Allelic variations in superoxide dismutase-1 (SOD1) gene and renal and cardiovascular morbidity and mortality in type 2 diabetic subjects.

BACKGROUND: Oxidative stress is involved in the pathophysiology of renal and cardiovascular complications of diabetes. Superoxide dismutase (SOD) enzymes play a major role in detoxification of reactive oxygen species and protection against oxidative stress. Associations of SOD1 gene variants with diabetic nephropathy were reported in patients with type 1 diabetes. We investigated associations of allelic variations in SOD1 gene with nephropathy and cardiovascular complications in patients with type 2 diabetes. METHODS: Seven SNPs in SOD1 region were analyzed in 3744 type 2 European Caucasian diabetic patients from the DIABHYCAR (a 6-year prospective study) and DIABHYCAR_GENE cohorts. Odds ratios or hazard ratios for prevalence and incidence of diabetic nephropathy and cardiovascular events were estimated. RESULTS: We observed an association of rs1041740 with the prevalence of microalbuminuria at baseline (OR 1.51, 95% CI 1.10-2.10, p=0.01). No association with the incidence of renal events (doubling of the serum creatinine levels or the requirement of hemodialysis or renal transplantation) or cardiovascular events (myocardial infarction or stroke) was observed during follow-up. However, three variants were associated with increased risk of death from cardiovascular causes (sudden death, fatal myocardial infarction or stroke) during the follow-up: rs9974610 (HR 0.64, 95% CI 0.46-0.88, p=0.005), rs10432782 (HR 1.71, 95% CI 1.16-2.48, p=0.007) and rs1041740 (HR 1.78, 95% CI 1.10-2.78, p=0.02). CONCLUSIONS: Our results are consistent with a major role for SOD1 in the mechanisms of cardiovascular protection against oxidative stress in type 2 diabetic subjects.

Allelic variations in superoxide dismutase-1 (SOD1) gene are associated with increased risk of diabetic nephropathy in type 1 diabetic subjects.

BACKGROUND: Oxidative stress is involved in the pathophysiology of diabetic nephropathy. The superoxide dismutase (SOD) enzymes play a major role in detoxification of reactive oxygen species and have a protective effect against diabetic nephropathy. We investigated associations of allelic variations in SOD1 gene with nephropathy in patients with type 1 diabetes. METHODS: Seven SNPs in SOD1 region were analyzed in 1285 type 1 European Caucasian diabetic patients from the SURGENE prospective study (n=340; ten year follow-up), and the Genesis France-Belgium (n=501) and GENEDIAB (n=444) cross-sectional studies. Cox proportional hazards and logistic regression analyses were used to estimate hazard ratios or odds ratios for incidence and prevalence of diabetic nephropathy. RESULTS: In the SURGENE study, the T-allele of rs1041740 was associated with the prevalence of incipient (OR 5.75, 95% CI 1.78-19.39, p=0.004) and established/advanced nephropathy at baseline (OR 8.95, 95% CI 1.51-58.42, p=0.02), and with the incidence of incipient nephropathy during follow-up (HR 1.46, 95% C.I. 1.13-1.90, p=0.004). The variant was also associated with decreased estimated glomerular filtration rate (eGFR) throughout the study. In cross-sectional study of Genesis/GENEDIAB cohorts, the G-allele of rs17880135 was associated with incipient (OR 7.53, 95% CI 2.30-25.45, p=0.001), established (OR 6.04, 95% CI 1.52-23.91, p=0.01) and advanced nephropathy (OR 10.03, 95% CI 2.95-35.44, p=0.0003). CONCLUSIONS: SOD1 allelic variations were associated with the prevalence of diabetic nephropathy, with the incidence of microalbuminuria and with decreased eGFR in type 1 diabetic subjects. These results are consistent with an implication of oxidative stress in the pathophysiology of diabetic nephropathy and with the major role for antioxidant enzymes as a mechanism of renal protection.

