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The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor.sup.1. Although some MRAP2 mutations have been described in people with obesity.sup.1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance.sup.4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets. Large-scale sequencing of coding exons of MRAP2 in 9,418 adults and adolescents identifies loss-of-function mutations that are associated with monogenic obesity, hypertension and hyperglycemia., Author(s): Morgane Baron [sup.1] , Julie Maillet [sup.1] , Marlène Huyvaert [sup.1] , Aurélie Dechaume [sup.1] , Raphaël Boutry [sup.1] , Hélène Loiselle [sup.1] , Emmanuelle Durand [sup.1] , Bénédicte [...]

Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10(-14)) and serum enzyme levels (P < 2.20 × 10(-16)), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = -0.15 (0.02) kg/m(2); P = 6.93 × 10(-10)) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10(-10)). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies.

OBJECTIVE: Rare variants in DYRK1B have been described in some patients with central obesity, type 2 diabetes, and early-onset coronary disease. Owing to the limited number of conducted studies, the broader impact of DYRK1B variants on a larger scale has yet to be investigated. RESEARCH DESIGN AND METHODS: DYRK1B was sequenced in 9,353 participants from a case-control study for obesity and type 2 diabetes. Each DYRK1B variant was functionally assessed in vitro. Variant pathogenicity was determined using criteria from the American College of Medical Genetics and Genomics (ACMG). The effect of pathogenic or likely pathogenic (P/LP) variants on metabolic traits was assessed using adjusted mixed-effects score tests. RESULTS: Sixty-five rare, heterozygous DYRK1B variants were identified and were not associated with obesity or type 2 diabetes. Following functional analyses, 20 P/LP variants were pinpointed, including 6 variants that exhibited a fully inhibitory effect (P/LP-null) on DYRK1B activity. P/LP and P/LP-null DYRK1B variants were associated with increased BMI and obesity risk; however, the impact was notably more pronounced for the P/LP-null variants (effect of 8.0 ± 3.2 and odds ratio of 7.9 [95% CI 1.2–155]). Furthermore, P/LP-null variants were associated with higher fasting glucose and type 2 diabetes risk (effect of 2.9 ± 1.0 and odds ratio of 4.8 [95% CI 0.85–37]), while P/LP variants had no effect on glucose homeostasis. CONCLUSIONS: P/LP, total loss-of-function DYRK1B variants cause monogenic obesity associated with type 2 diabetes. This study underscores the significance of conducting functional assessments in order to accurately ascertain the tangible effects of P/LP DYRK1B variants. [ABSTRACT FROM AUTHOR]

Background Nephrolithiasis (NL) is a complex multifactorial disease affecting up to 10%-20% of the human population and causing a significant burden on public health systems worldwide. It results from a combination of environmental and genetic factors. Hyperoxaluria is a major risk factor for NL. Methods We used a whole exome-based approach in a patient with calcium oxalate NL. The effects of the mutation were characterised using cell culture and in silico analyses. Results We identified a rare heterozygous missense mutation (c.1519C>T/p.R507W) in the SLC26A6 gene that encodes a secretory oxalate transporter. This mutation cosegregated with hyperoxaluria in the family. In vitro characterisation of mutant SLC26A6 demonstrated that Cl--dependent oxalate transport was dramatically reduced because the mutation affects both SLC26A6 transport activity and membrane surface expression. Cotransfection studies demonstrated strong dominant-negative effects of the mutant on the wild-type protein indicating that the phenotype of patients heterozygous for this mutation may be more severe than predicted by haploinsufficiency alone. Conclusion Our study is in line with previous observations made in the mouse showing that SLC26A6 inactivation can cause inherited enteric hyperoxaluria with calcium oxalate NL. Consistent with an enteric form of hyperoxaluria, we observed a beneficial effect of increasing calcium in the patient's diet to reduce urinary oxalate excretion. [ABSTRACT FROM AUTHOR]

Abstract Background Candidate gene and genome-wide association studies have both reproducibly identified several common Single Nucleotide Polymorphisms (SNPs) that confer type 2 diabetes (T2D) risk in European populations. Our aim was to evaluate the contribution to T2D of five of these established T2D-associated loci in the Arabic population from Tunisia. Methods A case-control design comprising 884 type 2 diabetic patients and 513 control subjects living in the East-Center of Tunisia was used to analyze the contribution to T2D of the following SNPs: E23K in KCNJ11/Kir6.2, K121Q in ENPP1, the -30G/A variant in the pancreatic β-cell specific promoter of Glucokinase, rs7903146 in TCF7L2 encoding transcription factor 7-like2, and rs7923837 in HHEX encoding the homeobox, hematopoietically expressed transcription factor. Results TCF7L2-rs7903146 T allele increased susceptibility to T2D (OR = 1.25 [1.06–1.47], P = 0.006) in our study population. This risk was 56% higher among subjects carrying the TT genotype in comparison to those carrying the CC genotype (OR = 1.56 [1.13–2.16], P = 0.002). No allelic or genotypic association with T2D was detected for the other studied polymorphisms. Conclusion In the Tunisian population, TCF7L2-rs7903146 T allele confers an increased risk of developing T2D as previously reported in the European population and many other ethnic groups. In contrast, none of the other tested SNPs that influence T2D risk in the European population was associated with T2D in the Tunisian Arabic population. An insufficient power to detect minor allelic contributions or genetic heterogeneity of T2D between different ethnic groups can explain these findings.

