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Background Diabetes (regardless of type) and obesity are associated with a range of musculoskeletal disorders. The causal mechanisms driving these associations are unknown for many upper limb pathologies. We used genetic techniques to test the causal link between glycemia, obesity and musculoskeletal conditions. Methods In the UK Biobank's unrelated European cohort (N  = 379 708) we performed mendelian randomisation (MR) analyses to test for a causal effect of long-term high glycaemia and adiposity on four musculoskeletal pathologies: frozen shoulder, Dupuytren's disease, carpal tunnel syndrome and trigger finger. We also performed single-gene MR using rare variants in the GCK gene. Results Using MR, we found evidence that long-term high glycaemia has a causal role in the aetiology of upper limb conditions. A 10-mmol/mol increase in genetically predicted haemoglobin A1C (HbA1c) was associated with frozen shoulder: odds ratio (OR) = 1.50 [95% confidence interval (CI), 1.20–1.88], Dupuytren's disease: OR = 1.17 (95% CI, 1.01–1.35), trigger finger: OR = 1.30 (95% CI, 1.09–1.55) and carpal tunnel syndrome: OR = 1.20 (95% CI, 1.09–1.33). Carriers of GCK mutations have increased odds of frozen shoulder: OR = 7.16 (95% CI, 2.93–17.51) and carpal tunnel syndrome: OR = 2.86 (95% CI, 1.50–5.44) but not Dupuytren's disease or trigger finger. We found evidence that an increase in genetically predicted body mass index (BMI) of 5 kg/m2 was associated with carpal tunnel syndrome: OR = 1.13 (95% CI, 1.10–1.16) and associated negatively with Dupuytren's disease: OR = 0.94 (95% CI, 0.90–0.98), but no evidence of association with frozen shoulder or trigger finger. Trigger finger (OR 1.96 (95% CI, 1.42–2.69) P  =   3.6e-05) and carpal tunnel syndrome [OR 1.63 (95% CI, 1.36–1.95) P  =   8.5e-08] are associated with genetically predicted unfavourable adiposity increase of one standard deviation of body fat. Conclusions Our study consistently demonstrates a causal role of long-term high glycaemia in the aetiology of upper limb musculoskeletal conditions. Clinicians treating diabetes patients should be aware of these complications in clinic, specifically those managing the care of GCK mutation carriers. Upper limb musculoskeletal conditions should be considered diabetes complications. [ABSTRACT FROM AUTHOR]

ONECUT1 (also known as HNF6) is a transcription factor involved in pancreatic development and β-cell function. Recently, biallelic variants in ONECUT1 were reported as a cause of neonatal diabetes mellitus (NDM) in two subjects, and missense monoallelic variants were associated with type 2 diabetes and possibly maturity-onset diabetes of the young (MODY). Here we examine the role of ONECUT1 variants in NDM, MODY, and type 2 diabetes in large international cohorts of subjects with monogenic diabetes and >400,000 subjects from UK Biobank. We identified a biallelic frameshift ONECUT1 variant as the cause of NDM in one individual. However, we found no enrichment of missense or null ONECUT1 variants among 484 individuals clinically suspected of MODY, in whom all known genes had been excluded. Finally, using a rare variant burden test in the UK Biobank European cohort, we identified a significant association between heterozygous ONECUT1 null variants and type 2 diabetes (P = 0.006) but did not find an association between missense variants and type 2 diabetes. Our results confirm biallelic ONECUT1 variants as a cause of NDM and highlight monoallelic null variants as a risk factor for type 2 diabetes. These findings confirm the critical role of ONECUT1 in human β-cell function. Article Highlights: We confirmed homozygous ONECUT1 variants as causative for neonatal diabetes with the identification of a third case. Rare heterozygous ONECUT1 variants were not enriched in a cohort of 484 individuals clinically suspected of having maturity-onset diabetes of the young. Heterozygous null ONECUT1 variants are significantly associated with type 2 diabetes in the UK Biobank European population. No association was observed between heterozygous ONECUT1 missense variants and type 2 diabetes in UK Biobank. [ABSTRACT FROM AUTHOR]

Objective: Precision medicine requires reliable identification of variation in patient-level outcomes with different available treatments, often termed treatment effect heterogeneity. We aimed to evaluate the comparative utility of individualized treatment selection strategies based on predicted individual-level treatment effects from a causal forest machine learning algorithm and a penalized regression model. Methods: Cohort study characterizing individual-level glucose-lowering response (6 month reduction in HbA1c) in people with type 2 diabetes initiating SGLT2-inhibitor or DPP4-inhibitor therapy. Model development set comprised 1,428 participants in the CANTATA-D and CANTATA-D2 randomised clinical trials of SGLT2-inhibitors versus DPP4-inhibitors. For external validation, calibration of observed versus predicted differences in HbA1c in patient strata defined by size of predicted HbA1c benefit was evaluated in 18,741 patients in UK primary care (Clinical Practice Research Datalink). Results: Heterogeneity in treatment effects was detected in clinical trial participants with both approaches (proportion predicted to have a benefit on SGLT2-inhibitor therapy over DPP4-inhibitor therapy: causal forest: 98.6%; penalized regression: 81.7%). In validation, calibration was good with penalized regression but sub-optimal with causal forest. A strata with an HbA1c benefit > 10 mmol/mol with SGLT2-inhibitors (3.7% of patients, observed benefit 11.0 mmol/mol [95%CI 8.0–14.0]) was identified using penalized regression but not causal forest, and a much larger strata with an HbA1c benefit 5–10 mmol with SGLT2-inhibitors was identified with penalized regression (regression: 20.9% of patients, observed benefit 7.8 mmol/mol (95%CI 6.7–8.9); causal forest 11.6%, observed benefit 8.7 mmol/mol (95%CI 7.4–10.1). Conclusions: Consistent with recent results for outcome prediction with clinical data, when evaluating treatment effect heterogeneity researchers should not rely on causal forest or other similar machine learning algorithms alone, and must compare outputs with standard regression, which in this evaluation was superior. [ABSTRACT FROM AUTHOR]

