SH2B1 Gene Research Articles

Whole Exome Sequencing Revealed Paternal Inheritance of Obesity-related Genetic Variants in a Family with an Exclusively Breastfed Infant.

Obesity is a serious health problem, that progressively affects individuals' lives with comorbidities involving heart disease, stroke, and diabetes mellitus. Since its prevalence increases particularly in children under age-of-five years, its genetic and environmental causes should be determined for prevention and control of the disease. This study aimed to detect underlying genetic risk factors in a family with an exclusively breastfed obese infant. A three-generation family was recruited to be evaluated for obesity. Detailed examinations along with body mass indexcalculations were performed on available family members. Whole exome sequencing was performed on 7-month-oldobese infant utilizing Illumina-NextSeq550. Bioinformatic analyses were performed on the Genomize SEQ platform with variant filtering at minor allele frequencies (MAF)<1% for all normal populations. Sanger sequencing was applied in variant confirmation and family segregation. Neuro-motor developmental features were normal and genetic syndromes were excluded from the index. Early-onset severe obesity (4.25SDS weight-for-height) was obvious in index case, where his father and grandmother were also obese (BMIs: 38.1kg/m2 and 31.3kg/m2, respectively). WES analysis revealed deleterious variants in SH2B1, PDE11A, ADCY3, and CAPN10 genes previously associated with obesity. All variants were evaluated as novel candidates for obesity except PDE11A and family segregation confirmed paternal inheritance. This study confirmed the paternal inheritance of all potentially deleterious obesity-related variants. The cumulative effect of individual variants might explain the obesity phenotype in this family. The infant is recommended to be under periodic follow-up due to increased risk for later childhood obesity.

Replication Study of GWAS-Associated Variants in the &lt;i&gt;TUFM&lt;/i&gt;, &lt;i&gt;SH2B1&lt;/i&gt;, &lt;i&gt;ZNF638&lt;/i&gt;, &lt;i&gt;NEGR1&lt;/i&gt;, &lt;i&gt;ATP2A1&lt;/i&gt;, &lt;i&gt;EXOC4&lt;/i&gt;, and &lt;i&gt;CSE1L&lt;/i&gt; Genes and Cognitive Abilities

To date, a large number of genome-wide association analyses (GWAS) of cognitive abilities (i.e. intelligence, educational level, executive functions, etc.) have been conducted in European populations. A replication analysis of GWAS-associated variants of the general factor of intelligence in the development of spatial (3D) abilities in the individuals from Russia is relevant. In order to estimate the main effect of the most significant GWAS loci on spatial abilities in the Russian cohort (N = 1011, 18–25 years old) a set of seven “top” SNPs (p 10–13) was formed: TUFM rs7187776, SH2B1 rs7198606, ZNF638 rs2287326, NEGR1 rs12128707, ATP2A1 rs8055138, EXOC4 rs1362739, and CSE1L rs6063353. Statistically significant differences (р 0.05) in genotype frequencies distribution of ATP2A1 rs8055138, NEGR1 rs12128707, and ZNF638 rs2287326 between Russians, Tatars, and Udmurts have been observed. As a result of analysis of genotype-by-environment interactions we revealed ethnicity-specific character of associations: in Russians maternal age at delivery (βST = 0.84, p = 0.005) and in Tatars bilingual/unilingual rearing (βST = 0.44, р = 0.020) modulated association of ZNF638 rs2287326 with spatial abilities. Moreover, urban/rural residency in childhood modulated association of TUFM rs7187776 with 3D abilities (βST = 0.41, р = 0.009). The data obtained indicate the involvement of the ZNF638, TUFM, SH2B1, and EXOC4 genes, which are responsible for adipogenesis, in the manifestation of cognitive abilities, and, therefore, confirms the relationship between cognitive and metabolic disorders. Nevertheless, ethnicity-specific character of demonstrated associations and differences in genotype frequencies of analyzed GWAS-SNPs point to the specific pattern of associated genetic loci characteristic for the Russian cohort and to the complexity of replication of data reported for the combined samples of Europeans.

