leptin and Cystic-Fibrosis

Leptin (LEP) acts as a proinflammatory cytokine and may play an important role in the pathophysiology of cystic fibrosis (CF). This review aimed to assess the quantitative difference in leptin status between CF patients and non-CF controls.. In this study, the researchers conducted systematic searches of various databases, such as PubMed, Excerpta Medica Database, Google Scholar, Web of Science, and the China National Knowledge Infrastructure. The data collected from the above databases were assessed using the Stata 11.0 and R 4.1.3 software. The correlation coefficients and the Standardized Mean Differences (SMD) were employed to assess the effect size. A combination analysis was also carried out with the help of either a fixed-effects or random-effects model. In addition, the single-cell sequencing GSE193782 dataset was obtained to determine the mRNA expression levels of LEP and leptin receptor (LEPR) in the bronchoalveolar lavage fluid, to verify the different leptin expression between the CF patients and healthy controls.. A total of 919 CF patients and 397 controls from 14 articles were included in this study. CF patients and non-CF controls showed similar serum/plasma leptin levels. Gender, specimen testing, age, and study design were all taken into account for carrying out subgroup analyses. The results revealed no variations in serum/plasma leptin levels between the controls and CF patients in the various subgroups. Female CF patients exhibited higher leptin concentrations compared to male CF patients, and male healthy individuals showed lower leptin levels than female healthy participants. Aside from the fact that serum/plasma leptin appeared to be favorably linked to fat mass and BMI, the findings in this study also indicated that serum/plasma concentrations were not associated with Forced Expiratory Volume in the first second (FEV1). No statistically significant differences were observed in the leptin and leptin receptor mRNA expression levels between the healthy controls and CF patients. The leptin receptor and leptin expression levels in alveolar lavage fluid were low in various cells, without any distinctive distribution patterns.. The current meta-analysis indicated the absence of significant differences in leptin levels between CF patients and healthy individuals. Gender, fat mass, and BMI may all be correlated with leptin concentrations.. https://www.crd.york.ac.uk/prospero/, identifier CRD42022380118.

Topics: China; Cystic Fibrosis; Female; Humans; Leptin; Male; Receptors, Leptin; RNA, Messenger

The relative importance of molecular biology in clinical practice is often underestimated. However, numerous procedures in clinical diagnosis and new therapeutic drugs have resulted from basic molecular research. Furthermore, understanding of the physiological and physiopathological mechanisms underlying several human diseases has been improved by the results of basic molecular research. For example, cloning of the gene encoding leptin has provided spectacular insights into the understanding of the mechanisms involved in the control of food intake and body weight maintenance in man. In cystic fibrosis, the cloning and identification of several mutations in the gene encoding the chloride channel transmembrane regulator (CFTR) have resolved several important issues in clinical practice: cystic fibrosis constitutes a molecular defect of a single gene. There is a strong correlation between the clinical manifestations or the severity of the disease (phenotype) with the type of mutations present in the CFTR gene (genotype). More recently, identification of mutations in the gene encoding a subunit of the renal sodium channel in the Liddle syndrome has provided important insight into the physiopathological understanding of mechanisms involved in this form of hereditary hypertension. Salt retention and secondary high blood pressure are the result of constitutive activation of the renal sodium channel by mutations in the gene encoding the renal sodium channel. It is speculated that less severe mutations in this channel could result in a less severe form of hypertension which may correspond to patients suffering from high blood pressure with low plasma renin activity. Several tools, most notably PCR, are derived from molecular research and are used in everyday practice, i.e. in prenatal diagnosis and in the diagnosis of several infectious diseases including tuberculosis and hepatitis. Finally, the production of recombinant proteins at lower cost and with fewer side effects is used in everyday clinical practice. Gene therapy remains an extraordinary challenge in correcting severe hereditary or acquired diseases. The use of genetically modified animal cell lines producing growth factors, insulin or erythropoetin, which are subsequently encapsulated and transferred to man, represents an attractive approach for gene therapy.

