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

OBJECTIVE

A1C is widely considered the gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between A1C and rs7072268 within HK1 (encoding hexokinase 1), which catalyzes the first step of glycolysis. HK1 deficiency in erythrocytes (red blood cells [RBCs]) causes severe nonspherocytic hemolytic anemia in both humans and mice.

RESEARCH DESIGN AND METHODS

The contribution of rs7072268 to A1C and the RBC-related traits was assessed in 6,953 nondiabetic European participants. We additionally analyzed the association with hematologic traits in 5,229 nondiabetic European individuals (in whom A1C was not measured) and 1,924 diabetic patients. Glucose control–related markers other than A1C were analyzed in 18,694 nondiabetic European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients.

RESULTS

Our study confirms a strong association between the rs7072268–T allele and increased A1C (β = 0.029%; P = 2.22 × 10⁻⁷). Surprisingly, despite adequate study power, rs7072268 showed no association with any other markers of glucose control (fasting- and 2-h post-OGTT–related parameters, n = 18,694). In contrast, rs7072268–T allele decreases hemoglobin levels (n = 13,416; β = −0.054 g/dl; P = 3.74 × 10⁻⁶) and hematocrit (n = 11,492; β = −0.13%; P = 2.26 × 10⁻⁴), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018).

CONCLUSIONS

HK1 variation, although strongly associated with A1C, does not seem to be involved in blood glucose control. Since HK1 rs7072268 is associated with reduced hemoglobin levels and favors anemia, we propose that HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in RBCs. These findings may have implications for type 2 diabetes diagnosis and clinical management because anemia is a frequent complication of the diabetes state.Type 2 diabetes is a major source of early excess morbidity and mortality, which result from lack of adequate blood glucose control in most diabetic patients (1). In the absence of widely available continuous glucose monitoring, the A1C assay has become the most popular index to evaluate the efficiency of type 2 diabetes treatments on long-term blood glucose control (2,3). A1C, which is formed through the nonenzymatic attachment of glucose to the NH₂-terminal of the β-chain of hemoglobin, is indeed commonly considered a surrogate marker of mean blood glucose concentration over the previous 8–12 weeks (i.e., a 120-day life span of erythrocytes) (4). Furthermore, the A1C assay is often used for confirming type 2 diabetes diagnosis when fasting plasma glucose (FPG) is in the pre-diabetes range (6.1 ≤ FPG <7.0 mmol/l, defining normal glycemia and overt diabetes, respectively [2]), as postprandial or post–glucose load measurements of blood glucose are difficult to widely apply in clinical practice. However, the A1C measurement displays well-known caveats, such as genetically inherited hemoglobin defects or erythrocyte (red blood cell [RBC]) life span heterogeneity in hematologically normal people, that would oblige the use of more complex measurement of glycated serum proteins or fructosamine as a surrogate of blood glucose levels (5,6).Thus far, several genome-wide association (GWA) studies have identified 22 genes or loci, increasing the risk for type 2 diabetes or modulating FPG levels (7–19). Recently, Pare et al. (20) reported a single nucleotide polymorphism (SNP), rs7072268, at the hexokinase 1 (HK1) locus (chr10q22) that strongly associates with increased A1C in a nondiabetic population. The four isozymes of the hexokinase family (HK1, HK2, HK3, and glucokinase) contribute to commit glucose to the glycolytic pathway. The predominant HK1 isozyme is expressed in the vast majority of cells and tissues, including cells that are strictly dependent on glucose uptake for their metabolic needs (21). Importantly, while most tissues express more than one HK isozyme, RBC glucose metabolism only depends on HK1 activity (22). In humans, mutations including nonsynonymous substitutions in the active site of HK1 and intragenic deletions have been shown to cause HK1 enzymatic deficiency associated with autosomal recessive severe nonspherocytic hemolytic anemia (21,23–25). A similar phenotype has been described in the Downeast Anemia (dea) mice displaying HK1 deficiency (22).Based on these observations, we postulated that HK1 genetic variation may modulate the maintenance of the RBC pool and thus indirectly alter A1C measurements independently of the ambient blood glucose concentration. We evaluated this hypothesis by assessing the impact of HK1 rs7072268 on A1C, other glucose control-related traits, type 2 diabetes risk, and RBC-related parameters in several prospective and case-control European cohorts. Our data suggest that HK1 variation through its anemic effect impairs A1C assays, which may have important clinical implications for both type 2 diabetes diagnosis and management because anemia is commonly associated with diabetes.     

