Long-term weight loss of distal gastric bypass is moderately superior compared to proximal gastric bypass in patients with a BMI of 37-44 Kg/m2.

PURPOSE: The laparoscopic Roux-en-Y gastric bypass (LRYGB) is one of the standard procedures in metabolic surgery. Different limb lengths have been proposed in the past to maximize weight loss (WL) and reduce metabolic complications. Distal gastric bypass surgery with a very short common channel (CC) (up to 100 cm) has been often criticized due to frequent side effects such as malnutrition, bone weakening and short-bowel syndrome. We introduced a modified version of a distal LRYGB with a 50-70 cm long biliopancreatic limb (BPL) and an intermediate short CC (120-150 cm). Our primary goal was to compare the long-term WL between distal and proximal LRYGB in two cohorts of patients. Secondary outcomes were weight regain (WR), insufficient weight loss (IWL), postoperative complications and metabolic changes 5 years after surgery. METHODS: In this retrospective study we collected data from 160 patients operated between 2014 and 2015, with a BMI of 37-44 Kg/m2. 101 patients underwent a distal and 59 patients a proximal LRYGB in two bariatric centers. WL was calculated as percent of excess of BMI loss (%EBMIL), loss of body mass index (Delta-BMI), percent of excess weight loss (%EWL) and percent of total weight loss (%TWL). Data were collected 3, 6, 9, 12, 24, 48 and 60 months after surgery. RESULTS: The distal LRYGB resulted in significantly better 5-year-WL compared to the proximal bypass in terms of %EBMIL (median at 5 years: 83% vs. 65%, p = 0.001), %TWL (median at 5 years: 32% vs. 26%, p = 0.017) and %EWL (median at 5 years: 65% vs. 51%, p = 0.029), with equal major complications and metabolic alterations. In addition, WR was significantly lower in patients with distal bypass (18% vs. 35%, p = 0.032). CONCLUSIONS: Distal LYRGB with a 120-150 long CC results in better WL and WL-maintenance compared to proximal LRYGB without major side effects after five years.

Variation in FTO contributes to childhood obesity and severe adult obesity.

We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.

Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Once Daily Empagliflozin 25 mg for the Treatment of Postprandial Hypoglycemia After Roux-en-Y Gastric Bypass.

Aims: To investigate the effect of empagliflozin on glucose dynamics in individuals suffering from postbariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). Methods: Twenty-two adults with PBH after RYGB were randomized to empagliflozin 25 mg or placebo once daily over 20 days in a randomized, double-blind, placebo-controlled, crossover trial. The primary efficacy outcome was the amplitude of plasma glucose excursion (peak to nadir) during a mixed-meal tolerance test (MMTT). Outcomes of the outpatient period were assessed using continuous glucose monitoring (CGM) and an event-tracking app. Results: The amplitude of glucose excursion during the MMTT was 8.1 ± 2.4 mmol/L with empagliflozin versus 8.1 ± 2.6 mmol/L with placebo (mean ± standard deviation, P = 0.807). CGM-based mean amplitude of glucose excursion during the 20-day period was lower with empagliflozin than placebo (4.8 ± 1.3 vs. 5.2 ± 1.6. P = 0.028). Empagliflozin reduced the time spent with CGM values >10.0 mmol/L (3.8 ± 3.5% vs. 4.7 ± 3.8%, P = 0.009), but not the time spent with CGM values <3.0 mmol/L (1.7 ± 1.6% vs. 1.5 ± 1.5%, P = 0.457). No significant difference was observed in the quantity and quality of recorded symptoms. Eleven adverse events occurred with empagliflozin (three drug-related) and six with placebo. Conclusions: Empagliflozin 25 mg reduces glucose excursions but not hypoglycemia in individuals with PBH. Clinical Trial Registration: Clinicaltrials.gov: NCT05057819.

Successful multi-intervention treatment of severe obesity: a 7-year prospective study with 96% follow-up.

