A Simple Questionnaire as a First-Step Tool to Detect Specific Frailty Profiles: The Lorraine Frailty-Profiling Screening Scale.

OBJECTIVES: To propose a simple frailty screening tool able to identify frailty profiles. DESIGN: Cross-sectional observational study. SETTING: Participants were recruited in 3 different clinical settings: a primary care outpatient clinic (RURAL population, N=591), a geriatric day clinic (DAY-CLINIC population, N=76) and healthy volunteers (URBAN population, N=147). PARTICIPANTS: A total of 817 older adults (>70 years old) living at home were included. INTERVENTION: A 9-item questionnaire (Lorraine Frailty Profiling Screening Scale, LoFProSS), constructed by an experts' working group, was administered to participants by health professionals. MEASUREMENTS: A Multiple Correspondence Analysis (MCA) followed by a hierarchical clustering of the results of the MCA performed in each population was conducted to identify participant profiles based on their answers to LoFProSS. A response pattern algorithm was resultantly identified in the RURAL (main) population and subsequently applied to the URBAN and DAY-CLINIC populations and, in these populations, the two classification methods were compared. Finally, clinically-relevant profiles were generated and compared for their ability to similarly classify subjects. RESULTS: The response pattern differed between the 3 sub-populations for all 9 items, revealing significant intergroup differences (1.2±1.4 positive responses for URBAN vs. 2.1±1.3 for RURAL vs. 3.1±2.1 for DAY-CLINIC, all p<0.05). Five clusters were highlighted in the main RURAL population: "non-frail", "hospitalizations", "physical problems", "social isolation" and "behavioral", with similar clusters highlighted in the remaining two populations. Identification of the response pattern algorithm in the RURAL population yielded a second classification approach, with 83% of tested participants classified in the same cluster using the 2 different approaches. Three clinically-relevant profiles ("non-frail" profile, "physical frailty and diseases" profile and "cognitive-psychological frailty" profile) were subsequently generated from the 5 clusters. A similar double classification approach as above was applied to these 3 profiles revealing a very high percentage (95.6%) of similar profile classifications using both methods. CONCLUSION: The present results demonstrate the ability of LoFProSS to highlight 3 frailty-related profiles, in a consistent manner, among different older populations living at home. Such scale could represent an added value as a simple frailty screening tool for accelerated and better-targeted investigations and interventions.

Body mass index growth trajectories associated with the different parameters of the metabolic syndrome at adulthood.

BACKGROUND: Growth trajectories have shown to be related to obesity and metabolic risks in later life, however body mass index (BMI) trajectories according to the presence or absence of metabolic syndrome (MS) and its parameters in adulthood are scarce in literature. OBJECTIVES: To investigate BMI trajectories during childhood in relation to MS and its parameters in adult age. METHODS: A total of 1919 subjects (43.4% male, 20-60 y) participated in this retrospective cohort study. Height, weight, waist circumference (WC), blood glucose, high-density lipoprotein cholesterol, triglycerides and blood pressure were measured at adulthood. Childhood weight and height were collected retrospectively from health booklets. Differences between BMI growth curves of subjects with and without MS were assessed using mixed models for correlated data. RESULTS: BMI trajectories differed according to the presence or not of MS at adulthood, from the age of 4 years forward (all P<0.05), to the presence or not of hypertriglyceridemia from 1.5 years forward (all P<0.05), and to WC>94 cm (men) / 80 cm (women) compared to lower WC, at all ages (all P<0.05). CONCLUSIONS: BMI growth curves differ according to the presence or not of MS at adulthood, but differences only appeared after the age of 4 years. Changes vary according to the MS parameters considered. Deviation of the MS-associated BMI curve from normal pattern could correspond to alteration in body composition. These differences in BMI trajectories during childhood support the theory of an early origin of the MS, justifying early prevention.

Age at adiposity rebound: determinants and association with nutritional status and the metabolic syndrome at adulthood.