Hypertension in people with diabetes and the metabolic syndrome: Pathophysiologic insights and therapeutic update

Hypertension (HTN) and type 2 diabetes mellitus (T2DM) are emerging as epidemics of the 21st century and are important components of the metabolic syndrome (MS). Evidence demonstrates a relationship between HTN, T2DM, and several vascular and metabolic abnormalities that are components of the MS. HTN affects nearly 70 million Americans and over one billion worldwide; likewise, the MS affects 44% of the US population above the age of 60 years and is rapidly increasing. HTN associated with the MS has certain pathophysiologic characteristics that provide clinical challenges. There is growing evidence that tissue activation of the renin-angiotensin system contributes to endothelial dysfunction, microalbuminuria, insulin resistance, and subsequent increased risk for cardiovascular and chronic kidney disease. The notion that HTN is a metabolic as well as a vascular disease provides a new treatment paradigm.     

Inhaled corticosteroids in chronic obstructive pulmonary disease

The effectiveness of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) remains controversial. Randomized controlled trials, meta-analyses, medication withdrawal studies, and observational reports have examined this question, with mixed results. Observational studies have been subject to criticism because of study design involving immortal time bias. Some randomized controlled trials suggest small benefits in lung function and health status, and a reduction in the rate of acute exacerbations of COPD and mortality, but their incomplete follow-up and statistical methods have been criticized. The greatest benefits of ICS in COPD have been reported with use of ICS and long-acting beta-agonist combination therapy, although no benefit was found for the primary outcome studied under the most rigorous methodology by the recent TORCH and Optimal randomized trials. Thus, although future randomized trials will need to be conducted with the most rigorous methodology for all outcomes, much uncertainty remains regarding the potential benefits of ICS in COPD.     

Multidetector computed tomography for the detection of left atrial appendage thrombus: a comparative study with transesophageal echocardiography

OBJECTIVE: To determine the diagnostic performance of multidetector computed tomography (MDCT) for the detection of left atrial appendage (LAA) thrombus as compared with transesophageal echocardiography. METHODS: Multidetector computed tomography was evaluated in 43 patients qualitatively for the presence or absence of a filling defect in the LAA and compared with transesophageal echocardiography. Additionally, a ratio of the mean computed tomographic attenuation in the LAA apex to the mean computed tomographic attenuation in the aortic root was used for quantitative evaluation. RESULTS: A filling defect visualized in the LAA by MDCT corresponded to a sensitivity of 70% (7/10), a specificity of 82% (27/33), and a negative predictive value of 90% (27/30) for detection of LAA thrombus. When using quantitative parameters, MDCT demonstrated a sensitivity of 80% (8/10), a specificity of 73% (24/33), and a negative predictive value of 92% (24/26). Multidetector computed tomography was not able to differentiate LAA thrombus from spontaneous echo contrast by either visual evaluation or by quantitative parameters. CONCLUSIONS: Multidetector computed tomography remains limited for the detection of LAA thrombus. However, a subgroup of patients at very high risk for LAA thrombus may benefit from the high negative predictive value of cardiac MDCT.     

Impact of the neuroendocrine system on thymus and bone marrow function

The nervous, endocrine, and immune systems interact to adapt to infection, inflammation, and tissue injury. Neural control is mediated in several ways, one of them being through the neuroendocrine regulation of the secretion of hypothalamic and pituitary hormones. The hormonal effects on the immune system range from the impact of steroidal hormones, which exhibit inhibitory effects over immune functions, to growth hormone, prolactin and neurohypophyseal hormones, known to stimulate and modulate humoral and cellular aspects of the immune system. This review will discuss the mechanisms behind the immunomodulatory role of the neuroendocrine system, including the critically important feedback loops required to maintain balance for these bidirectional interactions and alterations that occur with age.     

Increase in Anhedonia Level in Menopausal Women is Accompanied by a Shift in Olfactory Function

During menopause, some women suffer from anhedonia. Anhedonia is an inability to experience pleasure from normally pleasurable life events, such as eating a favorite meal or smelling agreeable flowers. In this study, we explored whether degree of anhedonia in menopausal women was associated with performance on the European Test of Olfactory Capabilities (Thomas-Danguin et al., Rhinology, 41:142–151 2003). Also, we investigated whether degree of anhedonia predicted how menopausal women would appreciate pleasant, neutral or unpleasant odors. We found that women who were more anhedonic had a worst olfactory function than women who were less anhedonic. Also, we found that only the women in the less anhedonic group rated less odors as unpleasant than as neutral or pleasant. Anhedonia was correlated negatively with percentage of odors categorized as being pleasant but was not with percentage of odors perceived as neutral or unpleasant. Our results are consistent with studies showing that not all menopausal women exhibit disrupted affect, such as anhedonia. However, we suggest that when anhedonia occurs, it does so together with a decreased olfactory function and a shift in olfactory hedonism.