Revealing a subclinical salt-losing phenotype in heterozygous carriers of the novel S562P mutation in the α subunit of the epithelial sodium channel

Objective  Pseudohypoaldosteronism type I (PHA1) is a rare inborn disease causing severe salt loss. Mutations in the three coding genes of the epithelial sodium channel (ENaC) are responsible for the systemic autosomal recessive form. So far, no phenotype has been reported in heterozygous carriers.
Patients  A consanguineous family from Somalia giving birth to a neonate suffering from PHA1 was studied including clinical and hormonal characteristics of the family, mutational analysis of the SCNN1A , SCNN1B , SCNN1G and CFTR genes and in vitro analysis of the functional consequences of a mutant ENaC channel.
Results  CFTR mutations have been excluded. SCNN1A gene analysis revealed a novel homozygous c.1684T > C mutation resulting in a S562P substitution in the αENaC protein of the patient. Functional analysis showed a significantly reduced S562P channel function compared to ENaC wild type. Protein synthesis and channel subunit assembly were not altered by the S562P mutation. Co-expression of mutant and wild-type channels revealed a dominant negative effect. In heterozygote carriers, sweat sodium and chloride concentrations were increased without additional hormonal or clinical phenotypes.
Conclusion  Hence, the novel mutation S562P is causing systemic PHA1 in the homozygous state. A thorough clinical investigation of the heterozygote SCNN1A mutation carriers revealed increased sweat sodium and chloride levels consistent with a dominant effect of the mutant S562P allele. Whether this subclinical phenotype is of any consequence for the otherwise asymptomatic heterozygous carriers has to be elucidated.     

A Novel SCNN1A Variation in a Patient with Autosomal-recessive Pseudohypoaldosteronism Type 1

Pseudohypoaldosteronism type 1 (PHA1) is an autosomal-recessive disorder characterized by defective regulation of body sodium (Na) levels. The abnormality results from mutations in the genes encoding subunits of the epithelial Na channel. Patients with PHA1 present in infancy as being in adrenal crisis. A 41-day-old female who presented with recurrent adrenal crisis did not adequately respond to hydrocortisone and required mineralocorticoid therapy. The patient’s demographic data and clinical features were recorded. Blood samples were collected and tested for endocrine and metabolic characteristics and for use in genetic studies. Bidirectional Sanger sequencing of SCNN1A was conducted. The entire coding region of 12 exons and 20 bp of flanking intron were sequenced. Genetic analyses revealed a new mutation - c.729_730delAG (p.Val245Glyfs*65) - in SCNN1A exon four. Adrenal crisis during the neonatal period highlights the importance of early screening for PHA1. Genetic testing could help to anticipate the prognosis, severity, onset of the disease, and the mode of inheritance, especially given its extensive phenotype.     

Genetic screening of SCNN1B and SCNN1G genes in early-onset hypertensive patients helps to identify Liddle syndrome

Background: Liddle syndrome is an autosomal dominant form of monogenic hypertension. Phenotypic variability makes it difficult to identify patients with Liddle syndrome, resulting in misdiagnosis and severe complications at early age. Objectives: To identify mutation in SCNN1B and SCNN1G genes in an adolescent with suspicious Liddle syndrome and his family members and to explore the screening target subjects of Liddle syndrome. Methods: Genetic analysis of the C-terminus of SCNN1B and SCNN1G genes was conducted in an adolescent, with treatment-resistant hypertension and hypokalemia, who was suspected of having Liddle syndrome, and his family members. A Medline research of the reported cases with Liddle syndrome was also performed. Results: A recurrent SCNN1B mutation, c.1853C>A (p.P618H), was detected in the 19-year-old male patient, and family screening identified five additional members who were heterozygous for the mutation. The diagnosis of Liddle syndrome was made in all affected individuals. Despite the phenotypic variability, a systematic review of 54 reported index cases revealed the early-onset hypertension, aged no more than 30 years, as a common feature. Conclusions: Genetic screening for Liddle syndrome should be considered in hypertensive subjects with early penetrance, maybe no more than 30 years, after exclusion of common secondary causes of hypertension.     