Insights into genotype-phenotype correlations in spinal muscular atrophy: a retrospective study of 103 patients.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder associated with homozygous deletion of the survival motor neuron 1 gene (SMN1). Its centromeric copy gene, SMN2, is the major modifying factor. However, the genotype-phenotype correlation is incomplete and is therefore not useful in clinical practice. We studied a cohort of 103 patients in order to refine this correlation. In addition to standard disease severity data, we collected three additional criteria: age at death; brainstem involvement; and loss of ambulation. Gene dosage analysis was conducted by multiplex ligation-dependent probe amplification (MLPA). SMN2 copynumber was highly correlated with survival duration in SMA type I and ambulation conservation or loss in type III. Among SMA severity groups, it was not significantly different in cases with brainstem involvement. Although the SMN2 copynumber could provide prognostic indications, clinical discrepancies still exist among patients, suggesting the existence of unidentified modifying factors.

Dairy products and the metabolic syndrome in a prospective study, DESIR.

OBJECTIVE: In previous cross-sectional analyses of the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort, we have found inverse associations between dairy product consumption and metabolic syndrome (MetS) traits. We have now analyzed in a prospective way the influence of dairy product and calcium consumption at inclusion on the 9-year cumulative incidence of the MetS and associated traits in the French prospective study with a 9-year follow-up, DESIR. METHODS: After exclusion of diabetic subjects and those being on a diet at inclusion, 3417 men and women who completed a food frequency at baseline could be studied. Logistic regression models were used to study associations between dairy products and dietary calcium density at baseline and incident MetS and impaired fasting glycemia/type 2 diabetes (IFG/T2D) after adjusting for gender, age, and lifestyle parameters (alcohol, smoking, physical activity, fat intake). An additional model adjusting for the same covariates and for body mass index (BMI) was also used. Associations between dairy products and continuous variables were studied by repeated measures analysis of covariance, using the same covariates. RESULTS: Total dairy product consumption, dairy (except cheese) consumption, and dietary calcium density were inversely associated with incident MetS and IFG/T2D. Cheese consumption was negatively associated with incident MetS but not with glycemic disorders. All parameters were associated with lower diastolic blood pressure and triglycerides (average over the 9-year period) and with a lower BMI gain in the same period. Higher total dairy and cheese intake and calcium density were associated with a lower increase in waist circumference and triglycerides during the 9-year follow-up. CONCLUSION: In the French general population, these results show beneficial effects of dairy product consumption on the metabolic syndrome and glycemic disorders. Therefore, dairy product consumption could be protective against cardiovascular risk.

Association of ADIPOQ genetic variants and plasma adiponectin isoforms with the risk of incident renal events in type 2 diabetes.

BACKGROUND: Adiponectin levels are high in cases of diabetic nephropathy, but it remains unclear whether these high levels are a cause or a consequence of the disease. We investigated the possible association of polymorphisms in the adiponectin gene and baseline adiponectin levels with the incidence of renal events in subjects with type 2 diabetes. METHODS: We studied three adiponectin polymorphisms (-11391G > A, +45T > G and +276G > T) in 3086 subjects with type 2 diabetes and high levels of albumin excretion from the diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events and ramipril (DIABHYCAR) trial. Baseline concentrations of total adiponectin and of adiponectin isoforms were determined in cases with incident renal events and in controls matched for sex, age, body mass index (BMI) and adiponectin genotype. We used another cohort of type 2 diabetes patients-the survie, diabète de type 2 et génétique(SURDIAGENE) study (n = 1004)-for the replication of genetic data. RESULTS: In DIABHYCAR, the -11391A and +45G alleles were associated with a higher incidence of renal events [hazard ratio (HR) = 1.73; 95% confidence interval (CI), 1.10-2.71; and HR = 1.68; 95% CI, 1.14-2.47, respectively]. The haplotype containing susceptibility alleles, -11391A/+45G/+276G, was more frequent in cases with renal events (5.1% vs. 1.9% in those without, P = 0.005). In SURDIAGENE, the -11391A/+45G/+276G haplotype was also associated with renal events (5.6% vs. 1.9% in those without, P = 0.03). In DIABHYCAR, all isoforms were more abundant in subjects carrying the -11391A or +45G alleles. Medium- (MMW) and low-molecular weight (LMW) isoforms were more abundant in cases with renal events. CONCLUSIONS: In subjects with type 2 diabetes and early renal dysfunction, adiponectin gene variants are determinants of the renal risk. The -11391A and +45G alleles may affect renal risk by leading to high circulating adiponectin concentrations, at least those of MMW and LMW isoforms.

Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural tube defects: a multicenter case-control study.

Neural tube defects (NTDs) are severe congenital malformations due to failure of neural tube formation in early pregnancy. The proof that folic acid prevents NTDs raises the question of whether other parts of homocysteine (Hcy) metabolism may affect rates of NTDs. This French case-control study covered: 77 women aged 17-42 years sampled prior to elective abortion for a severe NTDs (cases) and 61 women aged 20-43 years with a normal pregnancy. Plasma and erythrocyte folate, plasma B6, B12 and Hcy were tested as five polymorphisms MTHFR 677 C --> T, MTHFR 1298 A --> C, MTR 2756 A --> G, MTTR 66 A --> G and TCN2 776 C --> G. Cases had significantly lower erythrocyte folate, plasma folate, B12 and B6 concentrations than the controls, and higher Hcy concentration. The odds ratio was 2.15 (95% CI: 1.00-4.59) for women with the MTRR 66 A --> G allele and it was decreased for mothers carrying the MTHFR 1298 A --> C allele. In multivariate analysis, only the erythrocyte folate concentration (P = 0.005) and plasma B6 concentration (P = 0.020) were predictors. Red cell folate is the main determinant of NTDs in France. Folic acid supplement or flour fortification would prevent most cases. Increased consumption of vitamins B12 and B6 could contribute to the prevention of NTDs. Genetic polymorphisms played only a small role. Until folic acid fortification becomes mandatory, all women of reproductive age should consume folic acid in a multivitamin that also contains B12 and B6.

Biomarkers of neuroendocrine tumors.

Neuroendocrine tumors (NET) are rare heterogenous tumors which prevalence is increasing. Their features vary by anatomical location, functionality and hormonal production. Their management needs a multidisciplinary approach. Functional tumors develop characteristic clinical syndromes in contrast to non-functional tumors that are diagnosed fortuitously or at advanced stage. NET can secrete many specific and general biomarkers. CgA is the most sensitive general marker. Its value should be interpreted along with the renal function and the gastrin level. Some new biomarkers such as NTproBNP, proGRP and NET gene transcripts have been identified. The latter are not yet routine in clinical practice. We present In this review biological biomarkers involved in NET with a focus on the assays and their use in clinical practice.

Homocysteine concentrations in adults with trisomy 21: effect of B vitamins and genetic polymorphisms.

BACKGROUND: The effects of supplementation with B vitamins and of common polymorphisms in genes involved in homocysteine metabolism on plasma total homocysteine (tHcy) concentrations in trisomy 21 are unknown. OBJECTIVES: We aimed to determine the effects of orally administered folic acid and of folic acid combined with vitamin B-12, vitamin B-6, or both on tHcy in adults with trisomy 21. The study was also intended to analyze the possible influence of gene polymorphisms. DESIGN: One hundred sixty adults with trisomy 21 and 160 healthy, unrelated subjects aged 26 +/- 4 y were included. Plasma tHcy, red blood cell folate, serum folate, and vitamin B-12 were measured. Genotyping for the common methylenetetrahydrofolate reductase (MTHFR) 677C-->T, MTHFR 1298A-->C, cystathionine beta-synthase 844Ins68, methionine synthase 2756A-->C, methionine synthase reductase 66A-->G, and reduced folate carrier 80G-->A polymorphisms was carried out. RESULTS: The mean tHcy concentration (9.8 +/- 0.7 micromol/L) of cases who did not use vitamins was not significantly different from that of controls (9.4 +/- 0.3 micromol/L). Plasma tHcy concentrations (7.6 +/- 0.3 mmol/L) in cases who used folic acid were significantly lower than in cases who did not. Folic acid combined with vitamin B-12 did not significantly change tHcy concentrations compared with those in cases who used only folic acid. Folic acid combined with vitamins B-6 and B-12 significantly lowered tHcy (6.5 +/- 0.5 micromol/L). The difference in tHcy according to MTHFR genotype was not significant. However, tHcy concentrations were slightly higher in TT homozygotes among the controls but not among the cases. CONCLUSION: This study provides information on the relation between several polymorphisms in genes involved in homocysteine and folate metabolism in adults with trisomy 21.