A Replication Study of GWAS-Associated Variants in the TUFM, SH2B1, ZNF638, NEGR1, ATP2A1, EXOC4, and CSE1L Genes and Cognitive Abilities

A Replication Study of GWAS-Associated Variants in the TUFM, SH2B1, ZNF638, NEGR1, ATP2A1, EXOC4, and CSE1L Genes and Cognitive Abilities

Analysis Of The Association Between Sh2B1 chr16.28884655 And Type 2 Diabetes.

To determine correlation between genetic susceptibility of type 2 diabetes mellitus (T2DM) and Src homology 2 B adapter protein 1 (SH2B1) gene polymorphism in a diabetic population. Methods: A total of 111 T2DM patients (DM group) and 34 healthy controls (NC group) from Shanxi Provincial People's Hospital were included in this study. Exon 9 of the SH2B1 gene was detected using the Sanger sequencing method, and the relationship between SH2B1 gene polymorphism and diabetes was analyzed. Results: Comparison of the data between the two groups showed that the values of TG, the updated HOMA of insulin resistance (HOMA2-IR), weight, body mass index, waist circumference, fasting blood glucose and fasting insulin levels of the DM group were higher than those of the NC group (P < 0.05). The HOMA2 insulin sensitivity (%S) of the DM group was lower than that of the NC group (P < 0.05). Sequencing analysis revealed that the following five single nucleotide polymorphisms in exon 9 of SH2B1 may be related to T2DM: rs181578610, rs550079240, chr16.28884655, chr16.28884659 and chr16.28884831. Among them, chr16.28884655 was found to be significantly related to diabetes; this site, located on the NM_015503 exon, was related to TG, LDL-C and waist circumference. The SH2B1 gene locus chr16.28884655 was found to be significantly related to genetic susceptibility to T2DM.

SH2B1 variants as potential causes of non-syndromic monogenic obesity in a Brazilian cohort.

SH2B1 gene encodes an important adaptor protein to receptor tyrosine kinases or cytokine receptors associated with Janus kinases. This gene has been associated with the structural and functional modulation of neurons and other cells, and impacts on energy and glucose homeostasis. Several studies suggested that alterations in this gene are strong candidates for the development of obesity. However, only a few studies have screened SH2B1 point variants in individuals with obesity. Therefore, the aim of this study was to investigate the prevalence of SH2B1 variants in a Brazilian cohort of patients with severe obesity and candidates to bariatric surgery. The cohort comprised 122 individuals with severe obesity, who developed this phenotype during childhood. As controls, 100 normal-weight individuals were included. The coding region of SH2B1 gene was screened by Sanger sequencing. A total of eight variants were identified in SH2B1, of which p.(Val345Met) and p.(Arg630Gln) variants were rare and predicted as potentially pathogenic by the in the silico algorithms used in this study. The p.(Val345Met) was not found in either the control group or in publicly available databases. This variant was identified in a female patient with severe obesity, metabolic syndrome and hyperglycemia. The p.(Arg630Gln) was also absent in our control group, but it was reported in gnomAD with an extremely low frequency. This variant was observed in a female patient with morbid obesity, metabolic syndrome, hypertension and severe binge-eating disorder. Our study reported for the first time two rare and potentially pathogenic variants in Brazilian patients with severe obesity. Further functional studies will be necessary to confirm and elucidate the impact of these variants on SH2B1 protein function and stability, and their impact on energetic metabolism. Level V, cross-sectional descriptive study.