Mutation analysis of SCNN1B in a family with Liddle's syndrome

Liddle's syndrome has been known as a disorder associated with abnormal sodium reabsorption in the distal tubule and transmitted as a rare autosomal dominant trait. It is caused by mutations in the SCNN1B or SCNN1C gene, which truncate the cytoplasmic carboxyl terminus of the β and γ subunit of the epithelial sodium channel (ENaC). Genetic analysis of ENaC in a Chinese family with Liddle's syndrome revealed P616H of SCNN1B coaggregated with the phenotype, while this variant was not detected in 100 unrelated subjects. No mutation at γ ENaC could be detected in all members of the family. P616H is located in the conserved proline-rich PY motif of the βENaC. The PY motif can interact with the WW domain in Nedd4 and affect the activity of ENaC. Structural bioinformatics analysis confirmed that the functional interaction between Nedd4 and ENaC reduces in Liddle-ENaC (P616H) when compared with wild-type ENaC. In summary, P616H may be an underlying mechanism for the signs and symptoms of this family.     

Hyperkalemia in the Hypertensive Patient

Purpose of Review

Hyperkalemia develops in a patient with systemic arterial hypertension (HTN) if one or more risk factors are present, namely chronic kidney disease (CKD) (especially severe stage 4-5 CKD), diabetes mellitus (DM), heart failure (HF), or pharmacological therapies that interfere with potassium homeostasis, mainly through renin-angiotensin-aldosterone inhibition (RAASi). Hyperkalemia is a considerable reason of morbidity (emergency department (ED) visits and hospitalizations) and portends a higher mortality risk in patients at risk; for instance, hyperkalemia increases the risk of mortality within 1 day of a hyperkalemic event. This review aims to identify the risk factors for high-serum potassium, highlight the risk versus benefit of RAASi in certain patient populations, and outline preventive as well as therapeutic strategies for hyperkalemia.

Recent Findings

A growing body of evidence supports the safety and efficacy of cation-exchange resins, patiromer, or sodium zirconium cyclosilicate, in patients with a compelling indication for RAASi, yet in whom such therapy was complicated by hyperkalemia, allowing these patients to benefit from continued RAASi therapy.

Summary

In summary, novel cation exchange polymers present the clinician with a new and safe strategy to address hyperkalemia in patients with a compelling indication for ongoing RAASi therapy instead of withdrawal of such therapy.

     

Clinical and Genetic Characteristics of Patients with Corticosterone Methyloxidase Deficiency Type 2: Novel Mutations in CYP11B2

Corticosterone methyloxidase deficiency type 2 is an autosomal recessive disorder presenting with salt loss and failure to thrive in early childhood and is caused by inactivating mutations of the CYP11B2 gene. Herein, we describe four Turkish patients from two families who had clinical and hormonal features compatible with corticosterone methyloxidase deficiency and all had inherited novel CYP11B2 variants. All of the patients presented with vomiting, failure to thrive and severe dehydration, except one patient with only failure to thrive. Biochemical studies showed hyponatremia, hyperkalemia and acidosis. All patients had normal cortisol response to adrenocorticotropic hormone stimulation test and had elevated plasma renin activity with low aldosterone levels. Three patients from the same family were found to harbor a novel homozygous variant c.1175T>C (p.Leu392Pro) and a known homozygous variant c.788T>A (p.Ile263Asn) in the CYP11B2 gene. The fourth patient had a novel homozygous variant c.666_667delCT (p.Phe223ProfsTer35) in the CYP11B2 gene which caused a frame shift, forming a stop codon. Corticosterone methyloxidase deficiency should be considered as a differential diagnosis in patients presenting with hyponatremia, hyperkalemia and growth retardation, and it should not be forgotten that this condition is life-threatening if untreated. Genetic analyses are helpful in diagnosis of the patients and their relatives. Family screening is important for an early diagnosis and treatment. In our cases, previously unreported novel variants were identified which are likely to be associated with the disease.     

