Diabetes Case-control Study Research Articles

Urinary arsenic metabolism, genetic susceptibility, and their interaction on type 2 diabetes

Growing studies investigated the association of arsenic metabolism with type 2 diabetes (T2D), however, the epidemiological evidence is inconsistent. In addition, the interaction of arsenic metabolism-related genetic risk score (GRS)-arsenic on T2D risk was unclear. The present study aimed to evaluate the association of arsenic metabolism efficiency [inorganic arsenic (iAs)%, monomethylarsonic acid (MMA)%, and dimethylarsinic acid (DMA%)] with T2D risk. Moreover, the relationship of GRS and arsenic metabolism efficiency and the interaction of GRS-arsenic on T2D were investigated. Age- and sex-matched new-onset diabetes case-control study derived from the Dongfeng-Tongji cohort was conducted and 996 pairs participants were included in this study. The leave-one-out approach was used to evaluate the association of arsenic metabolism efficiency with T2D risk. The GRS and weight GRS (wGRS) were calculated based on 79 candidate SNPs. We estimated the relationship of GRS with arsenic metabolism efficiency by linear regression model. The interaction of GRS-arsenic on T2D was assessed by adding a multiplicative interaction term (GRS × arsenic) in the logistic regression models. Urinary iAs% was positively associated with T2D risk, and the OR (95% CI) was 1.06 (1.01, 1.12). MMA% and PMI were negatively associated with T2D risk, and the ORs (95% CI) were 0.87 (0.78, 0.97) and 0.64 (0.47, 0.86), respectively. Urinary DMA, As3+, and As5+ were positively associated with T2D risk. Similar relationships were found between arsenic metabolites and levels of FPG and HbA1c. Moreover, arsenic metabolism-related GRS/wGRS was positively associated with MMA% but negatively associated with DMA%. Genetic predisposition to arsenic metabolism modified the association of inorganic arsenic with T2D risk (Pinteraction = 0.033). Taken together, lower arsenic primary metabolism efficiency (higher iAs% and lower MMA%) may increase T2D risk. Genetic predisposition to arsenic metabolism was associated with arsenic metabolism efficiency, and might modify the association of inorganic arsenic with T2D risk.

Increased Oral Care Needs and Third Molar Symptoms in Women with Gestational Diabetes Mellitus: A Finnish Gestational Diabetes Case-Control Study.

(1) Hyperglycemia and oral pathology accelerate each other in diabetes. We evaluated whether gestational diabetes mellitus (GDM) is associated with self-reported increased oral health care needs and oral symptoms, including third molar symptoms, during pregnancy. (2) Pregnant women with (n = 1030) and without GDM (n = 935) were recruited in this multicenter Finnish Gestational Diabetes study in 2009–2012. Of the women with GDM, 196 (19.0%) receiving pharmacological treatment, 797 (77.0%) receiving diet treatment and 233 (23.0%) with recurrent GDM were analyzed separately. Oral health was assessed using structured questionnaires and analyzed by multivariable logistic regression adjusted for background risk factors. (3) Women with GDM were more likely to report a higher need for oral care than controls (31.1% vs. 24.5%; odds ratio (OR) 1.39; 95% confidence interval (CI) 1.14–1.69), particularly women with recurrent GDM (38.1% vs. 24.5%; OR 1.90; 95% CI 1.40–2.58). Women with pharmacologically treated GDM (46.9%) more often had third molar symptoms than controls (36.1%; OR 1.57; 95% CI 1.15–2.15) than women with diet-treated GDM (38.0%; OR 1.47; 95% CI 1.07–2.02). (4) GDM is associated with perceived oral care needs. Third molar symptoms were associated with pharmacologically treated GDM.

