPMC3152230 | biostudies-literature

LIPC variants as genetic determinants of adiposity status, visceral adiposity indicators, and triglyceride-glucose (TyG) index-related parameters mediated by serum triglyceride levels.

Project description:Background:Visceral adiposity indicators and the product of triglyceride and fasting plasma glucose (TyG) index-related parameters are effective surrogate markers for insulin resistance (IR) and are predictors of metabolic syndrome and diabetes mellitus. However, their genetic determinants have not been previously reported. Pleiotropic associations of LIPC variants have been observed in lipid profiles and atherosclerotic cardiovascular diseases. We aimed to investigate LIPC polymorphisms as the genetic determinants of adiposity status, visceral adiposity indicators and TyG index-related parameters. Methods:A total of 592 participants from Taiwan were genotyped for three LIPC single nucleotide polymorphisms (SNPs). Results:The LIPC SNPs rs2043085 and rs1532085 were significantly associated with body mass index (BMI), waist circumference (WC), lipid accumulation product, visceral adiposity index, and TyG index-related parameters [including the TyG index, TyG with adiposity status (TyG-BMI), and TyG-WC index], whereas the rs1800588 SNP was only significantly associated with the TyG index. The associations became nonsignificant after further adjustment for serum TG levels. No significant association was observed between any the studied LIPC SNPs and IR status. Conclusion:Our data revealed a pleiotropic association between the LIPC variants and visceral adiposity indicators and TyG index-related parameters, which are mediated by serum TG levels.

| S-EPMC6218991 | biostudies-literature

The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation.

Project description:Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals.The rs738409 variant was genotyped in the population-based Inter99 cohort examined by an oral glucose-tolerance test, and a combined study-sample consisting of 192 twins (96 twin pairs) and a sub-set of the Inter99 population (n?=?63) examined by a hyperinsulinemic euglycemic clamp (n(total)?=?255). In Inter99, we analyzed associations of rs738409 with components of the WHO-defined metabolic syndrome (n?=?5,847) and traits related to metabolic disease (n?=?5,663). In the combined study sample we elucidated whether the rs738409 G-allele altered hepatic or peripheral insulin sensitivity. Study populations were divided into individuals with normal glucose-tolerance (NGT) and with impaired glucose regulation (IGR).The case-control study showed no associations with components of the metabolic syndrome or the metabolic syndrome. Among 1,357 IGR individuals, the rs738409 G-allele associated with decreased fasting serum triglyceride levels (per allele effect(?)?=?-9.9% [-14.4%;-4.0% (95% CI)], p?=?5.1×10(-5)) and fasting total cholesterol (??=?-0.2 mmol/l [-0.3;-0.01 mmol/l(95% CI)], p?=?1.5×10(-4)). Meta-analyses showed no impact on hepatic or peripheral insulin resistance in carriers of the rs738409 G-allele.Our findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.

| S-EPMC3390392 | biostudies-literature

Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis.

Project description:Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 μg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.

| S-EPMC4116060 | biostudies-literature

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

Project description:Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

| S-EPMC4311266 | biostudies-literature

The potential effects of HECTD4 variants on fasting glucose and triglyceride levels in relation to prevalence of type 2 diabetes based on alcohol intake.

Project description:Excessive alcohol intake is an important cause of major public health problem in East Asian countries. Growing evidence suggests that genetic factors are associated with alcohol consumption and the risk for alcohol-associated disease, and these factors contribute to the risk of developing chronic diseases, including diabetes. This study aims to investigate the association of type 2 diabetes with genetic polymorphisms within HECTD4 based on alcohol exposure. We performed a genome-wide association study involving the cohorts of the KoGES-HEXA study (n = 50,028) and Ansan and Ansung study (n = 7,980), both of which are prospective cohort studies in Korea. The top three single-nucleotide polymorphisms (SNPs) of the HECTD4 gene, specifically rs77768175, rs2074356 and rs11066280, were found to be significantly associated with alcohol consumption. We found that individuals carrying the variant allele in these SNPs had lower fasting blood glucose, triglyceride, and GGT levels than those with the wild-type allele. Multiple logistic regression showed that statistically significant associations of HECTD4 gene polymorphisms with an increased risk of type 2 diabetes were found in drinkers. Namely, these SNPs were associated with decreased odds of diabetes in the presence of alcohol consumption. As a result of examining the effect of alcohol on the expression of the HECTD4 gene, ethanol increased the expression of HECTD4 in cells, but the level was decreased by NAC treatment. Similar results were obtained from liver samples of mice treated with alcohol. Moreover, a loss of HECTD4 resulted in reduced levels of CYP2E1 and lipogenic gene expression in ethanol-treated cells, while the level of ALDH2 expression increased, indicating a reduction in ethanol-induced hepatotoxicity.