Single nucleotide polymorphisms in the promoter region of the IL1B gene influence outcome in multiple myeloma patients treated with high-dose chemotherapy independently of relapse treatment with thalidomide and bortezomib

Little is known on the impact of polymorphisms in the IL1B gene on outcome in multiple myeloma. In a population-based study of 348 Danish myeloma patients treated with high-dose treatment (HDT), 146 patients treated with INF-?? maintenance treatment, and in 243 patients with relapse, we analysed the impact on outcome of HDT, INF-?? maintenance treatment, and treatment with thalidomide and bortezomib at relapse, in relation to the major identified functional polymorphisms in the promoter region of IL1B. The wild-type C-allele of IL1B C-3737T and non-carriage of the IL1B promoter haplotype TGT (?3737^T, ?1464^G and ?31^T), giving high IL1B promoter activity, were associated with longer time-to-treatment failure (TTF) (HR, 1.4 (1.0?C1.9) and 1.5 (1.1?C2.0)) and overall survival (HR, 1.8 (1.2?C2.6) and 1.6 (1.1?C2.3)) after HDT. Among INF-?? treated patients, a trend towards better TTF was found in patients carrying the wild-type C-allele of IL1B C-3737T (HR, 1.6 (1.1?C2.4)). Furthermore, among INF-?? treated patients, gene?Cgene interaction studies on IL1B C-3737T and NF??B1-94ins/del ATTG revealed a fourfold increase in TTF for homozygous carriers of wild-type alleles at both loci as compared to variant allele carriers at both loci. No relation to genotype and outcome was found for relapse patients treated with thalidomide or bortezomib. Our results indicate that a subpopulation of myeloma patients carrying the wild-type C-allele of IL1B C-3737T and non-carriers of the promoter haplotype TGT (?3737^T, ?1464^G and ?31^T) benefit from a better outcome of HDT and INF-?? treatment, an effect that may be related to the NF-??B pathway.     

Hyperkalemia as a limiting factor of neurohormonal blockade/modulation in everyday clinical practice

Introduction and objectivesNeurohormonal blockade (NB)/modulation is the combination of two renin-angiotensin-aldosterone system inhibitors (RAASi) with a beta blocker. It is the core therapy for heart failure with reduced ejection fraction (HFrEF). While improving long term prognosis, it also induces hyperkalemia (serum K⁺ >5.0 mEq/L) due to RAASi effects. This may cause lethal arrhythmias and increase mortality in the short term. Thus, hyperkalemia frequently leads to withholding or reducing the intensity of neurohormonal blockade/modulation, which is associated with worsening long term prognosis. We assessed the relevance of hyperkalemia as a limiting factor of neurohormonal blockade/modulation in real life clinical conditions.MethodsWe reviewed the medical records of HFrEF patients attending a HF clinic at a tertiary Portuguese hospital during 2018 (n=240). The number of patients not tolerating maximal neurohormonal blockade/modulation due to hyperkalemia was determined. The incidence and characteristics of hyperkalemia episodes were also assessed.ResultsOnly six patients (3%) achieved maximal doses of neurohormonal blockade/modulation. Hyperkalemia was the limiting factor in 48 (20%) patients. A total of 185 hyperkalemia episodes occurred in 100 (42%) patients. Forty-five (24%) episodes were moderate or severe (serum K⁺ >5.5 mEq/L). In these HFrEF patients, the co-existence of hypertension, diabetes or renal failure was associated with the occurrence of hyperkalemia.ConclusionsIn daily clinical practice, hyperkalemia is frequent and limits neurohormonal blockade/modulation by leading to the withholding or reducing of the intensity of RAAS inhibition. Considering the negative prognostic impact associated with sub-optimal neurohormonal blockade/modulation, addressing hyperkalemia is an important issue when treating HFrEF patients.     

Compound heterozygous mutations in the gamma subunit gene of ENaC (1627delG and 1570-1G-->A) in one sporadic Japanese patient with a systemic form of pseudohypoaldosteronism type 1

The systemic form of pseudohypoaldosteronism type 1 (PHA1) is a rare autosomal recessive disorder with salt-wasting, hyperkalemia, metabolic acidosis, and multiorgan aldosterone unresponsiveness. Recently, this form of PHA1 was found to be caused by the loss-of-function mutations in the gene of each subunit (alpha, beta, and gamma) of the epithelial sodium channel (ENaC). To investigate the molecular basis of one sporadic Japanese patient with a systemic form of PHA1, we determined the nucleotide sequence of the genes of every subunit of ENaC of this patient. The patient was found to be a compound heterozygote for one base deletion in exon 12 (1627delG) in combination with 1570-1-->GA substitution at the 5' splice acceptor site of intron 11 in the gamma subunit gene of ENaC. The 1627delG mutation altered a reading frame, resulting in a premature stop codon in exon 12. Messenger RNA from the allele harboring the splice site mutation was not identified by RT-PCR. In conclusion, two novel mutations in the gamma subunit gene of ENaC caused systemic PHA1 in the sporadic Japanese patient. Identification of the molecular basis of PHA1 is helpful for early diagnosis and understanding the pathophysiology of the disease.     

ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants

Background and AimsAlthough a good genotype-phenotype correlation has not been established in Wilson disease (WD), patients with loss-of-function (LOF) ATP7B variants demonstrate different clinical and biochemical characteristics. We aim to describe long-term treatment outcomes in the chronic liver disease (CLD) phenotype and evaluate an association with LOF variants.MethodsThis was a single-center retrospective review of WD patients with at least 1 variant in ATP7B. Demographic, biochemical, genetic, and clinical parameters were obtained. The composite clinical endpoint of liver transplantation or death was used for probands with CLD phenotype on chelators.ResultsOf 117 patients with hepatic WD: 71 had CLD, 27 had fulminant hepatic failure requiring urgent liver transplantation, and 19 were diagnosed through family screening. Median age at diagnosis was 13.1 (interquartile range, 9.7–17.6) years. In total, 91 variants in ATP7B were identified in the study population. At least 1 LOF variant was present in 60 (51.3%) patients. During median follow-up of 10.7 (interquartile range, 6.7–18.9) years, 10 (14.1%) of the probands with CLD reached the composite endpoint. There was a worse transplant-free survival for patients prescribed chelation therapy in patients with at least 1 LOF variant (P = .03).ConclusionsPatients with WD and CLD phenotype on chelators, who have at least 1 LOF variant in ATP7B, have a worse prognosis during long-term follow up. This subgroup of patients requires close monitoring for signs of progressive liver disease. Sequencing of ATP7B may be used in the diagnosis of WD, and in addition, it may provide useful prognostic information for patients with hepatic WD.     

Hepatic phenotypes of HNF1B gene mutations:A case of neonatal cholestasis requiring portoenterostomy and literature review

Hepatocyte nuclear factor 1-β(HNF1B)defects cause renal cysts and diabetes syndrome(RCAD),or HNF1B-maturity-onset diabetes of the young.However,the hepatic phenotype of HNF1B variants is not well studied.We present a female neonate born small for her gestational age[birth weight 2360 g;-2.02standard deviations(SD)and birth length 45 cm;-2.40 SD at the 38th gestational week].She developed neonatal cholestasis due to biliary atresia and required surgical intervention(portoenterostomy)when 32-d old.Following the operation,icterus resolved,but laboratory signs of liver dysfunction persisted.She had hyperechogenic kidneys prenatally with bilateral renal cysts and pancreatic hypoplasia postnatally that led to the diagnosis of an HNF1B deletion.This represents the most severe hepatic phenotype of an HNF1B variant recognized thus far.A review of 12 published cases with hepatic phenotypes of HNF1B defects allowed us to distinguish three severity levels,ranging from neonatal cholestasis through adult-onset cholestasis to noncholestatic liver impairment,all of these are associated with congenital renal cysts and mostly with diabetes later in life.We conclude that to detect HNF1B variants,neonates with cholestasis should be checked for the presence of renal cysts,with special focus on those who are born small for their gestational age.Additionally,patients with diabetes and renal cysts at any age who develop cholestasis and/or exocrine pancreatic insufficiency should be tested for HNF1B variants as the true etiological factor of all disease components.Further observations are needed to confirm the potential reversibility of cholestasis in infancy in HNF1B mutation/deletion carriers.     