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

Proteome-wide assessment of diabetes mellitus in Qatari identifies IGFBP-2 as a risk factor already with early glycaemic disturbances

BackgroundProteomics is expected to provide novel insights in the underlying pathophysiology of type 2 diabetes mellitus. In the present study, we aimed to identify and biochemically characterize proteins associated with diabetes mellitus in a Qatari population. MethodsIn a diabetes case-control study (175 cases, 164 controls; Arab, South Asian and Philippine ethnicities), we conducted a discovery study to screen 1141 blood protein levels for associations with diabetes mellitus. Additional analyses were done in controls in relation to Hb1Ac, and biochemical characterization of the main findings was performed with metabolomics (501 metabolites). We performed two-sample Mendelian Randomization to provide evidence of potential causality using data from European descent of the DIAGRAM consortium (74,124 cases of diabetes mellitus and 824,006 controls) for the identified proteins for T2D and Hb1Ac. ResultsAfter accounting for multiple testing, 30 protein levels were different (p-values<8.6e−5) between cases and controls. Of these, a higher Hb1Ac in controls was associated with a lower IGFBP-2 level (p-value = 4.1e−6). IGFBP-2 protein level was found lower among cases compared with controls across all ethnicities. In controls, IGFBP-2 was associated with 21 metabolite levels, but specifically connected to the metabolite citrulline in network analyses. We observed no evidence, however, that the association between IGFBP-2 and diabetes mellitus was causal. ConclusionsWe specifically identified IGFBP-2 to be associated with diabetes mellitus, although with no evidence for causality, which was specifically connected to citrulline metabolism.

Serotonin receptor 3B polymorphisms are associated with type 2 diabetes: The Korean Genome and Epidemiology Study

AimsSerotonin, or 5-hydroxytryptamine (5-HT), and serotonin receptor (HTR) subtypes contribute to controlling energy homeostasis. We investigated the association of polymorphisms of serotonin related genes with type 2 diabetes in Korean adults using a community-based prospective cohort study. MethodsA total of 8840 participants (4205 Ansung, 4635 Ansan) from the Korean Genome and Epidemiology Study (KoGES)-Ansan and Ansung were included. The mean follow-up duration was 7.6 years, and the Ansan and Ansung cohorts were treated as independent replicates. Individuals with existing and new-onset type 2 diabetes were identified at baseline and follow-up evaluations, respectively. Logistic regression analysis was used to evaluate the association of 3402 single nucleotide polymorphisms (SNPs) in serotonin related genes with type 2 diabetes after adjusting for baseline age, sex, body mass index, drinking status, and smoking status. ResultsThe baseline case-control comparison revealed significant association of 26 SNPs in HTR3B and HTR2A with type 2 diabetes. Interestingly, HTR3B SNP rs1176744, which is involved in behavioral disorders, was associated with type 2 diabetes (p-value = 0.0002). Furthermore, HTR3B polymorphisms that significantly associated with type 2 diabetes were located in the 3′ downstream region. The new-onset type 2 diabetes case-control study revealed significant association of 3 additional SNPs of the HTR4. ConclusionsWe found that rs1176744 in HTR3B was associated with type 2 diabetes. Additionally, our study suggests that polymorphisms in the downstream region of HTR3B may contribute to the development of type 2 diabetes.

Measurement of 1,5-anhydroglucitol in blood and saliva: from non-targeted metabolomics to biochemical assay

BackgroundDiabetes testing using saliva, rather than blood and urine, could facilitate diabetes screening in public spaces. We previously identified 1,5-anhydro-d-glucitol (1,5-AG) in saliva as a diabetes biomarker. The Glycomark™ assay kit is FDA approved for 1,5-AG measurement in blood. Here we evaluated its applicability for 1,5-AG quantification in saliva.MethodsUsing pooled saliva samples, we validated Glycomark™ assay use with a RX Daytona+ clinical chemistry analyser. We then used this set-up to analyse 82 paired blood and saliva samples from a diabetes case–control study, for which broad mass spectrometry-based characterization of the blood and saliva metabolome was also available. Osmolality was measured to account for potential variability in saliva samples.ResultsThe technical variability of the read-outs for the pooled saliva samples (CV = 2.05 %) was comparable to that obtained with manufacturer-provided blood surrogate quality controls (CV = 1.38–1.8 %). We found a high correlation between Glycomark assay and mass spectrometry measurements of serum 1,5-AG (r2 = 0.902), showing reproducibility of the non-targeted metabolomics results. The significant correlation between the osmolality measurements performed at two independent platforms with the time interval of 2 years (r2 = 0.887), also indicates the sample integrity. The assay read-out for saliva was not correlated with the mass spectrometry-based 1,5-AG saliva measurements. Comparison with the full saliva metabolome revealed a high correlation of the saliva assay read-outs with galactose.ConclusionsGlycomark™ assay read-outs for saliva were stable and replicable. However, the signal was dominated by galactose, which is biochemically similar to 1,5-AG and absent in blood. Adapting the 1,5-AG kit for saliva analysis will require enzymatic depletion of galactose. This should be feasible, since the assay already includes a similar step for glucose depletion from blood samples.