OBJECTIVE: Early-life growth characteristics and in particular age at adiposity rebound (AR), have been shown to impact nutritional status later in life but studies investigating the association with long-term health remain scarce. Our aims were to identify determinants of age at AR and its relationship with nutritional status and cardiometabolic risk factors at adulthood. DESIGN: A total of 1465 subjects aged 20-60 years participated in this retrospective cohort study. Height, weight, waist circumference, blood glucose, lipids and blood pressure were measured at adulthood. Childhood weight, height, gestational age, birth weight and early nutrition were collected retrospectively from health booklets and age at AR was assessed. Participants self-reported parental silhouettes. Associations were assessed using multiple linear and logistic regression. RESULTS: An earlier AR was associated with higher body mass index and waist circumference at adulthood in both men and women (P<0.0001). In addition, women with an earlier occurrence of AR had higher triglyceride (P=0.001), low-density lipoprotein-cholesterol (P=0.001), systolic (P=0.02) and diastolic blood pressure (P=0.04) at adulthood. Both men (odds ratio (OR) (95% confidence interval (CI)): 0.82 (0.70-0.95)) and women (OR (95% CI): 0.84 (0.73-0.96) with an AR occurring earlier were more likely to develop a metabolic syndrome. Larger parental silhouette was associated with an earlier AR. CONCLUSIONS: This long-term study showed that age at AR was associated with nutritional status and metabolic syndrome at adulthood. These results highlight the importance of monitoring childhood growth so as to help identify children at risk of developing an adverse cardiometabolic profile in adulthood. AR determinants for use in overweight surveillance were identified.

[Effect of coronary risk and of hypertension on renal risk in the general population]. / Impact du risque coronarien et de l'hypertension sur le risque rénal en population générale.

INTRODUCTION: Abnormal albuminuria (≥ 30 mg/g) and low estimated glomerular filtration rate (eGFR<60 mL/min/1.73 m(2)) not only are renal risk factors, but also cardiovascular and coronarian risk factors. Though, the relation between coronary risk and renal risk, and its interaction with insufficiently controlled brachial pressure (BP) is poorly described in the literature. SUBJECTS AND METHODS: We realised a cross-sectional study on subjects 40 and older, having attended a medical exam in 11 IRSA centers between 2006 and 2010. Every subject filled a questionnaire, underwent biological analysis, and a clinical examination. eGFR and albuminuria were measured, and the 10-year risk of coronarian event was calculated (Laurier's equation) RESULTS: We analysed 118,314 subjects, amongst whom 96,400 had no personal cardiovascular history. Amongst those, 9.1% had a 10-year coronary risk over 10%. There was a continuous relationship between coronary risk and renal risk: subjects with a risk above 15% had a significative risk of pathological albuminuria (OR: 6.87 [5.58-8.44]), and of low eGFR (2.26 [1.82-2.78]) compared to those with a risk under 5%. There was a continuous relationship between BP and renal risk, with a significative risk of pathological albuminuria (OR=7.75 [6.69-8.96]) and of low eGFR (OR: 1.33 [1.09-1.60]) in subjects with BP greater than or equal to 180/110 mmHg, compared to those with normal BP. CONCLUSION: In the French population, 9.1% of subjects have a 10-year coronary risk above 10%. This risk is associated to abnormalities of the renal function. The relation between coronary risk and renal risk is continuous and dose-dependent, as is the relation between BP and renal risk.

Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels.