Is hormonal activation during exercise useful for risk stratification in patients with moderate congestive heart failure?

BACKGROUND: We previously demonstrated that A-type natriuretic peptide (ANP) at peak exercise was an independent predictor of cardiac survival. No data are available concerning the predictive value of B-type natriuretic peptide (BNP) at peak exercise. METHODS: One hundred and fifty consecutive stable patients with moderate congestive heart failure (CHF) underwent echocardiography and a cardiopulmonary exercise test. Blood samples were drawn at rest and at peak exercise for the determination of plasma levels of ANP, BNP, and norepinephrine. RESULTS: Exercise significantly increased plasma values of ANP, BNP, and norepinephrine. After a median follow-up period of 1171 days, there were 35 cardiac related deaths. Mortality rates at 1 and 2 years were 4% and 8%, respectively. Independent predictors of cardiac survival were percent of maximal predicted oxygen consumption (RR = 4.8 [2.1-11], P =.002), BNP at rest (RR = 2.5 [1.2-5.6], P =.01), and left atrial diameter (RR = 2.8 [1.2-6.5], P =.02). CONCLUSIONS: In patients with stable, moderate CHF, plasma levels of ANP, BNP, and norepinephrine measured at peak exercise did not improve risk stratification. However, in addition to percent of maximal predicted oxygen consumption and left atrial diameter, plasma level of BNP at rest was an independent predictor of survival in CHF patients with low risk of cardiac events.

[Biological diagnosis of pheochromocytoma in 2014]. / Le diagnostic biologique de phéochromocytome en 2014.

Pheochromocytomas and/or paragangliomas are rare, heterogeneous tumors of the chromaffin cells. Thirty percent of the patients presented with these diseases in a hereditary context. The biological diagnosis relies on the identification of excessive secretion of the metanephrines which are more sensitive and specific than those of catecholamines. The published recommendations give the opportunity to choose between the metanephrines in sera or urines. The concentrations of the free plasmatic metanephrines reflect the ongoing production of tumor. They are little sensitive to the renal failure. The gold standard method to measure the free metaphrines in plasma is the LC-MS/MS chromatography. This is the technical event that we use since 2008, and we relate our experience.

The lactase persistence genotype is associated with body mass index and dairy consumption in the D.E.S.I.R. study.

OBJECTIVE: The T allele of a functional polymorphism (rs4988235: LCT-13910 C>T), close to the lactase gene, correlates with lactase persistence (LP) in adults. The LP genotype (TT+TC) has been associated with a higher BMI in European populations in cross-sectional studies. In the French D.E.S.I.R. cohort, a high consumption of dairy products was associated with a lower body weight gain over 9-years, and with a lower incidence of high plasma glucose levels and/or the metabolic syndrome. Our aim was to test in this study, the association of rs4988235 with BMI and related metabolic diseases, in interaction with dairy product consumption. METHODS: Among 5212 subjects from D.E.S.I.R., 3575 Caucasians born in mainland France were genotyped and followed over 9years. RESULTS: Those with the LP genotype (frequency: 78.5%) had a higher dairy product consumption, at inclusion and at year-9 (P<0.001). They also had a higher BMI at both time points (difference=0.3kg/m(2), P=0.05), but this effect was restricted to medium/high dairy product consumers (difference=0.5kg/m(2), P=0.006). This genotype was also associated with the metabolic syndrome (IDF definition), but this association disappeared after adjustment for BMI. In the whole population, the C allele was associated with a higher prevalence of impaired fasting glycemia and/or type 2 diabetes. CONCLUSIONS: The lactase persistence genotype was shown to be associated with a higher BMI in a longitudinal study, mainly in those consuming high amounts of dairy products. The association of the C allele, responsible for lactase non-persistence, with the risk of hyperglycemia needs to be replicated.