BACKGROUND: No long-term, high participation study of the outcome of bariatric surgery has examined how a multi-intervention approach to the treatment of severe obesity can achieve and sustain weight loss after an initial bariatric procedure. METHODS: We employed a multi-intervention treatment that combines adjustable gastric banding with intensive follow-up to support patient life-style change and use of an algorithm allowing reoperation-to bypass, if necessary-in the event of complications. Four hundred four severely obese patients with an average BMI = 42.6 at the outset had initial AGB surgery and were followed with a high rate of face-to-face consultations for 7 years. Seventy-five percent of the patients retained a gastric band throughout the study. Weight loss, complications, and comorbidities were studied, and quality of life was assessed using Bariatric Analysis and Reporting Outcome System (BAROS). RESULTS: Three hundred eighty-eight (96%) patients completed the 7-year follow-up. Average BMI reduction at 5 years was 28% and remained stable through year 7, at which the mean excess weight loss was 61%. The preoperative prevalence of metabolic syndrome, 59.7%, decreased to 13.3% at 7 years and was abolished for patients with more than 40% loss of initial BMI. Similar changes were seen for all components of metabolic syndrome. More than 60% of patients had a "good" or higher BAROS score; 10.1% were considered failures. Patients converted to gastric bypass, and those retaining gastric bands throughout the study had very similar outcomes. CONCLUSIONS: Long-term, multi-intervention treatment of severe obesity can achieve and preserve weight loss and thus improved quality of life and sustained reduction or disappearance of all components of metabolic syndrome, for a high proportion of severely obese patients with preoperative BMI between 35 and 55.

The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies.

BACKGROUND: Considering that a portion of the heterogeneity amongst previous replication studies may be due to a variable proportion of obese subjects in case-control designs, we assessed the association of genetic variants with type 2 diabetes (T2D) in large groups of obese and non-obese subjects. METHODS: We genotyped RETN, KCNJ11, HNF4A, HNF1A, GCK, SLC30A8, ENPP1, ADIPOQ, PPARG, and TCF7L2 polymorphisms in 1,283 normoglycemic (NG) and 1,581 T2D obese individuals as well as in 3,189 NG and 1,244 T2D non-obese subjects of European descent, allowing us to examine T2D risk over a wide range of BMI. RESULTS: Amongst non-obese individuals, we observed significant T2D associations with HNF1A I27L [odds ratio (OR) = 1.14, P = 0.04], GCK -30G>A (OR = 1.23, P = 0.01), SLC30A8 R325W (OR = 0.87, P = 0.04), and TCF7L2 rs7903146 (OR = 1.89, P = 4.5 x 10-23), and non-significant associations with PPARG Pro12Ala (OR = 0.85, P = 0.14), ADIPOQ -11,377C>G (OR = 1.00, P = 0.97) and ENPP1 K121Q (OR = 0.99, P = 0.94). In obese subjects, associations with T2D were detected with PPARG Pro12Ala (OR = 0.73, P = 0.004), ADIPOQ -11,377C>G (OR = 1.26, P = 0.02), ENPP1 K121Q (OR = 1.30, P = 0.003) and TCF7L2 rs7903146 (OR = 1.30, P = 1.1 x 10-4), and non-significant associations with HNF1A I27L (OR = 0.96, P = 0.53), GCK -30G>A (OR = 1.15, P = 0.12) and SLC30A8 R325W (OR = 0.95, P = 0.44). However, a genotypic heterogeneity was only found for TCF7L2 rs7903146 (P = 3.2 x 10-5) and ENPP1 K121Q (P = 0.02). No association with T2D was found for KCNJ11, RETN, and HNF4A polymorphisms in non-obese or in obese individuals. CONCLUSION: Genetic variants modulating insulin action may have an increased effect on T2D susceptibility in the presence of obesity, whereas genetic variants acting on insulin secretion may have a greater impact on T2D susceptibility in non-obese individuals.

Bowel habits after bariatric surgery.