| S-EPMC9325801 | biostudies-literature

Negative associations for fasting blood glucose, cholesterol and triglyceride levels with the development of giant cell arteritis.

Project description:ObjectivesTo investigate metabolic features that may predispose to GCA in a nested case-control study.MethodsIndividuals who developed GCA after inclusion in a population-based health survey (the Malmö Preventive Medicine Project; N = 33 346) were identified and validated through a structured review of medical records. Four controls for every validated case were selected from the database.ResultsA total of 76 cases with a confirmed incident diagnosis of GCA (61% female, 65% biopsy positive, mean age at diagnosis 70 years) were identified. The median time from screening to diagnosis was 20.7 years (range 3.0-32.1). Cases had significantly lower fasting blood glucose (FBG) at baseline screening compared with controls [mean 4.7 vs 5.1 mmol/l (S.d. overall 1.5), odds ratio (OR) 0.35 per mmol/l (95% CI 0.17, 0.71)] and the association remained significant when adjusted for smoking [OR 0.33 per mmol/l (95% CI 0.16, 0.68)]. Current smokers had a reduced risk of GCA [OR 0.35 (95% CI 0.18, 0.70)]. Both cholesterol [mean 5.6 vs 6.0 mmol/l (S.d. overall 1.0)] and triglyceride levels [median 1.0 vs 1.2 mmol/l (S.d. overall 0.8)] were lower among the cases at baseline screening, with significant negative associations with subsequent GCA in crude and smoking-adjusted models [OR 0.62 per mmol/l (95% CI 0.43, 0.90) for cholesterol; 0.46 per mmol/l (95% CI 0.27, 0.81) for triglycerides].ConclusionDevelopment of GCA was associated with lower FBG and lower cholesterol and triglyceride levels at baseline, all adjusted for current smoking, suggesting that metabolic features predispose to GCA.

| S-EPMC7590417 | biostudies-literature

The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population.

Project description:Hepatic glucokinase (GCK) is a key regulator of glucose storage and disposal in the liver, where its activity is competitively modulated, with respect to glucose, by binding to glucokinase regulatory protein (GCKR) in the presence of fructose 6-phosphate. Genome-wide association studies for type 2 diabetes identified GCKR as a potential locus for modulating triglyceride levels. We evaluated, in a general French population, the contribution of the GCKR rs1260326-P446L polymorphism to quantitative metabolic parameters and to dyslipidemia and hyperglycemia risk.Genotype effects of rs1260326 were studied in 4,833 participants from the prospective DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) cohort both at inclusion and using the measurements at follow-up.The minor T-allele of rs1260326 was strongly associated with lower fasting glucose (-1.43% per T-allele; P = 8 x 10(-13)) and fasting insulin levels (-4.23%; P = 3 x 10(-7)), lower homeostasis model assessment of insulin resistance index (-5.69%; P = 1 x 10(-8)), and, conversely, higher triglyceride levels (3.41%; P = 1 x 10(-4)) during the 9-year study. These effects relate to a lower risk of hyperglycemia (odds ratio [OR] 0.79 [95% CI 0.70-0.88]; P = 4 x 10(-5)) and of incident cases during the study (hazard ratio [HR] 0.83 [0.74-0.95]; P = 0.005). Moreover, an additive effect of GCKR rs1260326(T) and GCK (-30G) alleles conferred lower fasting glycemia (P = 1 x 10(-13)), insulinemia (P = 5 x 10(-6)), and hyperglycemia risk (P = 1 x 10(-6)).GCKR-L446 carriers are protected against type 2 diabetes despite higher triglyceride levels and risk of dyslipidemia, which suggests a potential molecular mechanism by which these two components of the metabolic syndrome can be dissociated.

| S-EPMC2494697 | biostudies-literature

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