Objective: Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes. In 2009, >80% of U.K. cases were estimated to be misdiagnosed. Since then, there have been a number of initiatives to improve the awareness and detection of MODY, including education initiatives (Genetic Diabetes Nurse [GDN] project), the MODY probability calculator, and targeted next-generation sequencing (tNGS). We examined how the estimated prevalence of MODY and other forms of monogenic diabetes diagnosed outside the neonatal period has changed over time and how the initiatives have impacted case finding.Research Design and Methods: U.K. referrals for genetic testing for monogenic diabetes diagnosed >1 year of age from 1 January 1996 to 31 December 2019 were examined. Positive test rates were compared for referrals reporting GDN involvement/MODY calculator use with those that did not.Results: A diagnosis of monogenic diabetes was confirmed in 3,860 individuals, more than threefold higher than 2009 (1 January 1996 to 28 February 2009, n = 1,177). Median age at diagnosis in probands was 21 years. GDN involvement was reported in 21% of referrals; these referrals had a higher positive test rate than those without GDN involvement (32% vs. 23%, P < 0.001). MODY calculator usage was indicated in 74% of eligible referrals since 2014; these referrals had a higher positive test rate than those not using the calculator (33% vs. 25%, P = 0.001). Four hundred ten (10.6%) cases were identified through tNGS. Monogenic diabetes prevalence was estimated to be 248 cases/million (double that estimated in 2009 because of increased case finding).Conclusions: Since 2009, referral rates and case diagnosis have increased threefold. This is likely to be the consequence of tNGS, GDN education, and use of the MODY calculator. [ABSTRACT FROM AUTHOR]

Aim: To describe population‐level time trends in prescribing patterns of type 2 diabetes therapy, and in short‐term clinical outcomes (glycated haemoglobin [HbA1c], weight, blood pressure, hypoglycaemia and treatment discontinuation) after initiating new therapy. Materials and methods: We studied 81 532 people with type 2 diabetes initiating a first‐ to fourth‐line drug in primary care between 2010 and 2017 inclusive in United Kingdom electronic health records (Clinical Practice Research Datalink). Trends in new prescriptions and subsequent 6‐ and 12‐month adjusted changes in glycaemic response (reduction in HbA1c), weight, blood pressure and rates of hypoglycaemia and treatment discontinuation were examined. Results: Use of dipeptidyl peptidase‐4 inhibitors as second‐line therapy near doubled (41% of new prescriptions in 2017 vs. 22% in 2010), replacing sulphonylureas as the most common second‐line drug (29% in 2017 vs. 53% in 2010). Sodium‐glucose co‐transporter‐2 inhibitors, introduced in 2013, comprised 17% of new first‐ to fourth‐line prescriptions by 2017. First‐line use of metformin remained stable (91% of new prescriptions in 2017 vs. 91% in 2010). Over the study period there was little change in average glycaemic response and in the proportion of people discontinuing treatment. There was a modest reduction in weight after initiating second‐ and third‐line therapy (improvement in weight change 2017 vs. 2010 for second‐line therapy: −1.5 kg, 95% confidence interval [CI] −1.9, −1.1; P < 0.001), and a slight reduction in systolic blood pressure after initiating first‐, second‐ and third‐line therapy (improvement in systolic blood pressure change 2017 vs. 2010 range: −1.7 to −2.1 mmHg; all P < 0.001). Hypoglycaemia rates decreased over time with second‐line therapy (incidence rate ratio 0.94 per year, 95% CI 0.88, 1.00; P = 0.04), mirroring the decline in use of sulphonylureas. Conclusions: Recent changes in prescribing of therapy for people with type 2 diabetes have not led to a change in glycaemic response and have resulted in modest improvements in other population‐level short‐term clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight.Methods and Findings: We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g [95% CI -2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15-9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g [95% CI -44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121-236 g, p = 1.43 × 10-9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy.Conclusions: Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments. [ABSTRACT FROM AUTHOR]

OBJECTIVE Small studies using ultrasensitive C-peptide assays suggest endogenous insulin secretion is frequently detectable in patients with long-standing type 1 diabetes (T1D), but these studies do not use representative samples. We aimed to use the stimulated urine C-peptide-to-creatinine ratio (UCPCR) to assess C-peptide levels in a large cross-sectional, population-based study of patients with T1D. RESEARCH DESIGN AND METHODS We recruited 924 patients from primary and secondary care in two U.K. centers who had a clinical diagnosis of T1D, were under 30 years of age when they received a diagnosis, and had a diabetes duration of >5 years. The median age at diagnosis was 11 years (interquartile range 6-17 years), and the duration of diabetes was 19 years (11-27 years). All provided a home postmeal UCPCR, which was measured using a Roche electrochemiluminescence assay. RESULTS Eighty percent of patients (740 of 924 patients) had detectable endogenous C-peptide levels (UCPCR >0.001 nmol/mmol). Most patients (52%, 483 of 924 patients) had historically very low undetectable levels (UCPCR 0.0013-0.03 nmol/mmol); 8% of patients (70 of 924 patients) had a UCPCR ≥0.2 nmol/mmol, equivalent to serum levels associated with reduced complications and hypoglycemia. Absolute UCPCR levels fell with duration of disease. Age at diagnosis and duration of disease were independent predictors of C-peptide level in multivariate modeling. CONCLUSIONS This population-based study shows that the majority of long-duration T1D patients have detectable urine C-peptide levels. While the majority of patients are insulin microsecretors, some maintain clinically relevant endogenous insulin secretion for many years after the diagnosis of diabetes. Understanding this may lead to a better understanding of pathogenesis in T1D and open new possibilities for treatment. [ABSTRACT FROM AUTHOR]

Background The UK Biobank study provides a unique opportunity to study the causes and consequences of disease. We aimed to use the UK Biobank data to study the well-established, but poorly understood, association between low birthweight and type 2 diabetes.Methods We used logistic regression to calculate the odds ratio for participants’ risk of type 2 diabetes given a one standard deviation increase in birthweight. To test for an association between parental diabetes and birthweight, we performed linear regression of self-reported parental diabetes status against birthweight. We performed path and mediation analyses to test the hypothesis that birthweight partly mediates the association between parental diabetes and participant type 2 diabetes status.Results Of the UK Biobank participants, 277 261 reported their birthweight. Of 257 715 individuals of White ethnicity and singleton pregnancies, 6576 had type 2 diabetes, 19 478 reported maternal diabetes (but not paternal), 20 057 reported paternal diabetes (but not maternal) and 2754 participants reported both parents as having diabetes. Lower birthweight was associated with type 2 diabetes in the UK Biobank participants. A one kilogram increase in birthweight was associated with a lower risk of type 2 diabetes (odds ratio: 0.74; 95% CI: 0.71, 0.76; P = 2 × 10−57). Paternal diabetes was associated with lower birthweight (45 g lower; 95% CI: 36, 54; P = 2 × 10−23) relative to individuals with no parental diabetes. Maternal diabetes was associated with higher birthweight (59 g increase; 95% CI: 50, 68; P = 3 × 10−37). Participants’ lower birthweight was a mediator of the association between reported paternal diabetes and participants’ type 2 diabetes status, explaining 1.1% of the association, and participants’ higher birthweight was a mediator of the association between reported maternal diabetes and participants’ type 2 diabetes status, explaining 1.2% of the association.Conclusions Data from the UK Biobank provides the strongest evidence by far that paternal diabetes is associated with lower birthweight, whereas maternal diabetes is associated with increased birthweight. Our findings with paternal diabetes are consistent with a role for the same genetic factors influencing foetal growth and type 2 diabetes. [ABSTRACT FROM PUBLISHER]