Abstract P335: High-sensitive C-reactive Protein and Risk of Undiagnosed and Incident Diabetes: The Singapore Chinese Health Study

Introduction: There has been growing evidence that elevated levels of C-reactive protein (CRP), as a biomarker of inflammation, are associated with increased risk of diabetes. However, previous prospective studies were mostly conducted among Caucasians, and few were done in Chinese. Thus, we assessed the hypothesis that elevated CRP levels are related to increased risk of type 2 diabetes among Chinese adults residing in Singapore. Methods: The Singapore Chinese Health Study (SCHS) is a population-based cohort that recruited 63,257 Chinese adults aged 45-74 years during 1993 and 1998, and morning blood samples were collected from about 32,000 participants during the first follow-up visit (1999-2004). In this diabetes case-control study nested within SCHS, all eligible participants were free of diagnosed diabetes, cardiovascular disease and cancer at blood collection, and 571 cases subsequently reported to have diabetes at the follow-up II visit (2006-2010), while 571 controls were matched to cases for age (±3 years) and date (±6 months) of blood collection, sex and dialect group and remained free of diabetes, cardiovascular disease at the follow-up II visit. Plasma high-sensitive CRP (hs-CRP) concentrations were assayed, and conditional logistical regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). Results: The mean (SD) concentrations of hs-CRP was 2.79 (2.65) and 1.86 (2.03) mg/L, respectively, in cases and controls (P&lt;0.001). After controlling for matching factors, education level, smoking status, alcohol intake, physical activity, baseline hypertension, fasting status, body mass index, triglycerides and HDL cholesterol, the ORs (95% CIs) across quartiles of hs-CRP were 1.00 (ref), 1.25 (0.79-1.98), 1.23 (0.78-1.95), and 1.73 (1.11-2.69; P for trend=0.01). Among the cases, there were 279 subjects who had HbA1C ≥6.5% at the time of blood collection and thus classified as undiagnosed diabetes, and the other 292 subjects had HbA1C &lt;6.5% at blood collection and were classified as incident diabetes. In the undiagnosed diabetes case-control sets, the ORs (95% CIs) across quartiles of hs-CRP were 1.00 (ref), 1.23 (0.59-2.56), 2.26 (1.10-4.66), and 2.46 (1.26-4.83; P for trend=0.009); while in the incident diabetes case-control sets, the ORs (95% CIs) were 1.00 (ref), 1.22 (0.63-2.36), 0.73 (0.38-1.41), and 1.25 (0.65-2.42; P for trend=0.39). Conclusions: In this prospective nested case-control study of Chinese adults, elevated CRP levels are not independently associated with increased risk of incident diabetes. The positive association between CRP and undiagnosed diabetes suggests that CRP may parallel with hyperglycemia. Our results do not support the independent role of CRP in the development of type 2 diabetes in Chinese population.