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Engineering; Genetic Therapy; Genetics, Medical; Humans; Hyperaldosteronism; Leptin; Molecular Biology; Obesity; Prenatal Diagnosis; Proteins; Sodium Channels

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator for people with CF and the G551D mutation. We aimed to investigate the biology of CFTR modulation and systemic effects of CFTR restoration by examining changes in circulating measurements of inflammation and growth and novel proteins with ivacaftor treatment.. Blood samples from 64 CF subjects with G551D-CFTR were analyzed for inflammatory and growth-related proteins at baseline, 1 and 6 months after ivacaftor initiation. In 30 subjects, plasma was assayed for 1,322 proteins using the SomaScan proteomic platform at baseline and 6 months post-ivacaftor. Correlations with clinical outcomes were assessed.. Significant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A, and granulocyte colony-stimulating factor (G-CSF), and an increase in insulin-like growth factor (IGF-1) occurred 1 month after ivacaftor. This treatment effect was sustained at 6 months for HMGB-1 and calprotectin. Correcting for multiple comparisons in the proteomic analysis, 9 proteins (albumin, afamin, leptin, trypsin, pancreatic stone protein [PSP], pituitary adenylate cyclase-activating polypeptide-38, repulsive guidance molecule A [RGMA], calreticulin, GTPase KRas) changed significantly with ivacaftor. Proteins changing with treatment are involved in lipid digestion and transport and extracellular matrix organization biological processes. Reductions in calprotectin and G-CSF and increases in calreticulin, and RGMA correlated with improved lung function, while increasing IGF-1, leptin and afamin and decreasing PSP correlated with increased weight.. Ivacaftor led to changes in inflammatory, lipid digestion, and extracellular matrix proteins, lending insights into the extrapulmonary effects of CFTR modulation.

Topics: Aminophenols; Calreticulin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Granulocyte Colony-Stimulating Factor; HMGB Proteins; Humans; Inflammation; Insulin-Like Growth Factor I; Leptin; Leukocyte L1 Antigen Complex; Lipids; Mutation; Proteome; Proteomics; Respiratory System Agents

Optimization of nutritional status is recommended in patients with cystic fibrosis (CF) given the association between lower body mass index (BMI) and poor clinical outcomes. However, higher BMI and body fat correlate with glucose impairment and higher leptin levels in the general population. Differences in body composition and leptin levels between the categories of glucose tolerance were assessed in youth with CF and healthy controls.. In a cross-sectional study, 59 adolescents and young adults with CF and 15 healthy controls matched by age and gender, underwent body composition analysis using dual energy X-ray absorptiometry (DXA) and a 2-hour oral glucose tolerance test (OGTT). Measures of insulin sensitivity, β-cell insulin secretion and fasting leptin levels were obtained.. Of the participants with CF, 62% were classified as abnormal glucose tolerant and 22% with cystic fibrosis related diabetes (CFRD). Patients with CFRD had a lower fat mass index (FMI) z-score, wt z-score and leptin levels compared to the control group (-1.86 vs. - 0.59, p=0.01; -1.86 vs 0.44, p=<0.001 and 7.9 vs vs. 27.7 µg/L, p=0.01). Leptin correlated positively with FMI z-score, BMI, weight z-score and indices of insulin secretion. FMI z-score correlated positively with higher insulin resistance (HOMA-IR), and lower insulin sensitivity (Matsuda index) (r=0.31; p =0.01 and r=-0.29; p=0.02, respectively) in the CF group.. This study shows that despite new therapeutic strategies, youth with CF have lower body fat, weight z-score and leptin levels, particularly in subjects with early onset CFRD.