OBJECTIVE--Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of low-frequency WFS1 variants in type 2 diabetes risk. RESEARCH DESIGN AND METHODS--For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between case and control subjects. RESULTS--Of 31 tagging SNPs, the strongest associated was the previously untested 3′ untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 x 10[sup -7] on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r[sup 2] = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency [MAF] <0.01) nonsynonymous variants between type 2 diabetic case and control subjects (P = 0.79). Two intermediate frequency (MAF 0.01-0.05) nonsynonymous changes also showed no statistical association with type 2 diabetes. CONCLUSIONS--We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing. Diabetes 59:741-746, 2010 [ABSTRACT FROM AUTHOR]

OBJECTIVE--Mutations in the HNF1A gene are the most common cause of maturity-onset diabetes of the young (MODY). There is a substantial variation in the age at diabetes diagnosis, even within families where diabetes is caused by the same mutation. We investigated the hypothesis that common polygenic variants that predispose to type 2 diabetes might account for the difference in age at diagnosis. RESEARCH DESIGN AND METHODS--Fifteen robustly associated type 2 diabetes variants were successfully genotyped in 410 individuals from 203 HNF1A-MODY families, from two study centers in the U.K. and Norway. We assessed their effect on the age at diagnosis both individually and in a combined genetic score by summing the number of type 2 diabetes risk alleles carried by each patient. RESULTS--We confirmed the effects of environmental and genetic factors known to modify the age at HNF1A-MODY diagnosis, namely intrauterine hyperglycemia (-5.1 years if present, P = 1.6 x 1010) and HNF1A mutation position (-5.2 years if at least two isoforms affected, P = 1.8 x 10-2). Additionally, our data showed strong effects of sex (females diagnosed 3.0 years earlier, P = 6.0 x 10-4) and age at study (0.3 years later diagnosis per year increase in age, P = 4.7 x 10-38). There were no strong individual single nucleotide polymorphism effects; however, in the combined genetic score model, each additional risk allele was associated with 0.35 years earlier diabetes diagnosis (P = 5.1 x 10-3). CONCLUSIONS--We show that type 2 diabetes risk variants of modest effect sizes reduce the age at diagnosis in HNF1A-MODY. This is one of the first studies to demonstrate that clinical characteristics of a monogenic disease can be modified by common polygenic variants. Diabetes 59:266-271, 2010 [ABSTRACT FROM AUTHOR]

OBJECTIVE--Single nucleotide polymorphisms (SNPs) in the P2 promoter region of HNF4A were originally shown to be associated with predisposition for type 2 diabetes in Finnish, Ashkenazi, and, more recently, Scandinavian populations, but they generated conflicting results in additional populations. We aimed to investigate whether data from a large-scale mapping approach would replicate this association in novel Ashkenazi samples and in U.K. populations and whether these data would allow us to refine the association signal. RESEARCH DESIGN AND METHODS--Using a dense linkage disequilibrium map of 20q, we selected SNPs from a 10-Mb interval centered on HNF4A. In a staged approach, we first typed 4,608 SNPs in case-control populations from four U.K. populations and an Ashkenazi population (n = 2,516). In phase 2, a subset of 763 SNPs was genotyped in 2,513 additional samples from the same populations. RESULTS--Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and type 2 diabetes in the Ashkenazim (n = 991; P < 1.6 x 10[sup -6]). Importantly, these associations are significant in a subset of Ashkenazi samples (n = 531) not previously tested for association with P2 SNPs (odds ratio [OR] ∼1.7; P < 0.002), thus providing replication within the Ashkenazim. In the U.K. populations, this association was not significant (n = 4,022; P > 0.5), and the estimate for the OR was much smaller (OR 1.04; [95%CI 0.91-1.19]). CONCLUSIONS--These data indicate that the risk conferred by HNF4A P2 is significantly different between U.K. and Ashkenazi populations (P < 0.00007), suggesting that the underlying causal variant remains unidentified. Interactions with other genetic or environmental factors may also contribute to this difference in risk between populations. Diabetes 57:3161-3165, 2008 [ABSTRACT FROM AUTHOR]

Obesity is a major health problem, and many family-based studies have suggested that it has a strong genetic basis. We performed a genome-wide quantitative trait linkage scan for loci influencing BMI in 573 pedigrees from the U.K. We identified genome-wide significant linkage (logarithm of odds = 3.74, between D10S208 and D10S196, genomewide P = 0.0186) on chromosome 10p. The size of our study population and the statistical significance of our findings provide substantial contributions to the body of evidence for a locus on chromosome 10p. We examined eight single nucleotide polymorphisms (SNPs) in GAD2, which maps to this linkage region, tagging the majority of variation in the gene, and observed marginally significant (0.01 < P < 0.05) associations between four common variants and BMI. However, these SNPs did not account for our evidence of linkage to BMI, and they did not replicate (in direction of effect) the previous associations. We therefore conclude that these SNPs are not the etiological variants underlying this locus. We cannot rule out the possibility that other untagged variations in GAD2 may, in part, be involved, but it is most likely that alternative gene(s) within the broad gene-rich region of linkage on 10p are responsible for variation in body mass and susceptibility to obesity. [ABSTRACT FROM AUTHOR]