Influence of potassium levels on one-year outcomes in elderly patients with acute heart failure

BackgroundAbnormal serum potassium levels (K⁺) in patients with heart failure (HF) relate to worse prognosis. We evaluated whether admission K⁺ levels predict 1-year outcomes in elderly patients admitted for acute HF.MethodsWe evaluated 2865 patients aged >74 years from the RICA Spanish Heart Failure Registry, classified according to admission serum K⁺ levels: hyperkalemia (>5.5 mmol/L), normokalemia (3.5–5.5 mmol/L) and hypokalemia (<3.5 mmol/L). We explored whether K⁺ levels were significantly associated with one-year all-cause mortality or hospital readmission and their combination.ResultsMean admission K⁺ value was 4.3 ± 0.6 mmol/L; 97 patients (3.38%) presented with hyperkalemia and 174 (6.06%) with hypokalemia. Overall, 43% of the patients died or were readmitted for HF during the follow-up period; the risk was higher for those with hyperkalemia (59% vs 41% in hypokalemic patients). The HR for one-year mortality was 1.43 (p = .073) and 1.67 for readmissions (p = .007) when K⁺ was >5.5 mmol/L and 1.08 (p = .618) and 0.90 (p = .533) respectively for K⁺ < 3.5 mmol/L. The HR for the combined outcome was 1.59 (1.19–2.13); p = .002 in hyperkalemic patients and 0.96 (0.75–1.23); p = .751in hypokalemic patients. Multivariate analysis showed a significant association of admission K⁺ values >5.5 mmol/L with the combined outcome of mortality and readmission (HR 1.15 [95% CI 1.04–1.27], p = .008).ConclusionIn patients hospitalized for decompensated HF, admission hyperkalemia predicts a higher mid-term risk for HF readmission and mortality, probably related to the significant higher risk of readmission.     

New Therapeutic Approaches for the Treatment of Hyperkalemia in Patients Treated with Renin-Angiotensin-Aldosterone System Inhibitors

Hyperkalemia (serum potassium >?5.5 mEq/L) is a common clinical problem in patients with chronic kidney disease, hypertension, diabetes, and heart failure. It can result from increased K⁺ intake, impaired distribution between intracellular and extracellular spaces, and most frequently, decreased renal excretion. Patients at the highest risk of hyperkalemia are treated with renin-angiotensin-aldosterone system inhibitors (RAASIs) as they improve cardiovascular and renal outcomes and are strongly recommended in clinical guidelines. However, RAASIs cause or increase the risk of hyperkalemia, a key limitation to fully titrate RAASIs in patients who are most likely to benefit from treatment. Until recently, drugs for the treatment of hyperkalemia presented limited efficacy and/or safety concerns and there was an unmet need of new drugs to control hyperkalemia while maintaining RAASI therapy. We provide an overview of the mechanisms involved in K⁺ homeostasis and the epidemiology and management of hyperkalemia as a complication in cardiovascular patients and, finally, analyze the efficacy and safety of two new polymer-based, non-systemic agents, patiromer calcium and sodium zirconium cyclosilicate (ZS-9), designed to increase fecal K⁺ loss and to normalize elevated serum K⁺ levels and chronically maintain K⁺ homeostasis in hyperkalemic patients treated with RAASIs.     

Treatment Difficulties in Hypomagnesemia Secondary to the Transient Receptor Potential Melastatin 6 Gene: A Case Report with Novel Mutation

Hypomagnesemia is a rare cause of seizures in childhood but should be kept in mind in recurrent and intractable seizures and hypocalcemia in communities where consanguineous marriages are common. Familial hypomagnesemia with secondary hypocalcemia is a rare genetic cause of hypomagnesemia, due to variants in the transient receptor potential melastatin 6 (TRPM6) genes. Here, a three year-old boy with a novel variant in this gene and had difficulties with enteral hypomagnesemia treatment is presented. He had recurrent seizures since two years of age and was diagnosed with epilepsy and treated with multiple antiepileptic drugs. Subsequently, he was diagnosed with rickets due to severe hypocalcemia at another center. The patient was hypotonic and neurodevelopmentally poor. The most prominent laboratory finding was of hypomagnesemia with secondary hypocalcemia. The genetic analysis revealed a novel variant in the TRPM6 gene. After parental treatment of intravenous magnesium (Mg²⁺) sulfate and calcium, the treatment was switched to enteral Mg²⁺ medications, due to persistent hypomagnesemia and the gastrointestinal side-effects, different oral preparations were used. The patient was stable on an oral maintenance dose of Mg²⁺ oxide with borderline blood Mg²⁺ levels and resolution of hypocalcemia. Hypomagnesemia is one of the causes of hypocalcemia. Enteral replacement is the key treatment but the treatment should be individualized for each patient. Normalization of hypomagnesemia is not always easy and should not be the aim of the treatment.     