BACKGROUND: Disordered bowel habits might influence quality of life after bariatric surgery. Different types of bariatric operations-gastric banding (AGB), Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD)-might alter bowel habits as a consequence of the surgical procedure used. Whether change in bowel habits affects quality of life after AGB, RYGB, or BPD differently is unknown. METHODS: The study group contained 290 severely obese patients undergoing bariatric surgery between August 1996 and September 2004 [BPD: n = 103, 64.1% women, age 43 +/- 1 years (mean +/- SEM), BMI 53.9 +/- 0.9 kg/m(2), weight 153.4 +/- 2.9 kg; Roux-en-Y gastric bypass: n = 126, 73.0% women, age 43 +/- 1 years, BMI 44.2 +/- 0.3 kg/m(2), weight 123.8 +/- 1.5 kg; adjustable gastric banding (AGB): n = 61, 57.4% women, age 44 +/- 1 years, BMI 49.9 +/- 0.5 kg/m(2), weight 146.1 +/- 2.0 kg). Changes in bowel habits, flatulence, flatus odor, and effects on social life were estimated at least 4 months after surgery using a self-administered questionnaire. RESULTS: Fecal consistency changed significantly after surgery. Loose stools and diarrhea were more frequent after BPD and RYGB (P < 0.001) but more so after BPD than after either RYGB or AGB (P < 0.002). Constipation was more likely after AGB (P = 0.03). In addition, malodorous flatus affecting social life was more frequent after BPD than after either RYGB or AGB (P < 0.003). Furthermore, flatus frequency increased after BPD and RYGB, and patients were more bothered by their malodorous flatus than after AGB (all P < 0.001). Flatus severity score was highest in BPD, intermediate in RYGB, and lowest in AGB patients (all P < 0.001), a difference that was not influenced by frequency of metabolic syndrome before and after surgery. Moreover, observation period after surgery had no influence on overall results of bowel habits. Subsore quality of life bariatric analysis and reporting outcome system (BAROS) scores were largely similar between all three groups. However, flatulence severity score correlated inversely with quality of life estimated by BAROS in BPD and RYGB, but not in AGB patients. CONCLUSIONS: The type of bariatric surgery affects bowel habits in an operation-specific manner, resulting mainly in diarrhea after BPD and RYGB, and constipation after AGB. Flatulence severity impairs quality of life most in BPD, is intermediate in RYGB, and is only minor after AGB, a phenomenon that was only partially mirrored in quality-of-life measures of BAROS.

Severe recurrent hypoglycemia after gastric bypass surgery.

BACKGROUND: Bariatric surgery is, at present, the most effective method to achieve major, long-term weight loss in severely obese patients. Recently, severe recurrent symptomatic hyperinsulinemic hypoglycemia was described as a consequence of gastric bypass surgery (GBS) in a small series of patients with severe obesity. Pancreatic nesidioblastosis, a hyperplasia of islet cells, was postulated to be the cause, and subtotal or total pancreatectomy was the suggested treatment. METHODS: We observed that severe, disabling hypoglycemia after GBS occurred only in patients with loss of restriction. Whether restoration of gastric restriction might treat severe, recurrent hypoglycemia after GBS is unknown. RESULTS: Therefore, gastric restriction was restored by surgical placement of a silastic ring (n = 8, first two patients with additional distal pancreatectomy) or an adjustable gastric band (n = 4) around the pouch in 12 consecutive patients presenting with severe hypoglycemia (blood glucose below 2.2 mM). At follow-up after restoration of gastric restriction (median follow-up 7 months, range 5 to 19 months), 11 patients demonstrated no hypoglycemic episodes, while one had recurrence of hypoglycemia and underwent distal pancreatectomy. Procedural mortality was 0% and morbidity 8.3%. CONCLUSION: Patients suffering from severe recurrent hypoglycemia after GBS can be treated, in most cases, just by restoration of gastric restriction. Distal pancreatectomy should be considered a second-line treatment.

Binge eating as a major phenotype of melanocortin 4 receptor gene mutations.

BACKGROUND: Obesity, a multifactorial disease caused by the interaction of genetic factors with the environment, is largely polygenic. A few mutations in these genes, such as in the leptin receptor (LEPR) gene and melanocortin 4 receptor (MC4R) gene, have been identified as causes of monogenic obesity. METHODS: We sequenced the complete MC4R coding region, the region of the proopiomelanocortin gene (POMC) encoding the alpha melanocyte-stimulating hormone, and the leptin-binding domain of LEPR in 469 severely obese white subjects (370 women and 99 men; mean [+/-SE] age, 41.0+/-0.5 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 44.1+/-2.0). Fifteen women and 10 men without a history of dieting or a family history of obesity served as normal-weight controls (age, 47.7+/-2.0 years; body-mass index, 21.6+/-0.4). Detailed phenotypic data, including information on body fat, resting energy expenditure, diet-induced thermogenesis, serum concentrations of leptin, and eating behavior, were collected. RESULTS: Twenty-four obese subjects (5.1 percent) and one control subject (4 percent) had MC4R mutations, including five novel variants. Twenty of the 24 obese subjects with an MC4R mutation were matched for age, sex, and body-mass index with 120 of the 445 obese subjects without an MC4R mutation. All mutation carriers reported binge eating, as compared with 14.2 percent of obese subjects without mutations (P<0.001) and 0 percent of the normal-weight subjects without mutations. The prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of LEPR and noncarriers. No mutations were found in the region of POMC encoding alpha melanocyte-stimulating hormone. CONCLUSIONS: Binge eating is a major phenotypic characteristic of subjects with a mutation in MC4R, a candidate gene for the control of eating behavior.