Background: Birth weight is a composite of skeletal size and soft tissue. These components are likely to have different growth patterns. The aim of this paper is to investigate the association between established determinants of birth weight and these separate components. Methods: Weight, length, crown-rump, knee-heel, head circumference, arm circumference, and skinfold thicknesses were measured at birth in 699 healthy, term, UK babies recruited as part of the Exeter Family Study of Childhood Health. Corresponding measurements were taken on both parents. Principal components analysis with varimax rotation was used to reduce these measurements to two independent components each for mother, father and baby: one highly correlated with measures of fat, the other with skeletal size. Results: Gestational age was significantly related to skeletal size, in both boys and girls (r = 0.41 and 0.52), but not fat. Skeletal size at birth was also associated with parental skeletal size (maternal: r = 0.24 (boys), r = 0.39 (girls) ; paternal: r = 0.16 (boys), r = 0.25 (girls)), and maternal smoking (0.4 SD reduction in boys, 0.6 SD reduction in girls). Fat was associated with parity (first borns smaller by 0.45 SD in boys; 0.31 SD in girls), maternal glucose (r = 0.18 (boys); r = 0.27 (girls)) and maternal fat (r = 0.16 (boys); r = 0.36 (girls)). Conclusion: Principal components analysis with varimax rotation provides a useful method for reducing birth weight to two more meaningful components: skeletal size and fat. These components have different associations with known determinants of birth weight, suggesting fat and skeletal size may have different regulatory mechanisms, which would be important to consider when studying the associations of birth weight with later adult disease. [ABSTRACT FROM AUTHOR]

Background: Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO (KL) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population. Methods: We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring. Results: Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84-1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data. Conclusion: This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study. [ABSTRACT FROM AUTHOR]

Additional information on genetic susceptibility effects relevant to type 2 diabetes pathogenesis can be extracted from existing genome scans by extending examination to related phenotypes such as age at disease onset. In this study, we report the reanalysis of data from 573 U.K. sibships ascertained for multiplex type 2 diabetes, using age at onset (assessed by the proxy measure of age at diagnosis) as the phenotype of interest. Genome-wide evidence for linkage to age at diagnosis was evaluated using both variance components and Haseman-Elston (HECOM) regression approaches, with extensive simulations to derive empirical significance values. There was broad agreement across analyses with six regions of interest (logarithm of odds [LOD] >/==" BORDER="0">1.18) identified on chromosomes 1qter, 4p15-4q12, 5p15, 12p13-12q13, 12q24, and 14q12-14q21. The strongest empirically "suggestive" evidence for linkage comes from regions on chromosome 12. The first region (12p13-12q13), peaking at D12S310 (variance components LOD [LOD(VC)] = 2.08, empirical pointwise P = 0.0007; HECOM LOD [LOD(HECOM)] = 2.58, P = 0.0010) seems to be novel. The second (12q24) peaking between D12S324 and D12S1659 (LOD(VC) = 1.87, P = 0.0016; LOD(HECOM) = 1.93, P = 0.0027) overlaps a region showing substantial prior evidence for diabetes linkage. These data provide additional evidence that genes mapping to these chromosomal regions are involved in the susceptibility to, and/or development of, type 2 diabetes. [ABSTRACT FROM AUTHOR]

Summary objective To assess the association of polymorphisms in the aromatase gene (CYP19 ) and on the Y-chromosome, with adult height and insulin resistance in a UK Caucasian population, after a recent report indicated these variants explain 4 cm of adult male height variation. patients and design We performed an association study using 917 healthy UK Caucasian subjects from the Exeter Family Study, an ongoing consecutive-birth cohort. Our study had > 85% (95% for the CYP19 variant; 85% for the Y variant) power to detect the association suggested by the previous study. measurements Subjects’CYP19 genotype were determined using tetra-primer PCR, and the Y-chromosome variant genotype was identified using a restriction fragment length polymorphism (RFLP) method. Trained research nurses were responsible for measurement of height. Fasting insulin concentration was determined by an immunoenzymometric assay. results We did not find any evidence for an effect of the CYP19 polymorphism or Y-RFLP on adult height (P > 0·83 for both variants). In addition, there was no evidence for an effect on insulin resistance in a subset of 416 subjects (P > 0·46). conclusion We have not confirmed the initial observation in a larger replication cohort. Our results highlight the importance of replicating initial results from genetic association studies. [ABSTRACT FROM AUTHOR]

Variation in the calpain-10 gene (CAPN10) has been shown to be associated with type 2 diabetes in Mexican-Americans and in at least three Northern European populations. Studies in nondiabetic Pima Indians showed that one of the at-risk DNA polymorphisms, single-nucleotide polymorphism (SNP)-43, in CAPN10 was associated with insulin resistance, and individuals with the G/G-genotype had significantly higher fasting plasma glucose and 2-h insulin concentrations after a 75-g oral glucose tolerance test (OGTT). We have examined the effect of variation in CAPN10 on plasma glucose and insulin levels in a group of 285 nondiabetic British subjects after a 75-g OGTT. The results showed that subjects with G/G genotype at SNP-43 had higher 2-h plasma glucose levels than the combined G/A + A/A group (P = 0.05). We also examined the SNP-43, -19, and -63 haplotype combination 112/121, which is associated with an approximately threefold increased risk of diabetes. Subjects with the 112/121 haplotype combination (n = 29) had increased fasting (P = 0.004) and 2-h plasma glucose levels (P = 0.003) compared with the rest of the study population after correction for age, sex, and BMI. The 112/121 haplotype combination was also associated with a marked decrease in the insulin secretory response, adjusted for the level of insulin resistance (P = 0.002). We conclude that genetic variation in the CAPN10 gene influences blood glucose levels in nondiabetic British subjects and that this is due, at least in part, to the effects of calpain-10 on the early insulin secretory response. [ABSTRACT FROM AUTHOR]

Investigates the role of hepatocyte nuclear factor (HNF) 1beta gene in maturity-onset diabetes of the young (MODY) families recruited through referrals from hospital-based diabetologists in Great Britain. Examination of mutations in the HNF-1beta gene by specific screening for the R177X mutation; Autosomal dominant inheritance.

Background: It is unclear what to do when people with type 2 diabetes have had no or a limited glycemic response to a recently introduced medication. Intra-individual HbA1c variability can obscure true response. Some guidelines suggest stopping apparently ineffective therapy, but no studies have addressed this issue.Methods: In a retrospective cohort analysis using the UK Clinical Practice Research Datalink (CPRD), we assessed the outcome of 55,530 patients with type 2 diabetes starting their second or third non-insulin glucose-lowering medication, with a baseline HbA1c > 58 mmol/mol (7.5%). For those with no HbA1c improvement or a limited response at 6 months (HbA1c fall < 5.5 mmol/mol [0.5%]), we compared HbA1c 12 months later in those who continued their treatment unchanged, switched to new treatment, or added new treatment.Results: An increase or a limited reduction in HbA1c was common, occurring in 21.9% (12,168/55,230), who had a mean HbA1c increase of 2.5 mmol/mol (0.2%). After this limited response, continuing therapy was more frequent (n = 9308; 74%) than switching (n = 1177; 9%) or adding (n = 2163; 17%). Twelve months later, in those who switched medication, HbA1c fell (- 6.8 mmol/mol [- 0.6%], 95%CI - 7.7, - 6.0) only slightly more than those who continued unchanged (- 5.1 mmol/mol [- 0.5%], 95%CI - 5.5, - 4.8). Adding another new therapy was associated with a substantially better reduction (- 12.4 mmol/mol [- 1.1%], 95%CI - 13.1, - 11.7). Propensity score-matched subgroups demonstrated similar results.Conclusions: Where glucose-lowering therapy does not appear effective on initial HbA1c testing, changing agents does not improve glycemic control. The initial agent should be continued with another therapy added. [ABSTRACT FROM AUTHOR]