AIMS/HYPOTHESIS: We previously identified the G6PC2 locus as a strong determinant of fasting plasma glucose (FPG) and showed that a common G6PC2 intronic single nucleotide polymorphism (SNP) (rs560887) and two common G6PC2 promoter SNPs (rs573225 and rs13431652) are highly associated with FPG. However, these promoter SNPs have complex effects on G6PC2 fusion gene expression, and our data suggested that only rs13431652 is a potentially causative SNP. Here we examine the effect of rs560887 on G6PC2 pre-mRNA splicing and the contribution of an additional common G6PC2 promoter SNP, rs2232316, to the association signal. METHODS: Minigene analyses were used to characterise the effect of rs560887 on G6PC2 pre-mRNA splicing. Fusion gene and gel retardation analyses characterised the effect of rs2232316 on G6PC2 promoter activity and transcription factor binding. The genetic association of rs2232316 with FPG variation was assessed using regression adjusted for age, sex and BMI in 4,220 Europeans with normal FPG. RESULTS: The rs560887-G allele was shown to enhance G6PC2 pre-mRNA splicing, whereas the rs2232316-A allele enhanced G6PC2 transcription by promoting Foxa2 binding. Genetic analyses provide evidence for association of the rs2232316-A allele with increased FPG (ß = 0.04 mmol/l; p = 4.3 × 10(-3)) as part of the same signal as rs560887, rs573225 and rs13431652. CONCLUSIONS/INTERPRETATION: As with rs13431652, the in situ functional data with rs560887 and rs2232316 are in accord with the putative function of G6PC2 in pancreatic islets, and suggest that all three are potentially causative SNPs that contribute to the association between G6PC2 and FPG.

Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population.

CONTEXT: Obesity is the major determinant of type 2 diabetes (T2D), presumably through its effect on insulin resistance. Genome-wide association studies reported many single-nucleotide polymorphisms (SNPs) that increase obesity risk and body mass index (BMI), but their impact on T2D-related traits and risk is unclear. OBJECTIVE: We aimed at analyzing the effect of 24 obesity risk alleles, separately and in combination, on variation of both insulin resistance and ß-cell dysfunction, and on T2D risk. DESIGN: We genotyped 24 obesity-associated SNPs and calculated an obesity genotype score (sum of the obesity risk alleles per individual). We analyzed the contribution of each SNP and this score to the variation of four metabolic indices: homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of the pancreatic ß-cell function (HOMA-B), insulin sensitivity index (ISI) and insulinogenic index (II) (in up to 8050 nondiabetic French individuals) and to T2D risk (in 2077 T2D cases and 3085 controls). RESULTS: We found a highly significant effect of the obesity genotype score on increased insulin resistance adjusted for age and gender (ß=0.02; P-value=7.16 × 10(-9) for HOMA-IR). Individually, we identified nominal or significant association between increased insulin resistance and risk alleles in FAIM2, FTO, GNPDA2, MC4R, NPC1, PTER and SH2B1. Most signals, including the obesity genotype score and FTO SNP, were also associated with increased ß-cell function (ß=0.01; P-value=1.05 × 10(-6) and ß=0.04; P-value=3.45 × 10(-4), respectively). In our T2D case-control study, only the obesity genotype score and the well-known FTO locus significantly contributed to T2D risk (OR=1.03; P-value=9.99 × 10(-3) and OR=1.15; P-value=9.46 × 10(-4), respectively). Adjustment for BMI abolished all significant associations. CONCLUSIONS: Genetic predisposition to obesity contributes to increased insulin resistance and to its compensation through increased ß-cell function, and weakly increases the T2D risk. These associations are mediated by BMI.

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes.