Health-related quality of life in patients with class II and class III obesity.

BACKGROUND: Severe obesity may substantially impact quality of life. We estimated the health-related quality of life (HRQoL) in patients with class II and class III obesity, and explored the impact of patient characteristics and co-morbidities on quality of life. METHODS: 110 patients with BMI > or = 35 kg/m2 presenting for evaluation for bariatric surgery were asked to complete the EuroQoL questionnaire. Co-morbidities of the patients were recorded, including coxarthralgia, gonarthralgia, foot problems (pain and arthrosis), diabetes, dyslipidemia, hypertension, infertility, coronary heart disease, low back pain, peptic esophagitis, sleep apnea syndrome, urinary stress incontinence, and venous insufficiency. The determinants of HRQoL on the EQ-VAS score and EQ-5D index (both ranging from 0-100) were analyzed in a univariate and multivariate linear regression model. RESULTS: The mean EQ-5D index (societal perspective) was 76, whereas the mean EQ-VAS (patient perspective) was 66 (P<0.0001). The mean number of comorbidities was 4.9 (range 0-11). Dyslipidemia (68%), low back pain (63%) and venous insufficiency (57%) were the 3 most frequent co-morbidities. However, low back pain (beta= -11.4) and foot problems (beta= -8.5) were significantly associated with a reduction in the EQ-VAS score, whereas low back pain (beta= -8.4) and coronary heart disease (beta= -24.9) were significantly associated with a reduction in the EQ-5D index. CONCLUSION: The number and type of co-morbidities determine HRQoL in patients with severe obesity. Within our study population, a higher BMI, however, was not associated with a lower quality of life.

Impact of age, sex and body mass index on outcomes at four years after gastric banding.

BACKGROUND: Adjustable gastric banding for weight reduction in severely obese persons allows reversible individualized restriction during postoperative follow-up. It is unknown whether preoperative age, sex and BMI might modulate treatment outcome. METHODS: 404 severely obese patients (79% women; age 42 +/- 0.5 years [mean +/- SEM]; BMI 42.1 +/- 0.2 kg/m2) completed 4-year follow-up after banding. Weight loss, complications, and Bariatric Analysis and Reporting Outcome System (BAROS) scores were recorded prospectively. RESULTS: 4 years after banding, younger (<50 years) women lost more weight than older (50 years) men (28.2 +/- 0.7% vs 19.4+/- 1.6%; P=0.001); older women and younger men lost similar weight. Patients with preoperative BMI >50 lost more weight than patients with BMI <35 (30.5 +/- 2.3% vs 22.8 +/- 2.6%; P=0.03). 22.3% of patients (n=90) had band system-related complications. Compared to women, men had more band leaks (7.0% vs 1.9%; P=0.007), and older men had more band slippages than younger men (8.4% vs 0.0%; P=0.035). Patients with preoperative BMI >50 were less likely than patients with BMI 35-40 or 40-50 to experience gastric complications (10.6%, 18.8%, 23.0%, respectively), but more likely to experience port/tube complications (15.8%, 2.4%, 7.9%, respectively; P<0.055). BAROS scores were different between men and women (P=0.05), and between younger and older people (P=0.001). Women and younger people were more likely than men and older people to score "very good" (P=0.03, P=0.001, respectively). CONCLUSIONS: Adjustable gastric banding is an effective intermediate-term treatment for severe obesity. Preoperative age, sex, and BMI are important modulators of outcome and should be considered during preoperative evaluation.

Salvage of gastric restriction following staple-line dehiscence after vertical banded gastroplasty by insertion of an adjustable gastric band.

BACKGROUND: Vertical banded gastroplasty (VBG) has been a common and safe surgical treatment for morbid obesity. However, the complication of staple-line dehiscence (SLD) results in VBG failure. We present a minimally invasive revision procedure when SLD occurs: gastric restriction is salvaged by adjustable gastric banding (AGB), usually laparoscopically, providing that the previous restriction had achieved sufficient weight loss initially and was well-tolerated. METHODS: 13 patients with unexplained weight regain after VBG were found to have SLD on endoscopy. AGB was performed to re-establish restriction. Weight loss and complications were compared with two control groups: the first undergoing uncomplicated VBG, and the second undergoing AGB alone. Follow-up of 4.3+/-0.1 (mean+/-SEM) years after salvage reoperation, including complications, reoperations and weight loss, were studied. RESULTS: Insertion of the band through the retrogastric tunnel was feasible in all cases, despite adhesions in the area of the VBG Marlex band, the proximal stomach, and left lobe of liver. There was no surgeryrelated mortality. Following "salvage AGB", weight loss and overall complication rates were similar between the study group and the two control groups. CONCLUSION: Salvage of gastric restriction by AGB after SLD secondary to VBG is safe and reliable, despite the possibility of adhesions. Morbidity is low and intermediate-term weight loss is comparable to patients with uncomplicated VBG.