The BAIR consortium has been formed to provide insight into the biological processes underlying insulin resistance through multidisciplinary research combining various genomic/proteomic/metabolomic approaches in animal models, followed by haman genetic analysis. Based on previously described associations, function and on BAIR biological data, we selected 11 candidate genes (ARNT; RBP4; HIF1a; EIF2S1; AKT1; ONECUT1; RPS6KB1; TRB3; FOXA2; PCK1; FOXO3A) for investigation. Pairwise tags (r²>0.8) spanning these genes were selected based on HapMap phase II CEU data to exhaustively capture common variation (MAF>0.05). 103 SNPs were genotyped in 5,602 samples (935 UKT2D, 1927 UK-controls, 926 French T2D, 934 French obese and 880 French controls) by iPLEX & SNPlex methods. Single-point analyses on 92 SNPs were carried out after stringent quality control. Coverage of common variation remained high (74%-100% per gene). There was no significant association with T2D or obesity (at the p=0.01 level) in 9 of the strong candidate genes examined. In the UK population, rs11908628 of PCK1 (encoding phosphoenolpyruvate carboxykinase 1, the main control point for the regulation of gluconeogenesis) was found to be protective against diabetes (MAFs 2.7% v 4.3%, OR(95%CIs): 0.62 (0.44-0.86); p=0.003 additive). Mantel-Haenszel meta-analysis of rs11908628 across the UK and French T2D samples provided additional support for this finding (p=0.002), although further investigation, given low MAFs, is warranted. When comparing genotypes between T2D cases and controls in the French population, 2 independent associations were seen in RPS6KB1: rs180535 (MAFs 18% v 15%; OR 1.29 (1.07 -1.55); p=0.006) and rs180531 (24% v 28%; OR 0.81 (0.69-0.95) p=0.008) (r²=0.06 in controls). RPS6KB1 codes for ribosomal protein S6 kinase 70KD 1, which negatively regulates insulin signalling. Interestingly, rs180531 (23% v 28%; OR 0.80 (0.69-0.94) p=0.005) was also associated with protection against obesity in the French. In conclusion, our genetic data suggest modest effects of the BAIR insulin resistance candidates PEPCK and S6K1 gene variation in UK (T2D) and French (T2D and obese) samples, results that require replication in additional populations. [ABSTRACT FROM AUTHOR]

The capacity to undertake systematic surveys of common variation through genome-wide association analysis has the potential to deliver substantial insights into type 2 diabetes (T2D) pathogenesis. We recently completed genotyping of 1954 T2D cases (enriched for positive family history/early onset) and 2922 population-based controls (all UK origin) on the Affymetrix 500k chip as part of the Wellcome Trust Case-Control Consortium. The preliminary analyses reported here are based on ∼309,000 SNPs with exemplary quality control and minor allele frequency (MAF)>5% [estimated to provide ∼60% coverage of CEU HapMap (MAF>5%, pairwise, r²>0.8)]. Variants within TCF7L2 emerge as the strongest cluster of susceptibility variants (12 SNPs, best = rs7901695, p=9.9x 10[sup -13]), but we find an additional 5 signals achieving nominal genome-wide significance with additive model p<6x10[sup -6] (controlling the false discovery rate at 0.05). These signals (located on chromosomes 1, 2, 6, 12 and 16) include a cluster of 5 SNPs with p< 10[sup -4] at ∼20.8Mbp on chr6, in a region including the CDK5 regulatory subunit associated protein 1-like 1 gene (CDKAL1) [for example, rs9465871, OR(95%CIs) for allele T (MAF∼80%) dominance: 0.51(0.37-0.70), exact p=1x10[sup -5]]. Extensive replication studies in 3073 T2D cases and 3879 controls (0.70(0.53-0.92), exact p=0.005) and meta-analysis across all ∼11800 subjects (0.61 (0.49-0.75), exact p=5.7x 10[sup -7]) provide supporting evidence for this finding. Haplotype-based analyses across a 2Mb region surrounding rs9465871 show no additional signal. Based on HapMap CEU data, rs9465871 is in perfect LD with several other intronic variants within CDKAL1; we have thus far covered ∼60% of common variation in the region (r²>0.8). Whilst further replication studies and fine-mapping will be required to refine the allelic architecture of this locus, these findings provide strong preliminary evidence that the CDKAL1 region harbours a novel locus affecting T2D risk. [ABSTRACT FROM AUTHOR]

The insulin gene is a strong candidate for a role in type 2 diabetes susceptibility. Both the VNTR minisatellite 5′ to the gene, and the -23HphI variant, with which it is in strong LD in non-African populations, are thought to have direct functional effects on insulin expression and splicing; and the relationship between class I VNTR alleles and T1D susceptibility is established. However, small-scale case-control and family-based studies associating possession of the longer class III VNTR alleles (and/or the T at -23HphI) with T2D have not been substantiated in recent larger studies. We typed 3 SNPs which tag major haplotype groups across INS, [rs689 (-23HphI), rs3842755 (+1404Fnu4HI) and rs2000993 (+3580MspI)] in a total of 2022 UK T2D cases (enriched for family history and early onset) and 2480 UK population controls, plus 387 UK parent-offspring triads. Single-point analyses revealed a significant association between the -23T (tagging the VNTR class III) allele and T2D risk (allele frequencies in cases and controls: 31.5% v. 28.9%; OR 1.13 (1.03-1.24); p=0.007 additive). There was a weaker association with the + 1404T allele (denoting the IIIA subclass) (23.9% v. 22.0%; OR 1.11 (1.00-1.23); p=0.04), but this was not independent of the -23T finding. There was marginal evidence for excess transmission of the -23T (class III allele) from heterozygous parents to T2D offspring (125 v.99, p=2.04 one-sided) extending an earlier report which featured ∼37% of this trio sample. A marginally significant parent of origin effect was observed for paternal overtransmission of the associated allele (52 v.32, p=0.03) Haplotype analyses did not contribute additional information. In summary, these findings are consistent with the hypothesis that individuals carrying the class III VNTR and -23T alleles are at modestly-increased risk (OR∼1.10) of developing T2D. The magnitude and direction of effect are consistent with the estimates from previous association studies and the known functional consequences of these alleles. [ABSTRACT FROM AUTHOR]