Topics: Absorptiometry, Photon; Adolescent; Adult; Body Composition; Child; Cross-Sectional Studies; Cystic Fibrosis; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Insulin-Secreting Cells; Leptin; Male; Young Adult

Negative energy balance is a prevalent feature of cystic fibrosis (CF). Pancreatic insufficiency, elevated energy expenditure, lung disease, and malnutrition, all characteristic of CF, contribute to the negative energy balance causing low body-growth phenotype. As low body weight and body mass index strongly correlate with poor lung health and survival of patients with CF, improving energy balance is an important clinical goal (e.g., high-fat diet). CF mouse models also exhibit negative energy balance (growth retardation and high energy expenditure), independent from exocrine pancreatic insufficiency, lung disease, and malnutrition. To improve energy balance through increased caloric intake and reduced energy expenditure, we disrupted leptin signaling by crossing the db/db leptin receptor allele with mice carrying the R117H Cftr mutation. Compared with db/db mice, absence of leptin signaling in CF mice (CF db/db) resulted in delayed and moderate hyperphagia with lower de novo lipogenesis and lipid deposition, producing only moderately obese CF mice. Greater body length was found in db/db mice but not in CF db/db, suggesting CF-dependent effect on bone growth. The db/db genotype resulted in lower energy expenditure regardless of Cftr genotype leading to obesity. Despite the db/db genotype, the CF genotype exhibited high respiratory quotient indicating elevated carbohydrate oxidation, thus limiting carbohydrates for lipogenesis. In summary, db/db-linked hyperphagia, elevated lipogenesis, and morbid obesity were partially suppressed by reduced CFTR activity. CF mice still accrued large amounts of adipose tissue in contrast to mice fed a high-fat diet, thus highlighting the importance of dietary carbohydrates and not simply fat for energy balance in CF. NEW & NOTEWORTHY We show that cystic fibrosis (CF) mice are able to accrue fat under conditions of carbohydrate overfeeding, increased lipogenesis, and decreased energy expenditure, although length was unaffected. High-fat diet feeding failed to improve growth in CF mice. Morbid db/db-like obesity was reduced in CF double-mutant mice by reduced CFTR activity.

Topics: Adipose Tissue; Animals; Cystic Fibrosis; Diet, Carbohydrate Loading; Female; Leptin; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Obesity; Signal Transduction

Cystic fibrosis (CF)-related diabetes is an important complication of CF caused by a decrease in insulin secretion that is associated with weight loss, poor nutritional status and increased mortality. Leptin, a hormone secreted from white adipose tissue, has an important role in energy homoeostasis by inhibiting food intake and increasing energy expenditure. Leptin secretion can be increased by nutrient signals such as insulin.. Considering that leptin plays a role in energy homoeostasis and that CF is associated to poor weight gain and decreased insulin secretion, leptin levels in CF patients with different glucose tolerances were investigated and compared with those of healthy control subjects.. Two-hour oral glucose tolerance tests (OGTT) were performed in 82 patients with CF and various glucose tolerances as well as in 17 healthy control subjects during which blood was withdrawn every 30 min to measure glucose and insulin. Fasting leptin, fibrinogen and fat mass were also measured, and body mass index (kg/m(2)) calculated for all participants. Early and late insulin secretion was separated by calculating the area under the curve from time 0 to 30 min and 30 to 120 min of the OGTT (AUC(0-30) and AUC(30-120)).. Leptin levels were comparable between CF patients and healthy control subjects. Interestingly, correlations were observed between leptin levels and insulin (AUC(0-120) and AUC(30-120)) after adjusting for gender and fat mass (P<0.05).. This study suggests a potential role of insulin in regulating leptin levels in adults with stable CF.

Topics: Adult; Area Under Curve; Blood Glucose; Body Mass Index; Canada; Cohort Studies; Cystic Fibrosis; Diabetes Mellitus; Fasting; Female; Fibrinogen; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Male; Prospective Studies