Exploring the association between specific genes and the onset of idiopathic scoliosis: a systematic review

BackgroundIdiopathic Scoliosis (IS) is the most common spinal deformity in adolescents, accounting for 80% of all spinal deformities. However, the etiology remains uncertain in most cases, being identified as Adolescent Idiopathic Scoliosis (AIS). IS treatments range from observation and sport to bracing or surgery. Several risk factors including sex and familiarity, have been linked with IS. Although there are still many uncertainties regarding the cause of this pathology, several studies report a greater incidence of the defect in families in which at least one other first degree relative is affected. This study systematically reviews the available literature to identify the most significant genes or variants related to the development and onset of IS.MethodsThe research question was formulated using a PIOS approach on the following databases: Medline, Embase, Cinahl, Scopus, Web of Science and Google Scholar. The search was performed from July to August 2021, and articles from the inception of the database to August 2021 were searched.Results24 of the 919 initially identified studies were included in the present review. The 24 included studies observed a total of 16,316 cases and 81,567 controls. All the considered studies stated either the affected gene and/or specific SNPs. CHD7, SH2B1, ESR, CALM1, LBX1, MATN1, CHL1, FBN1 and FBN2 genes were associated with IS development.ConclusionsAlthough association can be found in some candidate genes the field of research regarding genetic association with the onset of IS still requires more information.

Deleted genes associated with obesity in Mexican patients diagnosed with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a complex metabolic condition in which both lifestyle and genetic factors have a pathogenic role. The LEP gene encodes leptin, which regulates appetite, body weight, and several metabolic functions. Proopiomelanocortin (POMC), regulates food intake and energy balance. The aim of the study was to determine partial or complete deletions of genes associated with obesity in patients diagnosed with NAFLD. Blood samples and DNA from 43 individuals diagnosed with NAFLD by ultrasonographic technique (Fibroscan) were obtained. The partial or complete deletions of genes were determined by MLPA (Multiplex Ligation-dependent Probe Amplification) using the SALSA probemix P220-B2 Obesity only on 43 individuals. Fifty blood samples from healthy individuals were included. Eleven out of 43 individuals analyzed by MLPA presented some deletion of the genes analyzed: six were female and five were male. The partial or complete deletion of the LEPR and POMC genes was observed in eight patients (18.6%), SIM1 in six patients (13.9%), GRIK2 and SH2B1 in two patients (4.7%), SEZGL2 in four patients (9.3%), and MCR4 in one patient (2.3%). Partial deletion was observed in LEPR, POMC, SIM1, GRIK2, SH2B1, SEZGL2, and MCR4 genes in 26% of the cases, and we suggest that these alterations probably has a potential relationship for the development of NAFLD.

Severe obesity, hypogonadotropic hypogonadism and a WDR11 gene mutation.

Abstract Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease characterized by gonadotropin- releasing hormone (GnRH) deficiency. A number of variants were proved to be the pathogenesis gene of CHH, and a proportion of the patients of CHH were accompanied with severe early-onset obesity. We report on one adult male patient who manifested as CHH caused by WDR11 gene deletion mutation and severe obesity related to SH2B1 gene missense mutation, as well as early onset nasopharyngeal carcinoma (NPC). Our case emphasizes the importance of recognizing the heterogeneous underling diseases of the symptoms of morbid obesity and hypogonadism.

Genetic Obesity in Children: Overview of Possible Diagnoses with a Focus on SH2B1 Deletion

Introduction: Genetic obesity is rare and quite challenging for pediatricians in terms of early identification. Src-homology-2 (SH2) B adapter protein 1 (SH2B1) is an important component in the leptin-melanocortin pathway and is found to play an important role in leptin and insulin signaling and therefore in the pathogenesis of obesity and diabetes. Microdeletions in chromosome 16p11.2, encompassing the SH2B1 gene, are known to be associated with obesity, insulin resistance, hyperphagia, and developmental delay. The aim of our study is to report on a case series of young individuals with 16p11.2 microdeletions, including the SH2B1 gene, and provide detailed information on body mass index (BMI) development and obesity-associated comorbidities. In this way, we want to raise awareness of this syndromic form of obesity as a differential diagnosis of genetic obesity. Methods: We describe the phenotype of 7 children (3 male; age range: 2.8–18.0 years) with 16p11.2 microdeletions, encompassing the SH2B1 gene, and present their BMI trajectories from birth onward. Screening for obesity-associated comorbidities was performed at the time of genetic diagnosis. Results: All children presented with severe, early-onset obesity already at the age of 5 years combined with variable developmental delay. Five patients presented with elevated fasting insulin levels, 1 patient developed diabetes mellitus type 2, 4 patients had dyslipidemia, and 4 developed nonalcoholic fatty-liver disease. Discussion/Conclusion: Chromosomal microdeletions in 16p11.2, including the SH2B1 gene, in children are associated with severe, early-onset obesity and comorbidities associated with insulin resistance. Early genetic testing in suspicious patients and early screening for comorbidities are recommended.