The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A , HNF4A , and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%–97%). We highlight that pathogenic variants in HNF1A , HNF4A , and GCK are not ultra-rare in the population. For HNF1A and HNF4A , we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list. The prevalence of pathogenic variants in common MODY-associated genes are ∼1:1,500 in the population. The penetrance of pathogenic HNF1A and HNF4A variants, but not of GCK variants, is substantially lower when found incidentally. Our findings are important for incidental reporting of pathogenic variants in MODY and other monogenic disorders. [ABSTRACT FROM AUTHOR]

Determines the prevalence of cysteine at codon 282 (C282Y) mutation among patients with type 2 diabetes. The genetic susceptibility to haemochromatosis; Results of a test conducted in England.

Aims/hypothesis: Screening programmes can detect cases of undiagnosed diabetes earlier than symptomatic or incidental diagnosis. However, the improvement in time to diagnosis achieved by screening programmes compared with routine clinical care is unclear. We aimed to use the UK Biobank population-based study to provide the first population-based estimate of the reduction in time to diabetes diagnosis that could be achieved by HbA 1c -based screening in middle-aged adults., Methods: We studied UK Biobank participants aged 40-70 years with HbA 1c measured at enrolment (but not fed back to participants/clinicians) and linked primary and secondary healthcare data (n=179,923) and identified those with a pre-existing diabetes diagnosis (n=13,077, 7.3%). Among the remaining participants (n=166,846) without a diabetes diagnosis, we used an elevated enrolment HbA 1c level (≥48 mmol/mol [≥6.5%]) to identify those with undiagnosed diabetes. For this group, we used Kaplan-Meier analysis to assess the time between enrolment HbA 1c measurement and subsequent clinical diabetes diagnosis up to 10 years, and Cox regression to identify clinical factors associated with delayed diabetes diagnosis., Results: In total, 1.0% (1703/166,846) of participants without a diabetes diagnosis had undiagnosed diabetes based on calibrated HbA 1c levels at UK Biobank enrolment, with a median HbA 1c level of 51.3 mmol/mol (IQR 49.1-57.2) (6.8% [6.6-7.4]). These participants represented an additional 13.0% of diabetes cases in the study population relative to the 13,077 participants with a diabetes diagnosis. The median time to clinical diagnosis for those with undiagnosed diabetes was 2.2 years, with a median HbA 1c at clinical diagnosis of 58.2 mmol/mol (IQR 51.0-80.0) (7.5% [6.8-9.5]). Female participants with lower HbA 1c and BMI measurements at enrolment experienced the longest delay to clinical diagnosis., Conclusions/interpretation: Our population-based study shows that HbA 1c screening in adults aged 40-70 years can reduce the time to diabetes diagnosis by a median of 2.2 years compared with routine clinical care. The findings support the use of HbA 1c screening to reduce the time for which individuals are living with undiagnosed diabetes., (© 2022. The Author(s).)

Aims/hypothesis: Current clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing., Methods: We conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity)., Results: Thirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA 1c  ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases., Conclusions/interpretation: Recessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria., (© 2021. The Author(s).)

Objective: To evaluate the association between metformin use and anemia risk in type 2 diabetes, and the time-course for this, in a randomized controlled trial (RCT) and real-world population data., Research Design and Methods: Anemia was defined as a hemoglobin measure of <11 g/dL. In the RCTs A Diabetes Outcome Progression Trial (ADOPT; n = 3,967) and UK Prospective Diabetes Study (UKPDS; n = 1,473), logistic regression was used to model anemia risk and nonlinear mixed models for change in hematological parameters. In the observational Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) population ( n = 3,485), discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk., Results: In ADOPT, compared with sulfonylureas, the odds ratio (OR) (95% CI) for anemia was 1.93 (1.10, 3.38) for metformin and 4.18 (2.50, 7.00) for thiazolidinediones. In UKPDS, compared with diet, the OR (95% CI) was 3.40 (1.98, 5.83) for metformin, 0.96 (0.57, 1.62) for sulfonylureas, and 1.08 (0.62, 1.87) for insulin. In ADOPT, hemoglobin and hematocrit dropped after metformin initiation by 6 months, with no further decrease after 3 years. In UKPDS, hemoglobin fell by 3 years in the metformin group compared with other treatments. At years 6 and 9, hemoglobin was reduced in all treatment groups, with no greater difference seen in the metformin group. In GoDARTS, each 1 g/day of metformin use was associated with a 2% higher annual risk of anemia., Conclusions: Metformin use is associated with early risk of anemia in individuals with type 2 diabetes, a finding consistent across two RCTs and replicated in one real-world study. The mechanism for this early fall in hemoglobin is uncertain, but given the time course, is unlikely to be due to vitamin B 12 deficiency alone., (© 2020 by the American Diabetes Association.)