Open-source electronic data capture system offered increased accuracy and cost-effectiveness compared with paper methods in Africa

ObjectivesExisting electronic data capture options are often financially unfeasible in resource-poor settings or difficult to support technically in the field. To help facilitate large-scale multicenter studies in sub-Saharan Africa, the African Partnership for Chronic Disease Research (APCDR) has developed an open-source electronic questionnaire (EQ). Study Design and SettingTo assess its relative validity, we compared the EQ against traditional pen-and-paper methods using 200 randomized interviews conducted in an ongoing type 2 diabetes case–control study in South Africa. ResultsDuring its 3-month validation, the EQ had a lower frequency of errors (EQ, 0.17 errors per 100 questions; paper, 0.73 errors per 100 questions; P-value ≤0.001), and a lower monetary cost per correctly entered question, compared with the pen-and-paper method. We found no marked difference in the average duration of the interview between methods (EQ, 5.4 minutes; paper, 5.6 minutes). ConclusionThis validation study suggests that the EQ may offer increased accuracy, similar interview duration, and increased cost-effectiveness compared with paper-based data collection methods. The APCDR EQ software is freely available (https://github.com/apcdr/questionnaire).

The association of the mitochondrial DNA OriB variant (16184–16193 polycytosine tract) with type 2 diabetes in Europid populations

Aims/hypothesisThe association between the mitochondrial DNA 16181–16193 polycytosine variant (known as the OriB variant as it maps to the OriB origin of replication) and type 2 diabetes has not been reliably characterised, with studies reporting conflicting results. We report a systematic review of published literature in Europid populations, new data from the Norfolk Diabetes Case–Control Study and a meta-analysis to help quantify this association.MethodsWe performed a systematic review identifying all the studies of the OriB variant and type 2 diabetes in Europid populations published before January 2013. We typed the OriB variant by pyrosequencing and sequencing in the Norfolk Diabetes Case–Control Study, which comprised 5,574 type 2 diabetes cases and 6,950 population-based controls.ResultsOverall, the meta-analysis included eight published studies plus the current new results, with a total of 11,794 type 2 diabetes cases and 14,465 controls. In the Norfolk Diabetes Case–Control Study, the OR for type 2 diabetes for the OriB variant was 1.09 (95% CI 0.96, 1.24). In a combined analysis, the relative risk for type 2 diabetes for the OriB variant in Europid populations was 1.10 (95% CI 1.01, 1.20; p = 0.03)Conclusions/interpretationResults from this systematic review and meta-analysis suggest that the mitochondrial DNA OriB variant is modestly associated with an increased risk of type 2 diabetes in Europid populations, with an effect size comparable with that of recently identified variants from genome-wide association studies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-2945-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes

MODY is believed to be caused by at least 13 different genes. Five rare mutations at the BLK locus, including only one non-synonymous p.A71T variant, were reported to segregate with diabetes in three MODY families. The p.A71T mutation was shown to abolish the enhancing effect of BLK on insulin content and secretion from pancreatic beta cell lines. Here, we reassessed the contribution of BLK to MODY and tested the effect of BLK-p.A71T on type 2 diabetes risk and variations in related traits. BLK was sequenced in 64 unelucidated MODY samples. The BLK-p.A71T variant was genotyped in a French type 2 diabetes case-control study including 4,901 cases and 4,280 controls, and in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) and SUVIMAX (Supplementation en Vitamines et Mineraux Antioxydants) population-based cohorts (n = 6,905). The variant effects were assessed by logistic and linear regression models. No rare non-synonymous BLK mutations were found in the MODY patients. The BLK p.A71T mutation was present in 52 normoglycaemic individuals, making it very unlikely that this loss-of-function mutation causes highly penetrant MODY. We found a nominal association between this variant and increased type 2 diabetes risk, with an enrichment of the mutation in the obese diabetic patients, although no significant association with BMI was identified. No mutation in BLK was found in our MODY cohort. From our findings, the BLK-p.A71T mutation may weakly influence type 2 diabetes risk in the context of obesity; however, this will require further validation.

