Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth

OBJECTIVE

Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.

RESEARCH DESIGN AND METHODS

We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.

RESULTS

We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31], P = 2 × 10⁻⁵, and 14 g [4–23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (P_trend = 5 × 10⁻⁷). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus.

CONCLUSIONS

Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.Reduced birth weight is associated with late-onset diseases including type 2 diabetes, hypertension, and heart disease (1). The cause of this association is not known. It is often proposed to reflect fetal programming in utero in response to maternal malnutrition in pregnancy (2). An alternative explanation is that genetic variants that increase disease risk could also reduce fetal growth. In accordance with the fetal insulin hypothesis (3), we proposed that genetic variants that reduce insulin secretion or insulin sensitivity might reduce birth weight as well as predisposing to type 2 diabetes in adulthood, since fetal insulin is a key fetal growth factor.The fetal insulin hypothesis was initially based on observations of subjects with glucokinase (GCK) mutations, whose birth weight is reduced by 533 g (4) and who have mild hyperglycemia postnatally. Markedly reduced birth weights in patients with monogenic diabetes due to mutations in the INS, INSR, IPF1, KCNJ11, ABCC8, and HNF1B genes (3,5–8) have further established the principle that gene variants can cause both low birth weight and diabetes. However, mutations causing monogenic diabetes are too rare to explain the association between reduced birth weight and type 2 diabetes observed in population studies.There is epidemiological support for the fetal insulin hypothesis. Offspring of fathers who go on to develop type 2 diabetes later in life have lower birth weights than those born to fathers who do not develop diabetes (9–12). This is consistent with the fetus inheriting, on average, 50% of the father''s genetic predisposition to diabetes and this genetic predisposition reducing fetal growth.Maternal genotypes may have opposing effects on offspring birth weight compared with fetal genotypes (4). Type 2 diabetes risk alleles, which are present in the mother and which raise maternal glycemia in pregnancy, will increase fetal growth by increasing fetal insulin secretion. Maternal inheritance of common risk alleles in the GCK and TCF7L2 genes, which predispose to hyperglycemia and type 2 diabetes, respectively, were reproducibly associated with higher offspring birth weight (13,14). However, neither of these risk alleles at TCF7L2 and GCK or the type 2 diabetes risk alleles in the PPARG and KCNJ11 genes was associated with birth weight directly through the fetal genotype (13–15).In this study, we aimed to further test the relationship between known type 2 diabetes variants and size at birth. We selected variants at five loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8), recently identified through type 2 diabetes genome-wide association studies (16–21), that have not been investigated in relation to fetal growth. Each of these loci has been shown to predispose to diabetes by reducing insulin secretion (22–24). We used data from 19,200 offspring and 7,986 mothers from four studies of white Europeans to test the hypothesis that these variants are associated with birth weight, either through the fetal or maternal genotype.     

Interrogating Type 2 Diabetes Genome-Wide Association Data Using a Biological Pathway-Based Approach

OBJECTIVE

Recent genome-wide association studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. In a complementary approach to these single-marker studies, we attempted to identify biological pathways associated with type 2 diabetes. This approach could allow us to identify additional risk loci.

RESEARCH DESIGN AND METHODS

We used individual level genotype data generated from the Wellcome Trust Case Control Consortium (WTCCC) type 2 diabetes study, consisting of 393,143 autosomal SNPs, genotyped across 1,924 case subjects and 2,938 control subjects. We sought additional evidence from summary level data available from the Diabetes Genetics Initiative (DGI) and the Finland-United States Investigation of NIDDM Genetics (FUSION) studies. Statistical analysis of pathways was performed using a modification of the Gene Set Enrichment Algorithm (GSEA). A total of 439 pathways were analyzed from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and BioCarta databases.

RESULTS

After correcting for the number of pathways tested, we found no strong evidence for any pathway showing association with type 2 diabetes (top P_adj = 0.31). The candidate WNT-signaling pathway ranked top (nominal P = 0.0007, excluding TCF7L2; P = 0.002), containing a number of promising single gene associations. These include CCND2 (rs11833537; P = 0.003), SMAD3 (rs7178347; P = 0.0006), and PRICKLE1 (rs1796390; P = 0.001), all expressed in the pancreas.

CONCLUSIONS

Common variants involved in type 2 diabetes risk are likely to occur in or near genes in multiple pathways. Pathway-based approaches to genome-wide association data may be more successful for some complex traits than others, depending on the nature of the underlying disease physiology.Recent genome-wide association (GWA) studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. There are now 18 common variants with robust evidence of association with the disease (1–7). Individually, these variants only have a small effect on disease risk, and in combination they account for only ∼3% of the heritability of type 2 diabetes (6). GWA studies have focused on only the most statistically strongly associated individual variants, with robust association being declared only if a variant meets a stringent “genome-wide” level of statistical significance. However, GWA studies of a few thousand individuals are underpowered to detect variants with odds ratios of <1.2 at P < 1 × 10⁻⁵ —the typical P values used to take SNPs forward into replication studies. This means many real type 2 diabetes predisposing variants may not be detected in GWA data and are not yet followed up. The most robust way of testing for these variants is to increase sample sizes, and such efforts are ongoing. However, ever larger numbers of case and control subjects may be difficult to obtain. We therefore sought alternative approaches to investigating GWA data.     