Genetic variability at the six transmembrane protein of prostate 2 locus and the metabolic syndrome: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study.

CONTEXT: The six-transmembrane protein of prostate 2 (STAMP2) has been shown to be involved in insulin resistance in animal models, but in humans, its role is far from understood. Our hypothesis was that genetic variation of STAMP2 could be associated with insulin resistance phenotypes such as the metabolic syndrome (MetS) in humans. OBJECTIVE: Our objective was to search for associations between STAMP2 polymorphisms and the MetS in humans. SUBJECTS AND METHODS: Nine single-nucleotide polymorphisms (SNPs) were tested for associations with the International Diabetes Federation-defined MetS and its constituent parameters in 5212 French Caucasians from the prospective study, Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR), with a 9-yr follow-up. Methods included logistic regression and analysis of covariance adjusting for confounding variables and testing for interactions. RESULTS: None of the SNPs was significantly associated with the prevalence or the incidence of the MetS. The rs12386756 was marginally associated with two parameters of the MetS [triglycerides (P = 0.04) and fasting glucose (P = 0.05)]. An interaction effect between this SNP and fat intake was observed on high-density lipoprotein-cholesterol levels (P = 0.01) and systolic blood pressure (P = 0.03) that is consistent with an interrelation between STAMP2 and nutrition. Three SNPs were associated with insulin levels, but these SNPs were not associated with other features of the MetS. CONCLUSION: These findings suggest that the common polymorphisms of STAMP2 are unlikely to significantly contribute to the risk of the MetS in the general population, but relationships with insulin and interactions with fat intake need to be replicated.

Association of common variants in NPPA and NPPB with blood pressure does not translate into kidney damage in a general population study.

BACKGROUND: The polymorphisms rs198358, rs5068 and rs632793 in the natriuretic peptide precursor A-B gene region [encoding atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP)] have been recently associated with ANP and BNP plasma concentrations and blood pressure (BP) in a large cohort study. METHODS: We observed that GCG, the haplotype based on these polymorphisms and combining the three rare alleles associated with higher natriuretic peptides and lower BP in a recent report, was associated with BNP plasma levels and BP in a French study of 5212 middle-aged participants, Epidemiological Data on Insulin Resistance Syndrome study. With the 9-year follow-up of Epidemiological Data on Insulin Resistance Syndrome study, we were able to analyze the association of incident microalbuminuria (576 patients) and low estimated glomerular filtration rate (<60 ml/min; 246 incident patients) with the tested haplotypes. RESULTS: No haplotype, including GCG, the one combining the three rare alleles, was associated with incident patients of either microalbuminuria [odds ratio 1.27 (0.91-1.78), P = 0.15] or low estimated glomerular filtration rate [odds ratio 0.88 (0.54-1.46), P = 0.63]. CONCLUSION: This was consistent with a lack of effect on clinical renal outcomes found in previous studies and showed that even replicated and biologically plausible genetic association studies based on surrogate markers do not easily translate into clinically meaningful prognosis.