An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference

A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians. We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case-control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies. In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95%CI 0.24-0.67) kg/m(2) per A-allele (P=3.0 × 10(-5) ) and with waist circumference was 0.88 (95% CI 0.36-1.41) cm per A-allele (P=0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95%CI) 1.18 (1.07-1.30); P=0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95%CI 1.14-1.31); P=1.07 × 10(-8) ] even after adjusting for BMI [1.18 (95%CI 1.10-1.27); P=1.02 × 10(-5) ] or waist circumference [1.18 (95%CI 1.10-1.27); P=3.97 × 10(-5) ]. The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.

Type 2 diabetes genetic association database manually curated for the study design and odds ratio

BackgroundThe prevalence of type 2 diabetes has reached epidemic proportions worldwide, and the incidence of life-threatening complications of diabetes through continued exposure of tissues to high glucose levels is increasing. Advances in genotyping technology have increased the scale and accuracy of the genotype data so that an association genetic study has expanded enormously. Consequently, it is difficult to search the published association data efficiently, and several databases on the association results have been constructed, but these databases have their limitations to researchers: some providing only genome-wide association data, some not focused on the association but more on the integrative data, and some are not user-friendly. In this study, a user-friend database of type 2 diabetes genetic association of manually curated information was constructed.DescriptionThe list of publications used in this study was collected from the HuGE Navigator, which is an online database of published genome epidemiology literature. Because type 2 diabetes genetic association database (T2DGADB) aims to provide specialized information on the genetic risk factors involved in the development of type 2 diabetes, 701 of the 1,771 publications in the type 2 Diabetes case-control study for the development of the disease were extracted.ConclusionsIn the database, the association results were grouped as either positive or negative. The gene and SNP names were replaced with gene symbols and rsSNP numbers, the association p-values were determined manually, and the results are displayed by graphs and tables. In addition, the study design in publications, such as the population type and size are described. This database can be used for research purposes, such as an association and functional study of type 2 diabetes related genes, and as a primary genetic resource to construct a diabetes risk test in the preparation of personalized medicine in the future.

Genetic Variant in HK1 Is Associated With a Proanemic State and A1C but Not Other Glycemic Control–Related Traits

OBJECTIVEA1C is widely considered the gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between A1C and rs7072268 within HK1 (encoding hexokinase 1), which catalyzes the first step of glycolysis. HK1 deficiency in erythrocytes (red blood cells [RBCs]) causes severe nonspherocytic hemolytic anemia in both humans and mice.RESEARCH DESIGN AND METHODSThe contribution of rs7072268 to A1C and the RBC-related traits was assessed in 6,953 nondiabetic European participants. We additionally analyzed the association with hematologic traits in 5,229 nondiabetic European individuals (in whom A1C was not measured) and 1,924 diabetic patients. Glucose control–related markers other than A1C were analyzed in 18,694 nondiabetic European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients.RESULTSOur study confirms a strong association between the rs7072268–T allele and increased A1C (β = 0.029%; P = 2.22 × 10−7). Surprisingly, despite adequate study power, rs7072268 showed no association with any other markers of glucose control (fasting- and 2-h post-OGTT–related parameters, n = 18,694). In contrast, rs7072268–T allele decreases hemoglobin levels (n = 13,416; β = −0.054 g/dl; P = 3.74 × 10−6) and hematocrit (n = 11,492; β = −0.13%; P = 2.26 × 10−4), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018).CONCLUSIONSHK1 variation, although strongly associated with A1C, does not seem to be involved in blood glucose control. Since HK1 rs7072268 is associated with reduced hemoglobin levels and favors anemia, we propose that HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in RBCs. These findings may have implications for type 2 diabetes diagnosis and clinical management because anemia is a frequent complication of the diabetes state.

Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations.