Fat-free mass depletion has been related to increased inflammatory activity and to increased morbidity and mortality in chronic respiratory diseases. The aims of our study were to determine the nutritional status and serum levels of adipocytokines and inflammatory cytokines in patients with bronchiectasis of any etiology and their relation with respiratory parameters. A cross-sectional study was designed that included patients aged >14 years with diagnostic criteria for bronchiectasis. Anthropometric parameters; a diet questionnaire; hand grip dynamometry; levels of leptin, adiponectin, interleukin-6 (IL-6), tumor necrosis factor-α, and ultrasensitive C-reactive protein; as well as respiratory parameters (ie, clinical, radiologic, and spirometric values) were assessed. Ninety-three clinically stable patients were recruited, 43 with cystic fibrosis, 31 with noncystic fibrosis bronchiectasis, and 19 with cystic fibrosis transmembrane conductance regulator-related bronchiectasis. Fat-free mass depletion was present in 31% of patients, with no differences according to the etiology of the bronchiectasis. Correlations were found between inflammatory cytokines (ie, IL-6) and exacerbations, bronchorrea, forced expiratory volume in 1 second, and Bhalla score. Patients with worse respiratory disease severity, malnutrition, and diabetes had significantly higher levels of IL-6. Adiponectin correlated significantly and positively with fat mass and fat mass index and negatively with fat-free mass, fat-free mass index, and hand dynamometry. Leptin correlated positively with body mass index, fat mass and fat mass index, and negatively with fat-free mass, fat-free mass index, and dynamometry. Patients with bronchiectasis present a high percentage of fat-free mass depletion, independent of the etiology of the disease. The levels of inflammatory cytokines (especially IL-6) may be useful markers of disease severity. Adiponectin levels were higher in patients with fat-free mass depletion.

Topics: Adipokines; Adult; Biomarkers; Body Composition; Body Mass Index; Bronchiectasis; C-Reactive Protein; Cross-Sectional Studies; Cystic Fibrosis; Cytokines; Diet; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Leptin; Male; Muscle Strength Dynamometer; Muscle, Skeletal; Nutrition Assessment; Nutritional Status; Tumor Necrosis Factor-alpha

Weight loss in cystic fibrosis (CF) may be associated with altered levels of appetite stimulating peptide ghrelin and the appetite decreasing peptide leptin. However, prior data on leptin in CF are conflicting, while the data on ghrelin are scarce. We hypothesized that weight loss in CF is associated with low levels ghrelin and elevated levels of leptin.. Plasma ghrelin, leptin, TNF-alpha, IL-1 and IL-6, BMI, fat free mass (FFM), fat mass (FM) were measured in 74 CF adults and 20 controls. CF subjects were divided into 3 groups based on lung disease: mild (n=19), moderate (n=30) and severe (n=25).. Severe CF patients (% predicted FEV1 27+/-7; median BMI 21 kg/m2) had significantly elevated ghrelin and decreased leptin compared to controls and other CF subjects. Ghrelin correlated (r value, p value) with BMI (-0.35,<0.001), FFM (-0.22,<0.05), FM (-0.41,<0.0001), FEV1 (-0.62,<0.001), TNF-alpha (0.51,<0.0001), IL-1 (0.56,<0.0001), and IL-6 (0.33,<0.01). Leptin correlated (r value, p value) with BMI (0.40,<0.0001), FM (0.56,<0.0001), FEV1 (0.34,<0.05), IL-1 (-0.51,<0.05) and TNF-alpha (-0.43,<0.0001). BMI and FEV1 were independent predictors of ghrelin (-0.35,<0.05;-0.59,<0.001). FM was a predictor of leptin (0.56,<0.0001). Cytokines were elevated only in severe CF (severe CF vs. controls, pg/ml): TNF-alpha (3.4+/-0.6 vs. 1.2+/-0.4), IL-1 (3.5+/-1 vs. 0.2+/-0.1), IL-6 (17.4+/-4 vs. 2.4+/-2).. Elevated ghrelin and decreased leptin levels are a consequence rather than a cause of weight loss in advanced CF.