Management of failed adjustable gastric banding.

BACKGROUND: About 100,000 adjustable gastric band placements have been performed worldwide, but more than 10% of patients have needed reoperation for insufficient weight loss or device-related complications. This study investigates the complications following gastric banding, and the outcome using a structured management strategy. METHODS: In the period April 1996 to January 2002, 824 severely obese patients (body mass index 43 +/- 1 kg/m 2 [mean +/- standard error under the mean], age 43 +/- 1 years; 77% women) underwent gastric banding in a single institution and were followed prospectively. Complications, insufficient weight loss, and subsequent management were analyzed. RESULTS: By the fifth treatment year, excess weight loss (EWL) was 54.8 +/- 1.7%; 72.8% of patients lost weight continuously or attained EWL of at least 50%. Insufficient weight loss occurred in 143 patients, and band-related complications occurred in 131 patients, with a mean annual rate of 5.0%. Major reoperation was necessary in 121 patients, and the annual reoperation rate was 4.7%. Following major reoperation, band- and bypass-related complication rates ranged from 6.3% to 11.7% per year. Three deaths occurred, 1 after reoperation and 2 due to preexisting cardiovascular disease. CONCLUSIONS: Applying a structured reoperation algorithm, 5% annual failure after banding was corrected in most patients, and 72.8% of patients attained sufficient weight loss. Reoperation-related mortality was low (.8%), and its annual morbidity was acceptable (4.6%).

Analysis of sequence variability in the CART gene in relation to obesity in a Caucasian population.

BACKGROUND: Cocaine and amphetamine regulated transcript (CART) is an anorectic neuropeptide located principally in hypothalamus. CART has been shown to be involved in control of feeding behavior, but a direct relationship with obesity has not been established. The aim of this study was to evaluate the effect of polymorphisms within the CART gene with regards to a possible association with obesity in a Caucasian population. RESULTS: Screening of the entire gene as well as a 3.7 kb region of 5' upstream sequence revealed 31 SNPs and 3 rare variants; 14 of which were subsequently genotyped in 292 French morbidly obese subjects and 368 controls. Haplotype analysis suggested an association with obesity which was found to be mainly due to SNP-3608T>C (rs7379701) (p = 0.009). Genotyping additional cases and controls also of European Caucasian origin supported further this possible association between the CART SNP -3608T>C T allele and obesity (global p-value = 0.0005). Functional studies also suggested that the SNP -3608T>C could modulate nuclear protein binding. CONCLUSION: CART SNP -3608T>C may possibly contribute to the genetic risk for obesity in the Caucasian population. However confirmation of the importance of the role of the CART gene in energy homeostasis and obesity will require investigation and replication in further populations.

G protein polymorphisms do not predict weight loss and improvement of hypertension in severely obese patients.

Both the gene encoding the alpha subunit of G stimulatory proteins (GNAS1) and the beta3 subunit gene (GNB3) of G proteins are associated with obesity and/or hypertension. Moreover, the TT/TC825 polymorphism of GNB3 predicts greater weight loss than the CC825 polymorphism in obese patients (mean body mass index, 35 kg/m2) undergoing a structured nonpharmacologic weight loss program. Gastric banding enforces a low-calorie diet by diminishing the need for volitional adherence. It is unknown whether these polymorphisms predict the variable weight loss in patients after bariatric surgery. Three hundred and four severely obese patients (mean +/- SEM age, 42 +/- 1 years; 245 women and 59 men; mean +/- SEM body mass index, 43.9 +/- 0.3 kg/m2) followed prospectively for at least 3 years after surgery were genotyped for the GNB3 C825T, G814A, and GNAS1 T393 polymorphisms. All analyses were performed blinded to the phenotypic characteristics of the study group. Frequencies of polymorphisms were comparable to those previously published. No polymorphism studied predicted 3-year weight loss or was associated with high blood pressure in severely obese patients after gastric banding. Multivariate analysis of potentially confounding factors such as reoperation rate or use of sibutramine or orlistat revealed similar results (P > 0.1). Regardless of the mechanism(s) involved for these discordant findings, GNB3 C825T, G814A, and GNAS1 T393C polymorphisms do not seem to be reliable predictors of long-term weight loss.