Relationships between common polymorphisms of adenosine triphosphate-binding cassette transporter A1 and high-density lipoprotein cholesterol and coronary heart disease in a population with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (T2D) have a high coronary risk partly because of low levels of high-density lipoprotein-cholesterol (HDL-C). The adenosine triphosphate-binding cassette transporter A1 (ABCA1) plays a key role in HDL metabolism. We studied the association of common single nucleotide polymorphisms (SNPs) in the ABCA1 gene with HDL-C levels and coronary risk in a cohort of subjects with T2D. We studied 5 SNPs: +69C>T, +378G>C, R219K, I883M, and R1587K. The C allele of +378G>C was significantly associated with lower HDL-C concentrations (P = .04); and the M allele of I883M, with higher HDL-C concentrations (P = .03). No significant association was found between these SNPs and the incidence of new coronary events. Nevertheless, cross-sectional data on entry showed that the frequency of K219 was lower in patients with previous coronary heart disease (angina pectoris and/or myocardial infarction) (odds ratio, OR [95% confidence interval, CI] = 0.80 [0.65-0.98], P = .03, after adjustment for multiple risk factors other than HDL-C). The frequency of K1587 was higher in patients with angina pectoris (OR [95% CI] = 1.27 [1.01-1.58], P = .04, after multiple adjustment). The TT genotype of the C69T SNP was less frequent in subjects with prior myocardial infarction (OR [95% CI] = 0.28 [0.13-0.61], P = .001, after multiple adjustment). These associations persisted after further adjustment for HDL-C levels. In conclusion, common genetic variations of ABCA1 had a moderate influence on HDL-C levels and/or coronary heart disease in patients with T2D. These 2 effects were independent.

Local-regional recurrence of sporadic or syndromic abdominal extra-adrenal paraganglioma: incidence, characteristics, and outcome.

BACKGROUND: Operative excision of abdominal extra-adrenal paragangliomas (EAPs) does not preclude the late development of local-regional recurrence. We describe the incidence, characteristics, and outcome of this rarely reported feature. METHODS: Retrospective analysis of local-regional recurrence that occurred during follow-up of 51 consecutive patients operated for a sporadic (n = 26) or hereditary (n = 25) EAP. RESULTS: Seven patients with a sporadic or syndromic EAP (n = 4: von Hippel-Lindau syndrome and SDHB, SDHC, and SDHD gene mutations) underwent reoperation for a local-regional recurrence after a median time of 46 months (interquartile range [IQR], 16-100). The Kaplan-Meier estimated incidence of local-regional recurrence (+/- standard error of the mean) reached 15% +/- 7% at 5 years and 23% +/- 9% after 10 years. Recurrent EAPs were all secreting and 38% provoked clinical symptoms. New lesions were smaller than the primary EAP (P = .01) and more often associated with lymph node metastases (43% vs 4%, P = .01). Operative excision seemed complete in 5 patients. Clinical remission was maintained in 4 patients after a median follow-up of 57 months (IQR, 22-102). CONCLUSION: Local-regional recurrence of sporadic and syndromic EAPs is frequent and may be delayed beyond 10 years, requiring lifelong follow-up after the initial operation. When technically feasible, operative excision can lead to prolonged remission.

No association between common polymorphisms in genes of folate and homocysteine metabolism and the risk of Down's syndrome among French mothers.

The cause of the non-disjunction leading to trisomy 21 remains unclear. Recent evidence has suggested that 5,10-methylenetetrahydrofolate reductase (MTHFR) and/or methionine synthase reductase (MTRR) might contribute to the maternal risk of trisomy 21. The purpose of the present study was to analyse these findings among the French population and to investigate whether common polymorphisms in genes of the folate and homocysteine pathway, including the MTHFR 677C > T, MTHFR 1298A > C, the methionine synthase (MTR) 2756A > G, the cystathionine beta-synthase (CBS) 844Ins68 and the reduced folate carrier (RFC-1) 80G > A polymorphisms, contribute to the risk of trisomy 21. The risk was studied by analysing independent and combined genotypes in 119 case mothers and 119 control mothers. The MTHFR 677T, MTHFR 1298C, MTR2756G, MTRR66G, CBSIns68+ and the RFC-1 80G allele frequencies were not significantly different among French case mothers, compared with control mothers. The risk of having a child with trisomy 21 did not appear to be linked to polymorphisms in genes associated with folate and homocysteine metabolism.