Topics: Adult; Biomarkers; Body Mass Index; Case-Control Studies; Cystic Fibrosis; Female; Flow Cytometry; Ghrelin; Humans; Interleukin-1; Interleukin-6; Leptin; Male; Middle Aged; Regression Analysis; Respiratory Function Tests; Tumor Necrosis Factor-alpha; Weight Loss

Ghrelin and leptin are hormones implicated in energy balance coordination and body weight regulation. There are conflicting data regarding the levels and role of leptin while ghrelin has not been studied in CF. The aim of this study was to investigate fasting serum ghrelin and leptin levels in CF adolescents as compared to healthy controls and analyze their association with body fat.. Fourteen CF adolescents having pancreatic insufficiency and twenty healthy adolescents were enrolled in the study. Diabetic patients were excluded. In all participants' height, weight, body mass index (BMI) and body fat % (BF %) were estimated. Ghrelin and leptin levels were determined after an overnight fast.. Weight, BMI and BF% were significantly lower in CF adolescents than those of controls. Fasting leptin levels in CF were significantly higher in CF patients (p=0.030), compared to controls and significantly lower in CF males as compared to CF females (p=0.01). Fasting ghrelin levels were significantly lower in CF males as compared to male controls (p<0.001) and comparable in females.. As the overall clinical outcome of CF patients is related to the nutritional status and body weight, the role of ghrelin and leptin in these patients needs to be elucidated.

Topics: Adipose Tissue; Adolescent; Adult; Biomarkers; Body Mass Index; Child; Cystic Fibrosis; Fasting; Female; Ghrelin; Growth Hormone; Humans; Leptin; Male; Peptide Hormones; Prognosis; Radioimmunoassay

Children with cystic fibrosis (CF) are of increased risk of reduced fat body mass (FBM) and lean body mass (LBM). Serum concentrations of insulin-like growth factor-1 (IGF-1)and leptin could be markers of LBM and/or FBM depletion. To evaluate the relationships between disease activity, body composition, IGF-1 and leptin concentrations in CF children.. A cross-sectional study with 26 CF children aged 5.0-15.5 years and 33 healthy controls, mean age 9.4 years. Body composition was evaluated by dual-energy X-ray absorptiometry. Fasting blood samples were analyzed for leptin, IGF-1 and IGFBP-3.. FBM standard deviation score (SDS; CF boys -0.02 +/- 0.88 vs. 0.78 +/- 0.65, p < 0.01; CF girls -0.37 +/- 1.15 vs. 0.70 +/- 0.97, p < 0.05), leptin concentration (CF boys 2.07 +/- 0.79 vs. 3.07 +/- 1.28 ng/ml, p < 0.05; CF girls 2.71 +/- 0.86 vs. 5.00 +/- 2.95 ng/ml, p < 0.05) and IGF-1SDS (CF boys -1.43 +/- 1.50 vs. -0.32 +/- 0.88, p < 0.05; CF girls -0.66 +/- 1.66 vs. 0.64 +/- 0.57, p < 0.01) were lower in CF children compared to controls. Shwachman score was the strongest predictor of lean body mass (R = 0.63). Leptin levels explain 60% of the variability in FBM.. Serum concentrations of IGF-1 and leptin are decreased in children with CF and are associated with clinical conditions and body composition.

Topics: Adipose Tissue; Adolescent; Biomarkers; Body Composition; Child; Child Development; Child, Preschool; Cross-Sectional Studies; Cystic Fibrosis; Female; Humans; Inflammation; Insulin-Like Growth Factor I; Leptin; Male