Aims: Predicting likely durability of glucose-lowering therapies for people with type 2 diabetes (T2D) could help inform individualised therapeutic choices., Methods: We used data from UKPDS patients with newly-diagnosed T2D randomised to first-line glucose-lowering monotherapy with chlorpropamide-glibenclamide-basal insulin or metformin. In 2339 participants who achieved one-year HbA 1c values <7.5% (<59 mmol/mol)-we assessed relationships between one-year characteristics and time to monotherapy-failure (HbA 1c  ≥ 7.5% or requiring second-line therapy). Model validation was performed using bootstrap sampling., Results: Follow-up was median (IQR) 11.0 (8.0-14.0) years. Monotherapy-failure occurred in 72%-82%-75% and 79% for those randomised to chlorpropamide-glibenclamide-basal insulin or metformin respectively-after median 4.5 (3.0-6.6)-3.7 (2.6-5.6)-4.2 (2.7-6.5) and 3.8 (2.6- 5.2) years. Time-to-monotherapy-failure was predicted primarily by HbA 1c and BMI values-with other risk factors varying by type of monotherapy-with predictions to within ±2.5 years for 55%-60%-56% and 57% of the chlorpropamide-glibenclamide-basal insulin and metformin monotherapy cohorts respectively., Conclusions: Post one-year glycaemic durability can be predicted robustly in individuals with newly-diagnosed T2D who achieve HbA 1c values  < 7.5% one year after commencing traditional monotherapies. Such information could be used to help guide glycaemic management for individual patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Raised albumin-creatinine ratio (ACR) is an indicator of microvascular damage and renal disease. We aimed to identify genetic variants associated with raised ACR and study the implications of carrying multiple ACR-raising alleles with metabolic and vascular-related disease. We performed a genome-wide association study of ACR using 437 027 individuals from the UK Biobank in the discovery phase, 54 527 more than previous studies, and followed up our findings in independent studies. We identified 62 independent associations with ACR across 56 loci (P < 5 × 10-8), of which 20 were not previously reported. Pathway analyses and the identification of 20 of the 62 variants (at r2 > 0.8) coinciding with signals for at least 16 related metabolic and vascular traits, suggested multiple pathways leading to raised ACR levels. After excluding variants at the CUBN locus, known to alter ACR via effects on renal absorption, an ACR genetic risk score was associated with a higher risk of hypertension, and less strongly, type 2 diabetes and stroke. For some rare genotype combinations at the CUBN locus, most individuals had ACR levels above the microalbuminuria clinical threshold. Contrary to our hypothesis, individuals carrying more CUBN ACR-raising alleles, and above the clinical threshold, had a higher frequency of vascular disease. The CUBN allele effects on ACR were twice as strong in people with diabetes-a result robust to an optimization-algorithm approach to simulating interactions, validating previously reported gene-diabetes interactions (P ≤ 4 × 10-5). In conclusion, a variety of genetic mechanisms and traits contribute to variation in ACR., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as "clinically relevant" variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM&#95;175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Vitamin B12 and folate are critical micronutrients needed to support the increased metabolic demands of pregnancy. Recent studies from India have suggested that low vitamin B12 and folate concentrations in pregnancy are associated with increased obesity; however differences in diet, antenatal vitamin supplementation, and socioeconomic status may limit the generalisability of these findings. We aimed to explore the cross-sectional relationship of circulating serum vitamin B12 and folate at 28 weeks' gestation with maternal adiposity and related biochemical markers in a white non diabetic UK obstetric cohort., Methods: Anthropometry and biochemistry data was available on 995 women recruited at 28 weeks gestation to the Exeter Family Study of Childhood Health. Associations between B12 and folate with maternal BMI and other obesity-related biochemical factors (HOMA-R, fasting glucose, triglycerides, HDL and AST) were explored using regression analysis, adjusting for potential confounders (socioeconomic status, vegetarian diet, vitamin supplementation, parity, haemodilution (haematocrit))., Results: Higher 28 week BMI was associated with lower circulating vitamin B12 (r = -0.25; P<0.001) and folate (r = -0.15; P<0.001). In multiple regression analysis higher 28 week BMI remained an independent predictor of lower circulating B12 (β (95% CI) = -0.59 (-0.74, -0.44) i.e. for every 1% increase in BMI there was a 0.6% decrease in circulating B12). Other markers of adiposity/body fat metabolism (HOMA-R, triglycerides and AST) were also independently associated with circulating B12. In a similar multiple regression AST was the only independent obesity-related marker associated with serum folate (β (95% CI) = 0.16 (0.21, 0.51))., Conclusion: In conclusion, our study has replicated the previous Indian findings of associations between lower serum B12 and higher obesity and insulin resistance during pregnancy in a non-diabetic White British population. These findings may have important implications for fetal and maternal health in obese pregnancies.

Background: Reduced growth during infancy is associated with adult insulin resistance. In a UK Caucasian cohort, the CSH1.01 microsatellite polymorphism in the growth hormone-chorionic somatomammotropin hormone gene cluster was recently associated with increases in adult fasting insulin of approximately 23 pmol/l for TT homozygote males compared to D1D1 or D2D2 homozygotes (P = 0.001 and 0.009; n = 206 and 92, respectively), but not for females. TT males additionally had a 547-g lower weight at 1 year (n = 270; P = 0.008) than D2D2 males. We sought to replicate these data in healthy UK Caucasian subjects. We genotyped 1396 subjects (fathers, mothers and children) from a consecutive birth study for the CSH1.01 marker and analysed genotypes for association with 1-year weight in boys and fasting insulin in fathers., Results: We found no evidence for association of CSH1.01 genotype with adult male fasting insulin concentrations (TT/D1D1 P = 0.38; TT/D2D2 P = 0.18) or weight at 1 year in boys (TT/D1D1 P = 0.76; TT/D2D2 P = 0.85). For fasting insulin, our data can exclude the previously observed effect sizes as the 95 % confidence intervals for the differences observed in our study exclude increases in fasting insulin of 9.0 and 12.6 pmol/l for TT relative to D1D1 and D2D2 homozygotes, respectively. Whilst we have fewer data on boys' 1-year weight than the original study, our data can exclude a reduction in 1-year weight greater than 557 g for TT relative to D2D2 homozygotes., Conclusion: We have not found association of the CSH1.01 genotype with fasting insulin or weight at 1 year. We conclude that the original study is likely to have over-estimated the effect size for fasting insulin, or that the difference in results reflects the younger age of subjects in this study relative to those in the previous study.

Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) is an inhibitor of insulin-induced activation of the insulin receptor. There is strong evidence from several previous studies that a common coding variant of ENPP1 (K121Q) and a three-marker haplotype (Q121, IVS20delT-11, and G+1044TGA) are associated with type 2 diabetes and obesity. We examined the impact of ENPP1 variation on type 2 diabetes and obesity in a large U.K. genetic association study. We genotyped the three previously associated polymorphisms in 2,363 type 2 diabetic case and 4,045 control subjects, as well as 1,681 subjects from 529 type 2 diabetic families. We used the same subjects for morbid and moderate obesity association studies. For type 2 diabetes, moderate and morbid obesity, and for both the Q121 and three-marker haplotype, our results exclude with >95% confidence the effect sizes from previous studies (Q121 allele: odds ratio 1.02 [95% CI 0.93-1.12], P = 0.61; 1.00 [0.85-1.18], P = 0.99; and 0.92 [0.70-1.20], P = 0.41; three-marker haplotype: 1.10 [0.96-1.26], P = 0.17; 0.97 [0.77-1.23], P = 0.81; and 0.86 [0.57-1.30], P = 0.46 for type 2 diabetes, moderate, and morbid obesity, respectively). A K121Q type 2 diabetes meta-analysis of all previously published studies remained significant after the inclusion of this study (1.25 [1.10-1.43], P = 0.0007), although there was some evidence of publication bias. In conclusion, we find no evidence that previously associated variants of ENPP1 are associated with type 2 diabetes or obesity in the U.K. population.