Mutations at the gene encoding wolframin (WFS1) cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. Thus, our aim was to replicate those associations in a northern Swedish case-control study of type 2 diabetes. We also performed a meta-analysis of published and previously unpublished data from Sweden, Finland and France, to obtain updated summary effect estimates. Four WFS1 SNPs (rs10010131, rs6446482, rs752854 and rs734312 [H611R]) were genotyped in a type 2 diabetes case-control study (n = 1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex and BMI. We then performed a meta-analysis of 11 studies of type 2 diabetes, comprising up to 14,139 patients and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants. In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk [odds ratio (OR) 0.85, 95% CI 0.75-0.96, p=0.010]. Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent replication studies for SNP rs10010131 and correlated variants showed evidence for statistical association (OR 0.87, 95% CI 0.82-0.93, p=4.5 x 10(-5)). In an updated meta-analysis of all 11 studies, strong evidence of statistical association was also observed (OR 0.89, 95% CI 0.86-0.92; p=4.9 x 10(-11)). In this study of WFS1 variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and the risk of type 2 diabetes.

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes

Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PPARGC1A) is a transcriptional co-activator with a central role in energy expenditure and glucose metabolism. Several studies have suggested that the common PPARGC1A polymorphism Gly482Ser may be associated with risk of type 2 diabetes, with conflicting results. To clarify the role of Gly482Ser in type 2 diabetes and related human metabolic phenotypes we genotyped this polymorphism in a case-control study and performed a meta-analysis of relevant published data. Gly482Ser was genotyped in a type 2 diabetes case-control study (N=1,096) using MassArray technology. A literature search revealed publications that examined Gly482Ser for association with type 2 diabetes and related metabolic phenotypes. Meta-analysis of the current study and relevant published data was undertaken. In the pooled meta-analysis, including data from this study and seven published reports (3,718 cases, 4,818 controls), there was evidence of between-study heterogeneity (p<0.1). In the fixed-effects meta-analysis, the pooled odds ratio for risk of type 2 diabetes per Ser482 allele was 1.07 (95% CI 1.00-1.15, p=0.044). Elimination of one of the studies from the meta-analysis gave a summary odds ratio of 1.11 (95% CI 1.04-1.20, p=0.004), with no between-study heterogeneity (p=0.475). For quantitative metabolic traits in normoglycaemic subjects, we also found significant between-study heterogeneity. However, no significant association was observed between Gly482Ser and BMI, fasting glucose or fasting insulin. This meta-analysis of data from the current and published studies supports a modest role for the Gly482Ser PPARGC1A variant in type 2 diabetes risk.

Mutation screening and association of human retinoid X receptor γ variation with lipid levels in familial type 2 diabetes

Both type 2 diabetes (T2DM) and familial combined hyperlipidemia have been mapped to human chromosome 1q21–q24. This region includes the retinoid X receptor γ (RXR γ) , which is a strong candidate for both glucose and lipid metabolism. Retinoid X receptors form heterodimers with a variety of nuclear receptors, including peroxisome-proliferator-activated receptors α and γ ( PPARα and PPARγ), and are synergistic targets for drugs that alter glucose and lipid metabolism. We hypothesized that RXRγ variation could explain the linkage of diabetes and lipid disorders to this region. We screened each of the 10 exons, the flanking intronic sequences, the 3 ′ untranslated region, and the 5 ′ flanking region. We identified 14 variants, none of which altered the coding sequence. Of the 10 variants examined in a diabetes case-control study, three showed nominal ( p<0.05) associations with T2DM. We subsequently typed four variants in all members of the 63 multiplex families used in our previous linkage analysis. No individual variant showed excess transmission to offspring with T2DM using a transmission disequilibrium test and only a single rare haplotype showed evidence of an association with T2DM. Likewise, neither individual variants nor haplotypes were associated with either fasting or post-challenge glucose in non-diabetic subjects. In contrast, three of the four variants were associated with fasting free fatty acid (FFA) levels ( p=0.024–0.00044) and two variants were associated with triglyceride levels ( p<0.05). These findings were supported by the association of several haplotypes with FFA and triglyceride levels. RXRγ haplotypes were also associated with several measures of pancreatic β-cell function, consistent with the proposed role of lipid metabolism in insulin secretion. These data suggest that RXRγ may contribute to disordered lipid metabolism in members of familial T2DM kindreds, but this gene is unlikely to explain the linkage of T2DM with this region.