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).     

Determination of the solute removal index for urea by using a partial spent dialysate collection method

In 22 hemodialysis patients, during a dialysis session, the solute removal index (SRI) for urea obtained from the use of a partial spent dialysate collection method was compared with that derived from the use of a total spent dialysate collection technique. The partial spent dialysate collection method was used to harvest a small representative sample of the total spent dialysate. The volumes of spent dialysate collected by the partial and the total spent dialysate collection methods were 1.7 +/- 0.4 L and 129.6 +/- 15.3 L, respectively. The total amount of urea nitrogen removed by dialysis as estimated by the partial spent dialysate collection method was similar to that determined by the total spent dialysate collection approach. As a result, the SRI value for urea obtained by the partial spent dialysate collection method (namely, 63% +/- 8%) correlated very well (r = 0.95, P < 0.001) with that derived by the total spent dialysate collection technique (namely, 62% +/- 8%). Our data suggest that it is feasible to use a simple partial spent dialysate collection method to obtain SRI results in patients treated with hemodialysis.     

Reward expectation modulates feedback-related negativity and EEG spectra

The ability to evaluate outcomes of previous decisions is critical to adaptive decision-making. The feedback-related negativity (FRN) is an event-related potential (ERP) modulation that distinguishes losses from wins, but little is known about the effects of outcome probability on these ERP responses. Further, little is known about the frequency characteristics of feedback processing, for example, event-related oscillations and phase synchronizations. Here, we report an EEG experiment designed to address these issues. Subjects engaged in a probabilistic reinforcement learning task in which we manipulated, across blocks, the probability of winning and losing to each of two possible decision options. Behaviorally, all subjects quickly adapted their decision-making to maximize rewards. ERP analyses revealed that the probability of reward modulated neural responses to wins, but not to losses. This was seen both across blocks as well as within blocks, as learning progressed. Frequency decomposition via complex wavelets revealed that EEG responses to losses, compared to wins, were associated with enhanced power and phase coherence in the theta frequency band. As in the ERP analyses, power and phase coherence values following wins but not losses were modulated by reward probability. Some findings between ERP and frequency analyses diverged, suggesting that these analytic approaches provide complementary insights into neural processing. These findings suggest that the neural mechanisms of feedback processing may differ between wins and losses.