Background: The APOA5 gene variants, -1131T>C and S19W, are associated with altered triglyceride concentrations in studies of subjects of Caucasian and East Asian descent. There are few studies of these variants in South Asians. We investigated whether the two APOA5 variants also show similar association with various lipid parameters in Indian population as in the UK white subjects., Methods: We genotyped 557 Indian adults from Pune, India, and 237 UK white adults for -1131T>C and S19W variants in the APOA5 gene, compared their allelic and genotype frequency and determined their association with fasting serum triglycerides, total cholesterol, HDL and LDL cholesterol levels using univariate general linear analysis. APOC3 SstI polymorphism was also analyzed in 175 Pune Indian subjects for analysis of linkage disequilibrium with the APOA5 variants., Results: The APOA5 -1131C allele was more prevalent in Indians from Pune (Pune Indians) compared to UK white subjects (allele frequency 20% vs. 4%, p = 0.00001), whereas the 19W allele was less prevalent (3% vs. 6% p = 0.0015). Patterns of linkage disequilibrium between the two variants were similar between the two populations and confirmed that they occur on two different haplotypes. In Pune Indians, the presence of -1131C allele and the 19W allele was associated with a 19% and 15% increase respectively in triglyceride concentrations although only -1131C was significant (p = 0.0003). This effect size was similar to that seen in the UK white subjects. Analysis of the APOC3 SstI polymorphism in 175 Pune Indian subjects showed that this variant is not in appreciable linkage disequilibrium with the APOA5 -1131T>C variant (r2 = 0.07)., Conclusion: This is the first study to look at the role of APOA5 in Asian Indian subjects that reside in India. The -1131C allele is more prevalent and the 19W allele is less prevalent in Pune Indians compared to UK Caucasians. We confirm that the APOA5 variants are associated with triglyceride levels independent of ethnicity and that this association is similar in magnitude in Asian Indians and Caucasians. The -1131C allele is present in 36% of the Pune Indian population making it a powerful marker for looking at the role of elevated triglycerides in important conditions such as pancreatitis, diabetes and coronary heart disease.

Background: A limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (approximately 20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed., Methods and Findings: Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles., Conclusions: Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases.

Context: Vascular endothelial growth factor (VEGF) is important for pancreatic beta cell development and function. Common variation in the VEGF gene is associated with altered serum concentrations of VEGF and with several diseases, but its role in type 2 diabetes is not known. The single nucleotide polymorphisms C-2578A (rs699947), G-1154A (rs1570360) and G-634C (rs2010963) in the 5'-region of VEGF are associated with altered serum concentrations of the protein., Objective: We performed a large case-control and family-based study to test the hypothesis that these variants are associated with type 2 diabetes in a UK Caucasian population., Participants: We genotyped 1,969 cases, 1,625 controls and 530 families for the three single nucleotide polymorphisms., Main Outcome Measures: Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of alleles to affected offspring., Results: Despite good power (80%) to detect odds ratios of approximately 1.2, there were no significant associations between single alleles or genotypes and type 2 diabetes. Odds ratios (and 95% confidence intervals) comparing case and control allele frequencies for single nucleotide polymorphisms C-2578A, G-1154A and G-634C were 0.97 (0.88-1.07), 0.99 (0.90-1.09) and 0.97 (0.88-1.08), respectively., Conclusion: This is the first large-scale study to examine the association between common functional variation in VEGF and type 2 diabetes risk. We have found no evidence that these three single nucleotide polymorphisms, shown previously to alter VEGF concentrations, are risk factors for type 2 diabetes in a large UK Caucasian case-control and family-based study.

HNF1alpha (TCF1) is a key transcription factor that is essential for pancreatic beta-cell development and function. Rare mutations of HNF1alpha cause maturity-onset diabetes of the young. A common variant, G319S, private to the Oji-Cree population, predisposes to type 2 diabetes, but the role of common HNF1alpha variation in European populations has not been comprehensively assessed. We determined the linkage disequilibrium and haplotype structure across the HNF1alpha gene region using 29 single nucleotide polymorphisms (SNPs). Eight tagging SNPs (tSNPs) that efficiently capture common haplotypes and the amino acid-changing variant, A98V, were genotyped in 5,307 subjects (2,010 type 2 diabetic case subjects, 1,643 control subjects, and 1,654 members of 521 families). We did not find any evidence of association between the tSNPs or haplotypes and type 2 diabetes. We could exclude odds ratios (ORs) >1.25 for all tSNPs. The rare V98 allele (approximately 3% frequency) showed possible evidence of association with type 2 diabetes (OR 1.23 [95% CI 0.99-1.54], P = 0.07), a result that was supported by meta-analysis of this and published studies (OR 1.31 [1.08-1.59], P = 0.007). Further studies are required to investigate this association, demonstrating the difficulty of defining the role of rare (<5%) alleles in type 2 diabetes risk.

Objective: Young adults with newly diagnosed apparent type 2 diabetes present the clinician with a wide differential diagnosis of possible etiology, including autoimmune and genetic causes as well as young-onset type 2 diabetes (YT2D). The characteristics of these groups have been described, but it is not known in which subjects investigation for etiology may be beneficial., Research Design and Methods: A total of 268 unselected U.K. Caucasian subjects diagnosed at ages 18-45 years and not treated with permanent insulin for < or =6 months were studied. All subjects underwent clinical assessment and screening for GAD antibodies (GADA) and tyrosine phosphatase IA-2 antibodies (IA-2A). Screening for a common mutation in the hepatocyte nuclear factor-1 alpha (HNF-1 alpha) gene and the common mitochondrial mutation was performed in the antibody-negative subjects. Subjects without insulin resistance were selected for sequencing of the HNF-1 alpha gene., Results: A specific etiology was defined in 11.6% of the 268 subjects and in 24.7% of the lean subjects. Twenty-six subjects (9.7%) were positive for a beta-cell antibody, one subject had familial partial lipodystrophy and the lamin A/C mutation R482W, and two subjects had the mitochondrial mutation A3243G. Two of 15 selected subjects had HNF-1 alpha mutations, the novel missense mutation A501T, and the previously reported R583Q., Conclusions: This unselected series shows that there is considerable heterogeneity in apparent YT2D. beta-Cell autoantibodies should be performed in all those presenting at ages 18-45 years. Genetic investigations can be targeted to phenotypically defined subjects. The finding of a specific etiology will allow individualization of management and give patients valuable information about their condition.