Coincidence of pseudohypoaldosteronism with gluten-enteropathy

This is a 21-month-old boy with pseudohypoaldosteronism (PHA) in coincidence with celiac disease. The diagnosis of PHA was made on the basis of hyponatremia, hyperkalemia and large urinary salt losses, as well as high renin activity and aldosterone levels and increased urinary plasma aldosterone. Whereas mineralocorticoid therapy was ineffective, salt therapy has proven successful. The patient's HLA type was found to be characteristic of gluten-enteropathy (A1, B8, DR3). The combination of PHA and celiac disease has not yet been described and is probably a coincidence. However, it is suggested that other PHA patients be typed in order to investigate the segregation between HLA type, PHA and celiac disease.     

Genetic variation of the interleukin-1 family and nongenetic factors determining the interleukin-1 receptor antagonist phenotypes

The natural anti-inflammatory protein interleukin-1 receptor antagonist (IL-1Ra) inhibits the activity of IL-1 and is associated with vascular injury and metabolic disorders. We analyzed genetic and nongenetic determinants of the IL-1Ra phenotype. Fifteen haplotype-tagging single nucleotide polymorphisms (SNPs) in the IL-1α (IL1A), IL-1β (IL1B), and IL-1 receptor antagonist (IL-1RN) genes were determined in the Health 2000 survey (n = 6771) and European myocardial infarction (MI) survivors (n = 972). Three SNPs were genotyped in the FINRISK97 (FR97) study (n = 7222). We found 3 IL1RN variants that were associated with the IL-1Ra phenotype in the study populations and remained significant after Bonferroni correction with increasing significance in meta-analysis (P values for rs3213448,rs315952, rs315949, respectively: 5.5 x 10⁻¹¹, 1.5 x 10⁻¹¹, and 4.0 x 10⁻¹⁴). Minor allele of the rare IL1B variant rs1143642 was associated with decreased IL-1Ra levels in the Health 2000 and FR97 populations, and the association strengthened in the meta-analysis (P = 9.4 x 10⁻⁷). The proportion of variance explained by the IL1RN variant was larger in MI survivors (5.0%) than in the unselected population (0.5%). Body mass index was the strongest nongenetic predictor of the IL-1Ra phenotype, explaining 11.8% of the variance in Health 2000, 18.1% in FR97, and 25% in MI survivors. In conclusion, 3 IL1RN SNPs and 1 IL1B variant were determining IL-1Ra phenotype independently of body mass index and other metabolic phenotypes. The proportion of phenotypic variation in IL-1Ra explained by the genetic variants was, however, modest compared with the proportion explained by the body mass index.     

Incident Hyperkalemia,Hypokalemia, and Clinical Outcomes During Spironolactone Treatment of Heart Failure With Preserved Ejection Fraction: Analysis of the TOPCAT Trial

Background

In patients with heart failure and preserved ejection fraction (HF-PEF) randomized in the Americas as part of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, treatment with spironolactone enhanced the risk of hyperkalemia but reduced the risk of hypokalemia. We examined the clinical correlates and prognostic implications of incident hypo- and hyperkalemia during study follow-up.

A polymorphism in NFKB1 is associated with improved effect of interferon-α maintenance treatment of patients with multiple myeloma after high-dose treatment with stem cell support

Background

Maintenance therapy with interferon-α after high-dose treatment with stem cell support in multiple myeloma has been intensively debated. In this study, we evaluated the response to treatment with interferon-α in relation to genetic variation in genes related to inflammation.

Design and Methods

In a retrospective study of 296 patients with multiple myelom undergoing high-dose therapy between 1994 and 2004, 146 patients were treated with interferon-α as maintenance therapy. We tested the polymorphisms IL1B T-31C, IL6 G-174C, NFKB1-94ins/delATTG, CD3EAP G-21A and PPP1R13L IVS1 A4364G for associations with time to treatment failure and overall survival with and without interferon-α treatment.