Leptin plays an important role in the energy balance and may be affected by hormonal and metabolic derangement associated with chronic disease. The aim of this study was to assess the correlation between leptin, proinflammatory cytokines and nutritional status with regard to clinical status in homozygous delta F 508 cystic fibrosis patients.. Patients with mild (Shwachman score 71-100 points, group A) disease were compared with those with moderate disease (Shwachman score 41-55 points, group B) and age-matched controls (group C, n = 22). Leptin was assessed by enzyme-linked immunosorbent assay and cytokines (interleukin-8, tumor necrosis factor alpha) before and after stimulation with 5 ng lipopolysaccharide by a chemiluminescent immunometric assay.. Twenty-two patients were recruited for each group (median A/B/C forced expiratory volume in 1 second 80%/59%/-; median age 12/13.5/12.5 years). Leptin (median 3.25/2.65/3.3 pg/mL; P = 0.083) and body mass index were lower (group A/B/C 18.55/16.75/20.5 kg/m(2); P = 0.023), but dietary intake was significantly higher (group A/B/C 50.5/68/43 kcal/kg body weight; P = 0.026) in moderate disease. Cytokines before stimulation with lipopolysaccharide were highest in moderate disease, but there was no significant difference after stimulation (interleukin-8 median A/B/C before--15/25.1/8.0 pg/mL, P < 0.005; after--570.5/573.5/415.5 pg/mL, not significant; tumor necrosis factor alpha median A/B/C 43/56/30 pg/mL, P < 0.0001; 580/427/720.5 pg/mL, not significant.).. There is a physiological regulation of leptin even in more advanced states of disease with significantly lower body mass index than controls. However, our data do not support the idea of elevated cytokine levels inducing anorexia in homozygous delta F 508 cystic fibrosis patients.

Topics: Adolescent; Adult; Anorexia; Body Mass Index; Case-Control Studies; Child; Child, Preschool; Cystic Fibrosis; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Interleukin-8; Leptin; Lipopolysaccharides; Luminescence; Male; Nutritional Status; Severity of Illness Index; Tumor Necrosis Factor-alpha

Reduced bone mass in individuals with cystic fibrosis (CF) may result from alterations in calcium metabolism. Bone calcium deposition and resorption rates, calcium balance, and markers of bone turnover were assessed using stable isotopes of calcium in 22 prepubertal and pubertal girls with CF. Bone calcium deposition was associated with the availability of dietary calcium, total serum osteocalcin, and leptin concentrations. Reduced bone mass in individuals with CF may result from inadequate bone calcium (Ca) deposition, and excessive resorption, although these parameters have not been directly assessed in children with CF. We used stable Ca isotopes to measure rates of bone Ca deposition (Vo+), resorption, and retention in 22 clinically stable girls with CF (aged 7-18 yr). Rates of bone Ca deposition were determined by mathematically modeling the disappearance of iv Ca stable isotope ((42)Ca) for 6 d post dosing. Indirect markers of bone turnover and hormones associated with pubertal development were also assessed. Rates of bone Ca deposition and retention were highest during early puberty (Tanner stages 2 and 3). Calcium deposition rates in prepubertal (Tanner 1) and postmenarchal girls (Tanner stages 4 and 5) did not support substantial bone Ca retention. Net absorption of dietary Ca and serum osteocalcin and leptin concentrations were positively associated with Vo+. Time post menarche and serum leptin concentrations explained 91% of the variability in Vo+ (P = 0.0007). Serum total osteocalcin was low (10.9 +/- 5.4 ng/ml), and a substantial percentage of osteocalcin was undercarboxylated (54.3 +/- 11.8%). We concluded that increased calcium absorption and serum leptin concentrations were significantly associated with rates of bone Ca deposition, demonstrating an impact of nutritional status on this process. Rates of bone Ca deposition were lower than typically reported in healthy children, as were indirect markers of bone formation. These alterations in bone turnover contribute to reduced bone mass in girls with CF.

Topics: Absorption; Adolescent; Bone and Bones; Bone Remodeling; Calcium; Calcium, Dietary; Child; Cystic Fibrosis; Female; Humans; Leptin; Menarche; Osteocalcin; Time Factors

Bodyweight is an important prognostic indicator in children with cystic fibrosis (CF), but the relationships between body composition and clinical outcomes are less clear. We have investigated the role of leptin (a potential satiety factor) and changes in body composition, height and weight with respect to age and clinical outcome.. 143 children (77 boys) with CF and a median age (range) of 5.99 (2.27-17.98) y were followed with annual measurements of height, weight, skinfolds, forced expiratory volume (FEV1), Shwachman score assessment and fasting blood sample. Our control group comprised 40 children (20 boys, 20 girls) aged 8.6-10.2 y at recruitment who were participating in a longitudinal study of growth and puberty.. SD scores for height, weight and BMI decreased with age; fat and fat-free mass was lower in both sexes compared to controls. Shwachman score decreased with age in both sexes and was related to fat-free mass in girls, and to both fat-free and fat mass in boys. FEV1 decreased with age only in boys and was related to fat-free mass. Leptin levels by age and by fat mass were higher in CF children compared to controls.. Despite improvements in management, contemporary children with CF still gain less body fat and fat-free mass and are shorter than controls. The higher leptin levels we observed may be due to stimulatory effects of inflammatory cytokines and we postulate that they may contribute to the anorexia, poor weight gain and growth of these children.