A Novel Variant of the SH2B1 Gene in an Obese Child With Type 2 Diabetes

Obesity in children and adolescents is at epidemic levels in the United States and creates high risk for comorbidities later in life. Childhood obesity is thought to be the result of behavioral and nutritional problems. Although genetic factors may play a role in the etiology of obesity, monogenic forms of obesity are rare. We present a child with obesity, behavioral problems, leptin resistance, and type 2 diabetes who also carries a mutation of Sarcoma Homologous 2B adapter protein 1 (SH2B1). The subject was evaluated at 13 7/12 years old. He had polyphagia, learning disability, aggressive behavior and marked obesity. At ages 9,11, and 13 years respectively, his BMI was 9%, 16%, and 52% above the 95th percentile. At 13 7/12 years old, his height was at the 80th percentile and BMI was 66% above the 95th percentile. He had marked acanthosis nigricans and he was prepubertal. Fasting blood glucose and insulin levels were 116 mg/dl and 592 mIU/L, respectively. Hemoglobin A1c was 6.5% and metformin therapy was initiated for type 2 diabetes. Fasting leptin level (41.5 ng/mL) was markedly elevated indicating leptin resistance. DNA methylation study excluded Prader-Willi syndrome. DNA sequencing indicated a novel heterozygous c.1555G>T variant of SH2B1 gene, which is predicted to result in the amino acid substitution p. Asp519Tyr. The analysis by PolyPhen-2 and MutationTaster predicts that the variant is a pathogenic mutation affecting protein functions. SH2B1 interacts with JAK2 and may play a role in insulin signaling. Pathogenic heterozygous variants in SH2B1 have been associated with obesity, insulin resistance and maladaptive behavior phenotypes (Pearce et al, 2014). Sh2b1-null mice develop severe leptin resistance, obesity, and type 2 diabetes. Our report underscores the importance of investigating monogenic causes of obesity in subjects who present severe obesity, diabetes, and behavioral problems. Additional studies are needed to determine the association between this novel mutation and the clinical features of this patient.

Screening of MC4R, LEP, LEPR, POMC, SH2B1, and SIM1 genes in Turkish children with severe early-onset obesity

Screening of MC4R, LEP, LEPR, POMC, SH2B1, and SIM1 genes in Turkish children with severe early-onset obesity

A Combined Effect of Expression Levels of Obesity-Related Genes and Clinical Factors on Cancer Survival Rate.

Obesity is directly associated with the risk of cancer in different organs, including breast, colon, and kidney. However, adipocytes could be utilized to control progression for some types of cancer, such as leukemia and breast cancer. To explore the potential correlation between adipocytes and cancer, the combined effect of expression levels of obesity-related genes and clinical factors (i.e., gender, race, menopausal status, history of smoking, tumor grade, body mass index (BMI), and history of drinking) on cancer survival rate was systemically studied. The expression levels of obesity-related genes in cancer tissues and normal tissues were downloaded from The Cancer Genome Atlas (TCGA). Kaplan–Meier curves were plotted using R programming language. The log-rank test was applied to explore the correlation between different clinical subgroups. The overexpression of the nine obesity-related genes (MC4R, TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2, FTO, PCSK1, and GPR120) may associate with tumor-promoting factors in some organs (head and neck, gastrointestinal tract, liver, and gallbladder). Underexpressed LEPR, NEGR1, TMEM18, and SH2B1 genes prevented the progression and metastasis of kidney cancer. The combined effect of clinical factors and the expression levels of obesity-related genes on patients' survival was found to be significant. Our outcomes suggested that the alternations of DNA methylation patterns could result in the changes of expression levels of obesity-related genes, playing a critical role in tumor progression. The results of the current study may be utilized to supplement precision and personalized medicine, as well as provide novel insights for the development of treatment approaches for cancer.