Insights on pathogenesis of type 2 diabetes from MODY genetics

Maturity-onset diabetes of the young (MODY) is a type of non-insulin-dependent diabetes mellitus caused by rare autosomal-dominant mutations. MODY genes play key biochemical roles in the pancreatic β cell; therefore, common variants of MODY genes are excellent candidate genes for type 2 diabetes. We review recent studies that suggest that common MODY gene variation contributes modestly to the heritability of type 2 diabetes.     

Population-specific risk of type 2 diabetes conferred by HNF4A P2 promoter variants: a lesson for replication studies

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 × 10⁻⁶). 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.The presence of type 2 diabetes susceptibility genes on chromosome 20 has been suggested by linkage scans in several populations. The 20q12–q13 region (Online Mendelian Inheritance in Man [OMIM] 603694) is the best replicated and harbors the gene HNF4A, mutations that lead to type 1 maturity-onset diabetes of the young (OMIM 125850). Evidence for association between SNPs in the β-cell P2 promoter region of HNF4A has been recognized in Finnish (1) and Ashkenazi (2) populations, with data suggesting that the HNF4A P2 SNPs (or variants in strong linkage disequilibrium with them) contribute to the linkage signal on chromosome 20q (1,2). Association with HNF4A promoter SNPs has been replicated in some (3–7) but not all (8–12) populations tested. In other populations, there was evidence for association with SNPs or haplotypes in the HNF4A region other than the P2 SNPs (10,13–15). More recently, the association between HNF4A promoter SNPs and type 2 diabetes has been confirmed in Scandinavians but not in a broader meta-analysis with additional populations (16), suggesting that P2 SNPs confer varying risk effects in different populations, possibly due to the underlying causal variant not having been identified. We investigated a 10-Mb interval (38.1–48.2 Mb National Center for Biotechnology Information build 35) centered around HNF4A, including genotypes from 4,608 nonredundant (r² < 1) SNPs (one SNP per 2 Kb, on average) in five type 2 diabetic case-control populations, to evaluate whether we could confirm and refine the association signal in Ashkenazim and whether this association was also present in U.K. populations. We were also interested in assessing whether there was evidence for additional association signals within this broader interval. We tested an Ashkenazi type 2 diabetes case-control study (n = 998), including novel samples (n = 531) not previously tested for linkage or association with HNF4A P2 SNPs (2); two U.K. population-based case-control studies where linkage and association studies with HNF4A P2 had not be carried out (n = 2,189); and two additional U.K. case-control collections (n = 1,842), with one enriched for earlier-onset type 2 diabetes where linkage studies had not been done but that showed suggestive association with HNF4A P2 SNPs (4) and one that included samples where, despite no evidence of linkage to chromosome 20q, association of HNF4A P2 SNPs with type 2 diabetes risk had previously been suggested (4,17).     

Unit cost of Mohs and Dermasurgery Unit

Background Appropriate pricing for medical services of not‐for‐profit hospital is necessary. The prices should be fair to the public and should be high enough to cover the operative costs of the organization. Objective The purpose of this study was to determine the cost and unit cost of medical services performed at the Mohs and Dermasurgery Unit (MDU), Department of Dermatology, The University of Texas – MD Anderson Cancer Center, Houston, TX from the healthcare provider’s perspective. Methods MDU costs were retrieved from the Financial Department for fiscal year 2006. The patients’ statistics were acquired from medical records for the same period. Unit cost calculation was based on the official method of hospital accounting. Results The overall unit cost for each patient visit was $673.99 United States dollar (USD). The detailed unit cost of nurse visit, new patient visit, follow‐up visit, consultation, Mohs and non‐Mohs procedure were, respectively, $368.27, $580.09, $477.82, $585.52, $1,086.12 and $858.23 USD. With respect to a Mohs visit, the unit cost per lesion and unit cost per stage were $867.89 and $242.30 USD respectively. Conclusions Results from this retrospective study provide information that may be used for pricing strategy and resource allocation by the administrative board of MDU.     

Ceramic-on-ceramic vs ceramic-on-polyethylene,a comparative study with 10-year follow-up