Topics: Adolescent; Body Composition; Body Height; Body Mass Index; Case-Control Studies; Child; Child, Preschool; Cystic Fibrosis; Female; Humans; Leptin; Longitudinal Studies; Male; Prognosis; Weight Gain

Cystic fibrosis (CF) is the most common severe autosomal recessive disease among Caucasians and is caused by lesions within the cystic fibrosis transmembrane conductance regulator ( CFTR) gene. The variability of CF disease severity suggests the effect of modifying factors. Thirty-four highly concordant and highly discordant F508del homozygous sib pairs, who have been selected out of a group of 114 pairs for extreme disease phenotypes by nutritional and pulmonary status, were typed at single nucleotide polymorphisms (SNPs) and short tandem repeat polymorphisms (STRPs) in the 24-cM CFTR-spanning region between D7S525 and D7S495. Allele frequencies differed significantly at D7S495, located within a 21-cM distance 3' of CFTR, comparing concordant mildly affected, concordant severely affected and discordant sib pairs, as judged by hypothesis-free permutation analysis by Monte Carlo simulation. A rare haplotype of two SNPs within the leptin gene promotor was found exclusively among the concordant mildly affected pairs. All concordant sib pairs shared the paternal F508del chromosome between CFTR and D7S495, whilst the cohort of discordant sib pairs inherited equal proportions of recombined and non-recombined parental chromosomes. We conclude that disease manifestation in CF is modulated by loci in the partially imprinted region 3' of CFTR that determine stature, food intake and energy homeostasis, such as the Silver-Russel-Syndrome candidate gene region and LEP.

Topics: Chromosome Mapping; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Haplotypes; Homozygote; Humans; Leptin; Minisatellite Repeats; Monte Carlo Method; Phenotype; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Recombination, Genetic; Sequence Deletion; Siblings

The role of leptin in states of negative energy balance such as cystic fibrosis (CF) has not been explored. We hypothesized that leptin levels in patients with CF would be low due to correlation with body weight. Despite the importance of IGF-I in normal growth and anabolism, there are few data on IGF-I in CF. We studied 27 CF patients (25+/-5 yrs, 57+/-9 kg, 10M/17F) and 12 control subjects (25+/-4 yrs, 57+/-9 kg, 6M/6F). Each subject underwent analysis of lean body mass (LBM) and percent body fat by dual-energy x-ray absorptiometry (DEXA). Serum leptin and IGF-I levels were measured by radioimmunoassay. Serum leptin levels were similar both in CF and in controls (CF=5.3+/-4.1 ng/ml, C=4.4+/-3.6ng/ml; p=0.3), and there was no difference in percent body fat between the two groups (CF=26+/-13%, C=21+/-7%; p=0.3). Leptin levels were significantly lower in CF males than females corresponding to lower fat levels in males in both CF and controls. Leptin levels were positively correlated with percent body fat both in CF and controls (CF: r=0.8; p=0.01, CONTROL: r=0.8; p =0.2). Serum IGF-I levels were significantly lower in CF patients than in controls (CF=1.13+/-0.41 ng/ml, C=6.72+/-3.62 ng/ml; p=<0.01). We conclude that the physiological regulation of leptin is maintained in relation to body fat even in chronic illness and that the negative energy balance in CF is not caused by high leptin levels.

Topics: Adult; Body Composition; Body Mass Index; Body Weight; Cystic Fibrosis; Fasting; Female; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Proteins; Radioimmunoassay