Gene variants and binge eating as predictors of comorbidity and outcome of treatment in severe obesity.

Melanocortin-4 receptor gene (MC4R) variants are associated with obesity and binge eating disorder (BED), whereas the more prevalent proopiomelanocortin (POMC) and leptin receptor gene (LEPR) mutations are rarely associated with obesity or BED. The complete coding regions of MC4R, POMC, and leptin-binding domain of LEPR were comparatively sequenced in 300 patients (233 women and 67 men; mean +/- SEM age, 42 +/- 1 years; mean +/- SEM body mass index, 43.5 +/- 0.3 kg/m2) undergoing laparoscopic gastric banding. Eating behavior, esophagogastric pathology, metabolic syndrome prevalence, and postoperative weight loss and complications were retrospectively compared between carriers and noncarriers of gene variants with and without BED during 36 +/- 3-month follow-up. Nineteen patients (6.3%) carried 8 MC4R variants, 144 (48.0%) carried 13 POMC variants, and 247 (82.3%) carried 11 LEPR variants. All MC4R variant carriers had BED, compared with 18.1% of noncarriers (P < 0.001). BED rates were similar among POMC and LEPR variant carriers and noncarriers. Gastroscopy revealed more erosive esophagitis in bingers than in nonbingers before and after banding (P < 0.04), regardless of genotype. MC4R variant carriers lost less weight (P=0.003), showed less improvement in metabolic syndrome (P < 0.001), had dilated esophagi (P < 0.001) and more vomiting (P < 0.05), and had fivefold more gastric complications (P < 0.001) than noncarriers. Overall outcome was poorest in MC4R variant carriers, better in noncarriers with BED (P < 0.05), and best in noncarriers without BED (P < 0.001). MC4R variants influence comorbidities and treatment outcomes in severe obesity.

Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations.

We analyzed genome-wide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls. Thirty-eight markers showing strong association were further evaluated in 14,186 European subjects. In addition to FTO and MC4R, we detected significant association of obesity with three new risk loci in NPC1 (endosomal/lysosomal Niemann-Pick C1 gene, P = 2.9 x 10(-7)), near MAF (encoding the transcription factor c-MAF, P = 3.8 x 10(-13)) and near PTER (phosphotriesterase-related gene, P = 2.1 x 10(-7)).

Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees.

OBJECTIVE: Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown. RESEARCH DESIGN AND METHODS: We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations. RESULTS: Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P = 6.9 x 10(-10)). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged >52 years, 60% in 18- to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at >40 years). CONCLUSIONS: We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an "obesogenic" environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it.

Effects of TCF7L2 polymorphisms on obesity in European populations.

The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele was previously associated with type 2 diabetes (T2D) and decreased BMI whereas haplotypes carrying the rs7903146 C and rs10885406 A alleles (HapA) were associated with increased BMI. The functional relevance of TCF7L2 polymorphisms and their effects on T2D and obesity remained to be further investigated. In white European populations, we found that the rs7903146 T allele was more associated with T2D in 3,547 non-obese individuals (odds ratio (OR) = 1.88 (1.69-2.10)) than in 1,110 class III obese subjects (OR = 1.24 (1.03-1.50)). No direct effect of the rs7903146 C allele and HapA was found on any form of obesity in 3,507 normal glucose tolerant (NGT) individuals, 1,106 pedigrees with familial obesity and 5,512 individuals from the French general population. However, in T2D subjects, the rs7903146 C allele was less prevalent in the 1,111 non-obese individuals (55.2%) compared to 659 class III obese subjects (67.5% OR = 1.69 (1.46-1.95)). Functional studies showed that the rs7903146 T allele is less prone to be bound by protein factors than the C allele in 3T3-L1, HepG2 and beta-TC3 cell lines and that TCF7L2 expression decreases in subcutaneous adipose tissue from NGT obese T/T carriers under calorie restriction. In conclusion, TCF7L2 is not a risk factor for obesity in European populations, but its effect on T2D risk is modulated by obesity. Furthermore, our data suggest that the rs7903146 T allele may be possibly functional and associated with a nominal decrease in TCF7L2 expression in adipose tissue of individuals under calorie restriction.

Common nonsynonymous variants in PCSK1 confer risk of obesity.

Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.