Abstract Background The protein tyrosine phosphatase-1B, a negative regulator for insulin and leptin signalling, potentially modulates glucose and energy homeostasis. PTP1B is encoded by the PTPN1 gene located on chromosome 20q13 showing linkage with type 2 diabetes (T2D) in several populations. PTPN1 gene variants have been inconsistently associated with T2D, and the aim of our study was to investigate the effect of PTPN1 genetic variations on the risk of T2D, obesity and on the variability of metabolic phenotypes in the French population. Methods Fourteen single nucleotide polymorphisms (SNPs) spanning the PTPN1 locus were selected from previous association reports and from HapMap linkage disequilibrium data. SNPs were evaluated for association with T2D in two case-control groups with 1227 cases and 1047 controls. Association with moderate and severe obesity was also tested in a case-control study design. Association with metabolic traits was evaluated in 736 normoglycaemic, non-obese subjects from a general population. Five SNPs showing a trend towards association with T2D, obesity or metabolic parameters were investigated for familial association. Results From 14 SNPs investigated, only SNP rs914458, located 10 kb downstream of the PTPN1 gene significantly associated with T2D (p = 0.02 under a dominant model; OR = 1.43 [1.06–1.94]) in the combined sample set. SNP rs914458 also showed association with moderate obesity (allelic p = 0.04; OR = 1.2 [1.01–1.43]). When testing for association with metabolic traits, two strongly correlated SNPs, rs941798 and rs2426159, present multiple consistent associations. SNP rs2426159 exhibited evidence of association under a dominant model with glucose homeostasis related traits (p = 0.04 for fasting insulin and HOMA-B) and with lipid markers (0.02 = p = 0.04). Moreover, risk allele homozygotes for this SNP had an increased systolic blood pressure (p = 0.03). No preferential transmission of alleles was observed for the SNPs tested in the family sample. Conclusion In our study, PTPN1 variants showed moderate association with T2D and obesity. However, consistent associations with metabolic variables reflecting insulin resistance and dyslipidemia are found for two intronic SNPs as previously reported. Thus, our data indicate that PTPN1 variants may modulate the lipid profile, thereby influencing susceptibility to metabolic disease.

Genome-wide association studies have revealed that common noncoding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT2) increase type 2 diabetes (T2D) risk. Although the strongest association signal was highly significant (P < 1 × 10?20), its contribution to T2D risk was modest (odds ratio (OR) of ?1.10-1.15). We performed large-scale exon resequencing in 7,632 Europeans, including 2,186 individuals with T2D, and identified 40 nonsynonymous variants, including 36 very rare variants (minor allele frequency (MAF) <0.1%), associated with T2D (OR = 3.31, 95% confidence interval (CI) = 1.78-6.18; P = 1.64 × 10?4). A four-tiered functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF < 1%), and 4 were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial- or total-loss-of-function variants but not the neutral ones contributed to T2D (OR = 5.67, CI = 2.17-14.82; P = 4.09 × 10?4). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (8,153 individuals with T2D and 10,100 controls; OR = 3.88, CI = 1.49-10.07; P = 5.37 × 10?3). This study establishes a firm functional link between MTNR1B and T2D risk. [ABSTRACT FROM AUTHOR]

Background: The protein tyrosine phosphatase-1B, a negative regulator for insulin and leptin signalling, potentially modulates glucose and energy homeostasis. PTP1B is encoded by the PTPN1 gene located on chromosome 20q13 showing linkage with type 2 diabetes (T2D) in several populations. PTPN1 gene variants have been inconsistently associated with T2D, and the aim of our study was to investigate the effect of PTPN1 genetic variations on the risk of T2D, obesity and on the variability of metabolic phenotypes in the French population. Methods: Fourteen single nucleotide polymorphisms (SNPs) spanning the PTPN1 locus were selected from previous association reports and from HapMap linkage disequilibrium data. SNPs were evaluated for association with T2D in two case-control groups with 1227 cases and 1047 controls. Association with moderate and severe obesity was also tested in a case-control study design. Association with metabolic traits was evaluated in 736 normoglycaemic, non-obese subjects from a general population. Five SNPs showing a trend towards association with T2D, obesity or metabolic parameters were investigated for familial association. Results: From 14 SNPs investigated, only SNP rs914458, located 10 kb downstream of the PTPN1 gene significantly associated with T2D (p = 0.02 under a dominant model; OR = 1.43 [1.06-1.94]) in the combined sample set. SNP rs914458 also showed association with moderate obesity (allelic p = 0.04; OR = 1.2[1.01-1.43]). When testing for association with metabolic traits, two strongly correlated SNPs, rs941798 and rs2426159, present multiple consistent associations. SNP rs2426159 exhibited evidence of association under a dominant model with glucose homeostasis related traits (p = 0.04 for fasting insulin and HOMAB) and with lipid markers (0.02 = p = 0.04). Moreover, risk allele homozygotes for this SNP had an increased systolic blood pressure (p = 0.03). No preferential transmission of alleles was observed for the SNPs tested in the family sample. Conclusion: In our study, PTPN1 variants showed moderate association with T2D and obesity. However, consistent associations with metabolic variables reflecting insulin resistance and dyslipidemia are found for two intronic SNPs as previously reported. Thus, our data indicate that PTPN1 variants may modulate the lipid profile, thereby influencing susceptibility to metabolic disease. [ABSTRACT FROM AUTHOR]