AIMS/HYPOTHESIS: MODY is believed to be caused by at least 13 different genes. Five rare mutations at the BLK locus, including only one non-synonymous p.A71T variant, were reported to segregate with diabetes in three MODY families. The p.A71T mutation was shown to abolish the enhancing effect of BLK on insulin content and secretion from pancreatic beta cell lines. Here, we reassessed the contribution of BLK to MODY and tested the effect of BLK-p.A71T on type 2 diabetes risk and variations in related traits. METHODS: BLK was sequenced in 64 unelucidated MODY samples. The BLK-p.A71T variant was genotyped in a French type 2 diabetes case-control study including 4,901 cases and 4,280 controls, and in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) and SUVIMAX (Supplementation en Vitamines et Mineraux Antioxydants) population-based cohorts (n = 6,905). The variant effects were assessed by logistic and linear regression models. RESULTS: No rare non-synonymous BLK mutations were found in the MODY patients. The BLK p.A71T mutation was present in 52 normoglycaemic individuals, making it very unlikely that this loss-of-function mutation causes highly penetrant MODY. We found a nominal association between this variant and increased type 2 diabetes risk, with an enrichment of the mutation in the obese diabetic patients, although no significant association with BMI was identified. CONCLUSIONS/INTERPRETATION: No mutation in BLK was found in our MODY cohort. From our findings, the BLK-p.A71T mutation may weakly influence type 2 diabetes risk in the context of obesity; however, this will require further validation.

Dietary fat intake and polymorphisms at the PPARG locus modulate BMI and type 2 diabetes risk in the D.E.S.I.R. prospective study.

CONTEXT: Fat-rich diets are involved in many disorders such as obesity and type 2 diabetes (T2D). The Pro12Ala variant of peroxisome proliferator-activated receptor-γ (PPARγ) is known to modulate body mass index (BMI) and T2D risk. OBJECTIVE: Our aim was to study the interaction effect between PPARγ gene (PPARG) polymorphisms Pro12Ala and 1431C>T and fat intake on incident T2D and BMI in a 9-year prospective cohort drawn from the French general population, the D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance Syndrome) study (n=4676). METHODS: Nutritional intake was assessed by a food frequency self-questionnaire completed by each participant. Statistical analyses included logistic regression, analysis of covariance and haplotype analysis, with adjustment for confounding variables. RESULTS: A high fat consumption (the third sex-specific tertile of fat intake, as a percentage of energy intake) was associated with an increased T2D risk among ProPro and CC homozygotes (P(interaction)=0.05, odds ratio (OR) (95% confidence interval (95% CI))=1.73 (1.19-2.52) P=0.004 and OR=1.85 (1.27-2.71) P=0.001, respectively) but not in Ala and T carriers. There was a significant interaction effect between Pro12Ala and 1431C>T on BMI (P(interaction)=0.004); Ala was associated with lower BMI in CC homozygotes and with higher BMI in T carriers while the opposite was found for ProPro. There was also an interaction effect between Pro12Ala and dietary fat intake on BMI (P(interaction)=0.02); AlaAla individuals had a higher BMI than Pro carriers among high fat consumers (27.1 ± 1.0 versus 24.9 ± 0.1 for AlaAla and Pro+, respectively). There was no interaction effect between the 1431C>T single-nucleotide polymorphism and fat intake on BMI. CONCLUSION: Our results indicate strong genetic and nutritional interaction effects on BMI and T2D risk at the PPARG locus in a general population.

Evaluating physical activity: the AQAP questionnaire and its interpretation software.

OBJECTIVES: Updating Baecke physical activity questionnaire in French, validating this version named AQAP and developing software for a personalized interpretation of the results. METHOD: Validation conducted on 702 consultants in health prevention centers aged 18-79 years: reliability of the questionnaire when self-administered, validity according to the energy expenditure per interview and reproducibility after two weeks (n=31). After two months, assessment of the questionnaire's impact on knowledge and behaviors in 320 young adults aged 18-29 years. RESULTS: The results from self- and interviewer-administered questionnaire were correlated (Kappa>0.60). Furthermore, the total physical activity index was correlated to the energy expenditure (rho=0.39, P<0.0001). The four physical activity indexes calculated from self-administrated questionnaires barely varied at the two-week interval (P ≥ 0.23, power ≥ 77%, accepted difference ± 10%). Two months later, 80% of the participants had read the interpretation software report, 55% became conscious of their physical activity level, 43% increased their physical activity level and 42% reported being aware of the relationship between physical activity and health. CONCLUSION: AQAP characteristics are satisfactory and thus this questionnaire can be used on the general population in complement of an individual or collective action to promote physical activity and in epidemiological studies for analyzing the links between individual behaviors and health.

Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept.

AIMS/HYPOTHESIS: Evidence suggests that bacterial components in blood could play an early role in events leading to diabetes. To test this hypothesis, we studied the capacity of a broadly specific bacterial marker (16S rDNA) to predict the onset of diabetes and obesity in a general population. METHODS: Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) is a longitudinal study with the primary aim of describing the history of the metabolic syndrome. The 16S rDNA concentration was measured in blood at baseline and its relationship with incident diabetes and obesity over 9 years of follow-up was assessed. In addition, in a nested case-control study in which participants later developed diabetes, bacterial phylotypes present in blood were identified by pyrosequencing of the overall 16S rDNA gene content. RESULTS: We analysed 3,280 participants without diabetes or obesity at baseline. The 16S rDNA concentration was higher in those destined to have diabetes. No difference was observed regarding obesity. However, the 16S rDNA concentration was higher in those who had abdominal adiposity at the end of follow-up. The adjusted OR (95% CIs) for incident diabetes and for abdominal adiposity were 1.35 (1.11, 1.60), p = 0.002 and 1.18 (1.03, 1.34), p = 0.01, respectively. Moreover, pyrosequencing analyses showed that participants destined to have diabetes and the controls shared a core blood microbiota, mostly composed of the Proteobacteria phylum (85-90%). CONCLUSIONS/INTERPRETATION: 16S rDNA was shown to be an independent marker of the risk of diabetes. These findings are evidence for the concept that tissue bacteria are involved in the onset of diabetes in humans.

Number of children and change in markers of metabolic health over 9-years in men and women. Data from the DESIR study.

AIM: Parity is associated with an increased risk of coronary heart disease and type 2 diabetes, possibly mediated by long-term modification of metabolic health. Studying associations between the number of children with health and disease in men in addition to women allows for differentiation between the social and lifestyle influences of child-rearing, and the biological influences of childbearing. We sought to determine whether the number of children is associated with the incidence of raised fasting glucose (fasting plasma glucose≥6.1 mmol/L) and changes in glucose, insulin, insulin resistance and ß-cell function over 9-years. METHODS: Analysis of 1798 women and 1737 men from the DESIR study. RESULTS: The number of children was associated with change in fasting glucose for women (P(trend)=0.02) and men (P(trend)=0.03), and increased incidence of raised fasting glucose by 30% (95% CI: 15, 47%) per child for men, but not women (3% [95% CI: -8, 15%]). There was a J-shaped association between number of children and change in insulin (P=0.01) and insulin resistance (P=0.005) for women, and a reduction in ß-cell function in parous women (P=0.07). Men with children had increases in insulin (P=0.02), insulin resistance (P=0.02), and ß-cell function (P=0.07). CONCLUSIONS: The number of children a person has is associated with changes in metabolic health indices long after childbirth for both men and women. The distinct gender differences in deterioration of metabolic health indices emphasize that childbearing and child-rearing are likely to have differential influences on metabolic health.

Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study.

AIMS/HYPOTHESIS: We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study. METHODS: We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312. RESULTS: We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group. CONCLUSIONS/INTERPRETATION: The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.

[Adrenal tumors of fortuitous discovery. 13 cases]. / Tumeurs surrénaliennes de découverte fortuite. Treize observations.

An adrenal mass without any clinical or biological symptom was accidentally discovered in thirteen patients. All patients underwent surgical exploration. After surgery, pathological studies showed lesions of corticosuprarenaloma (5 considered benign, 1 malignant and 1 uncertain) myelolipoma (2 cases), adrenal cyst, ganglioneuroma, haemangioma and lymphangioma (1 case each). Since no reliable preoperative investigations are yet available to assess the nature of adrenal masses, and since these may be due to benign or malignant endocrine tumours, their surgical removal is indicated.