BACKGROUNDIn press-fit total hip arthroplasty (THA) ceramic-on-ceramic (CoC) bearings are a potential for overcoming the wear that is seen in ceramic-on-polyethylene (CoPE) bearings, and can lead to wear-induced osteolysis, resulting in loosening of the implant. However, CoC bearings show disadvantages as well, such as squeaking sounds and being more fragile, which can cause ceramic head or liner fracture. Because comparative long-term studies are limited, the objective of this study was to determine the long-term difference in wear, identify potential predictive factors for wear, investigate radiological findings such as osteolysis, and evaluate clinical functioning and complications between these bearings.AIMTo determine 10-year differences in wear, predictive factors for wear, and investigate radiological findings and clinical functioning between CoC and CoPE.METHODSThis observational prospective single-center cohort study with a 10-year follow-up includes a documented series of elective THAs. Primary outcome was wear measured by anteroposterior (AP) radiographs. Secondary outcomes were potential predictive factors for wear, complications during follow-up, Harris hip score (HHS), and radiological findings such as presence of radiolucency, osteolysis, atrophy, and hypertrophy around the cup. Due to the absence of wear in the CoC group, stratified analysis to identify risk factors for wear was only performed in the CoPE group by use of univariate linear regression analysis. HHS was expressed as a change from baseline and the association with bearing type was assessed by use of multivariate linear regression analysis, adjusted for potential confounders.RESULTSA total of 17 CoPE (63.0%) and 25 CoC (73.5%) cases were available for follow-up and showed a linear wear of respectively 0.130 mm/year (range 0.010; 0.350) and 0.000 mm/year (range 0.000; 0.005), which was significant (P < 0.001) between both groups. Wear always occurred in the cranial direction. Cup inclination was the only predictive factor for polyethylene (PE) wear. No dislocations, ceramic head, or liner fractures were seen. The HHS showed a mean change from baseline of 37.1 points (SD 18.5) in the CoPE group and 43.9 (SD 17.0) in the CoC group. This crude difference of 6.8 (range -5.2; 18.7) in favor of the CoC group was not significant (P = 0.26) and was not significant when adjusted for age, gender, and diagnosis either (P = 0.99). No significant differences in complications and radiological findings were seen between groups. CONCLUSIONCoC bearing shows lower wear rates compared to CoPE at 10-year follow-up with cup inclination as a predictive factor for wear and no differences in complications, HHS, and radiological findings.     

Highly cross-linked versus conventional polyethylene inserts in total hip arthroplasty,a five-year Roentgen stereophotogrammetric analysis randomised controlled trial

BACKGROUND Polyethylene(PE) particles produced by wear of the acetabular insert are thought to cause osteolysis and thereby aseptic loosening of the implant in total hip arthroplasty(THA). As highly cross-linked polyethylene(HXLPE) is presumed to give lower wear rates, in vivo studies are needed to confirm this.AIM To compare the wear of REXPOL, a HXPLE, with conventional PE within the first five years after implantation using Roentgen stereophotogrammetric analysis(RSA).METHODS Patients were randomised to receive either a HXLPE(REXPOL) or a conventional PE insert during primary THA. RSA images were obtained directly postoperative and after 6 wk, 12 wk, 6 mo, 12 mo, 24 mo and five years. Functional outcomes were assessed using the Hip Injury and Osteoarthritis Outcome Score and Harris Hip Score at baseline and five years after surgery.RESULTS The HXLPE(REXPOL) showed less wear in the latero-medial direction. Significant wear rates of conventional PE were seen in the latero-medial and center-proximal direction and in volume and corrected volume, whereas the REXPOL did not show these outcomes over time. Improvement from baseline in functional outcome did not significantly differ.CONCLUSION Total 3 D wear is less in THAs inserted with a REXPOL inlay than a conventional PE inlay after five years. This study confirms, for the first, that the REXPOL HXLPE inlay is preferred to standard PE.     

Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes

The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K(ATP)) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles.     

Gene variants influencing measures of inflammation or predisposing to autoimmune and inflammatory diseases are not associated with the risk of type 2 diabetes

Aims/hypothesis  There are strong associations between measures of inflammation and type 2 diabetes, but the causal directions of these associations are not known. We tested the hypothesis that common gene variants known to alter circulating levels of inflammatory proteins, or known to alter autoimmune-related disease risk, influence type 2 diabetes risk. Methods  We selected 46 variants: (1) eight variants known to alter circulating levels of inflammatory proteins, including those in the IL18, IL1RN, IL6R, MIF, PAI1 (also known as SERPINE1) and CRP genes; and (2) 38 variants known to predispose to autoimmune diseases, including type 1 diabetes. We tested the associations of these variants with type 2 diabetes using a meta-analysis of 4,107 cases and 5,187 controls from the Wellcome Trust Case Control Consortium, the Diabetes Genetics Initiative, and the Finland–United States Investigation of NIDDM studies. We followed up associated variants (p < 0.01) in a further set of 3,125 cases and 3,596 controls from the UK. Results  We found no evidence that inflammatory or autoimmune disease variants are associated with type 2 diabetes (at p ≤ 0.01). The OR observed between the variant altering IL-18 levels, rs2250417, and type 2 diabetes (OR 1.00 [95% CI 0.99–1.03]), is much lower than that expected given (1) the effect of the variant on IL-18 levels (0.28 SDs per allele); and (2) estimates, based on other studies, of the correlation between IL-18 levels and type 2 diabetes risk (approximate OR 1.15 [95% CI 1.09–1.21] per 0.28 SD increase in IL-18 levels). Conclusions/interpretation  Our study provided no evidence that variants known to alter measures of inflammation, autoimmune or inflammatory disease risk, including type 1 diabetes, alter type 2 diabetes risk. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.