Results

The wild type ins-allele of polymorphism NFKB1-94 ins/delATTG was, by multivariate Cox analysis, associated with longer time to treatment failure (p=0.01) and overall survival (p=0.0084) when tested between treatment arms and in the subgroup of patients treated with interferon-α the wild type ins-allele was associated with longer overall survival (p=0.002). In the absence of interferon-α treatment, there was no association between the polymorphisms and treatment outcome, except for patients homozygous for the wild type G allele of IL6 G-174C who survived longer (p= 0.0074) than variant allele carriers. There was no association between the polymorphisms IL1B T-31C, CD3EAP G-21A and PPP1R13L IVS1 A4364G and treatment outcome for interferon-α.

Conclusions

Patients who are homozygous carriers of the wild type ins-allele of the NFKB1 -94ins/delATTG polymorphism may benefit from treatment with interferon-α, in contrast to patients carrying the variant allele. This result may indicate that the effect of interferon-α treatment is dependent on the availability of nuclear factor-κB and the polymorphism in NFKB1 may, therefore, be a good prognostic marker for multiple myeloma patients on maintenance treatment with interferon-α after high-dose therapy. A prospective study of interferon-α treatment in relation to NFKB1 -94ins/delATTG is highly warranted.     

A common variant in MTNR1B, encoding melatonin receptor 1B, is associated with type 2 diabetes and fasting plasma glucose in Han Chinese individuals

Aims/hypothesis

Recently, three groups independently reported that variation in MTNR1B, the gene encoding melatonin receptor 1B, was associated with an increased risk of type 2 diabetes, increased fasting plasma glucose and impaired insulin secretion in populations of European ancestry. In the present study, we investigated whether a single MTNR1B polymorphism was associated with type 2 diabetes in Han Chinese individuals, to elucidate whether this is a cross-populational effect.

Methods

The MTNR1B variant rs10830963 was genotyped in 1,165 type 2 diabetic patients and 1,105 normoglycaemic control individuals of southern Han Chinese ancestry who were residents of the metropolitan area of Shanghai. The risk of developing type 2 diabetes was calculated using a logistic regression model adjusted for age, sex and BMI. A possible association with fasting plasma glucose was analysed in the normoglycaemic control individuals using a multiple linear regression analysis with adjustments for age, sex and BMI.

Results

The genetic variant rs10830963 was associated with an increased risk of type 2 diabetes in our Han Chinese cohort (OR 1.16, 95% CI 1.03–1.31, p?=?0.015). As previously described, the risk variant was also associated with increased fasting plasma glucose, showing an increase of 0.068 mmol/l (95% CI 0.036–0.100, p?=?4?×?10^?5) per risk allele.

Conclusions/interpretation

A common variant in the MTNR1B gene is associated with an increased risk of type 2 diabetes and increased fasting plasma glucose in Han Chinese, suggesting an important role for this polymorphism in populations of different ethnic and environmental backgrounds.

     

Chronic enteropathy associated with SLCO2A1 gene and hereditary fructose intolerance: A coincidence of two rare diseases

Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a rare disorder characterized by multiple small intestine ulcers. Patients with CEAS typically present with chronic anemia and gastrointestinal bleeding. Besides CEAS, SLCO2A1 mutations cause primary hypertrophic osteoarthropathy (PHO) which is considered as an extraintestinal manifestation in CEAS patients. Since CEAS and Crohn’s disease are clinically indistinguishable, patients are often misdiagnosed with Crohn’s disease. Herein, we describe a 4-year-old Turkish girl with CEAS due to homozygous pathogenic variant (c.656C > T) in SLCO2A1 with concomitant hereditary fructose intolerance (HFI) caused by homozygous pathogenic variant (c.1005C > G) in ALDOB. Prompt restriction of fructose, sucrose and sorbitol resulted in hepatomegaly regression and mild amelioration of patient’s symptoms. Despite budesonide and azathioprine treatments, patient’s protein losing enteropathy and chronic anemia did not improve. Although previous CEAS cases were reported from East Asian countries, it is likely to occur in people from other geographic areas. CEAS seems to be underdiagnosed and high index of suspicion is required for the diagnosis of this rare entity. Patients with prior diagnosis of Crohn’s disease with no response to immunosuppressive treatment or anti-TNF therapy should be re-evaluated for possible CEAS diagnosis.