Genetic Association of SH2B1 Gene Polymorphisms in Jordanian Arab Patients with Type 2 Diabetes Mellitus.

ObjectiveTo investigate the genotypic and allelic association of Src homology 2 B adapter protein 1 (SH2B1) gene polymorphisms with type 2 diabetes mellitus (T2DM) in Jordanian patients.Patients and MethodsThree hundred patients were screened, but only 200 adult Jordanian patients diagnosed with T2DM (53.5% male and 46.5% female) have participated in this study. Blood samples were collected from both patients and healthy individuals for DNA extraction according to well-established procedures. Exon 1 and exon 9 of the SH2B1 gene were sequenced using an efficient and sensitive DNA sequencing method in order to identify specific single nucleotide polymorphisms (SNPs) in the SH2B1 gene associated with T2DM. Genetic and haplotype correlation analysis was performed for the chosen SNPs to detect any association if existent. In addition, SNPStats Web Tool and Hardy–Weinberg equilibrium (HWE) analyses for the genotype distribution were used. The significance was determined according to the P-value, and the level of significance taken as P < 0.05. The normality of the data distribution was statically analysed by the Shapiro–Wilk test with a P-value >0.05. Also, the patient’s characteristics and clinical data about all participants were mentioned.ResultsTwo novel variations were present in the SH2B1 gene in Jordanian patients with T2DM: c.827C>G and c.2026G>A, and previously reported five SNPs: rs146946750, rs565131715, rs370302573, rs143212778, rs200470848. Our results showed a strong genetic association of rs565131715 SNP polymorphism within the SH2B1 gene in T2DM patients (χ2 test, P < 0.001). Additionally, rs143212778 SNP presented a genetic correlation with T2DM patients (χ2 test, P = 0.035) as compared to control individuals. GTACG haplotype of SH2B1 has a highly significant association with responders (P< 0.0001).ConclusionOur findings indicated a strong association between the rs565131715 polymorphism and the risk of T2DM among the Jordanian population. Moreover, our data showed that the rs143212778 polymorphism significantly elevated the danger of T2DM among this population. This study reveals the first data regarding the SH2B1 gene polymorphisms in Jordanian patients of Arab descent with diabetes.

The Role of Natural Selection in the Formation of the Genetic Structure of Populations by SNP Markers in Association with Body Mass Index and Obesity

Obesity is one of the major challenges in modern society. More than a third of the world's population suffers froms overweight. This phenotype affects the quality of life and is associated with cardiovascular diseases, diabetes, cancer and reproductive disorders. The population variability of allele frequencies of 26 single nucleotide polymorphisms, in association with obesity and body mass index, according to data from genome-wide association studies (GWASs) is discussed in this study. Genetic variability was analyzed in populations of Northern Eurasia and populations from the human genome diversity project (HGDP). The population samples are characterized by high genetic diversity that correlates with climatic and geographical parameters. The results of the test for searching for natural selection signals revealed a selection effect for rs1167827 of the HIP1 gene, rs7138803 and rs7164727 located in the intergenic region, rs7141420 of the NRXN3 gene, rs7498665 of the SH2B1 gene, and rs7903146 of the TCF7L2 gene.

Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI

Patients with bipolar disorder (BD) show higher frequency of obesity and type 2 diabetes (T2D), but the underlying genetic determinants and molecular pathways are not well studied. Using large publicly available datasets, we (1) conducted a gene-based analysis using MAGMA to identify genes associated with BD and body mass index (BMI) or T2D and investigated their functional enrichment; and (2) performed two meta-analyses between BD and BMI, as well as BD and T2D using Metasoft. Target druggability was assessed using the Drug Gene Interaction Database (DGIdb). We identified 518 and 390 genes significantly associated with BD and BMI or BD and T2D, respectively. A total of 52 and 12 genes, respectively, were significant after multiple testing correction. Pathway analyses conducted on nominally significant targets showed that genes associated with BD and BMI were enriched for the Neuronal cell body Gene Ontology (GO) term (p = 1.0E−04; false discovery rate (FDR) = 0.025) and different pathways, including the Signaling by Hedgehog pathway (p = 4.8E−05, FDR = 0.02), while genes associated with BD and T2D showed no specific enrichment. The meta-analysis between BD and BMI identified 64 relevant single nucleotide polymorphisms (SNPs). While the majority of these were located in intergenic regions or in a locus on chromosome 16 near and in the NPIPL1 and SH2B1 genes (best SNP: rs4788101, p = 2.1E−24), five were located in the ETV5 gene (best SNP: rs1516725, p = 1E−24), which was previously associated with both BD and obesity, and one in the RPGRIP1L gene (rs1477199, p = 5.7E−09), which was also included in the Signaling by Hedgehog pathway. The meta-analysis between BD and T2D identified six significant SNPs, three of which were located in ALAS1 (best SNP: rs352165, p = 3.4E−08). Thirteen SNPs associated with BD and BMI, and one with BD and T2D, were located in genes which are part of the druggable genome. Our results support the hypothesis of shared genetic determinants between BD and BMI and point to genes involved in Hedgehog signaling as promising targets.

Genome-Wide DNA Methylation Analysis Reveals Epigenetic Pattern of SH2B1 in Chinese Monozygotic Twins Discordant for Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Aberrant DNA methylation has been observed in ASD but the mechanisms remain largely unknown. Here, we employed discordant monozygotic twins to investigate the contribution of DNA methylation to ASD etiology. Genome-wide DNA methylation analysis was performed using samples obtained from five pairs of ASD-discordant monozygotic twins, which revealed a total of 2,397 differentially methylated genes. Further, such gene list was annotated with Kyoto Encyclopedia of Genes and Genomes and demonstrated predominant activation of neurotrophin signaling pathway in ASD-discordant monozygotic twins. The methylation of SH2B1 gene was further confirmed in the ASD-discordant, ASD-concordant monozygotic twins, and a set of 30 pairs of sporadic case-control by bisulfite-pyrosequencing. The results showed that there was a greater DNA methylation difference in ASD-discordant monozygotic twins than ASD-concordant monozygotic twins. Further, verification of the Chr.16:28856743 of SH2B1 showed significant differences in DNA methylation between case and control. These results suggest abnormal methylation of SH2B1 is associated with ASD etiology. Our data suggest that it might be worthwhile to further explore the functions of SH2B1 and related genes of neurotrophin signaling pathway in ASD.

The effect of copy number variations in chromosome 16p on body weight in patients with intellectual disability.

Syndromic monogenic obesity is a rare and severe early-onset form of obesity. It is characterized by intellectual disability, congenital malformations, and/or dysmorphic facies. The diagnosis of patients is challenging due to the genetic heterogenicity of this condition. However, the use of microarray technology in combination with public databases has been successful on genotype-phenotype correlations, especially for body mass index (BMI) alteration. In this study, the relationship between copy number variations (CNVs) detected by microarray mapping on 16p region and BMI alterations in syndromic patients were assessed. In order to achieve this goal, 680 unrelated Spanish children with intellectual disability were included. 16p region was characterized by using microarray platforms. All detected variants were classified as: (I) one previously non-described 10-Mb duplication in 16p13.2p12.3 region considered causal of intellectual disability and severe overweight, and (II) eleven 16p11.2 CNVs of low prevalence but with recurrence in syndromic patients with severe BMI alteration (nine proximal and two distal). Proximal 16p11.2 CNVs have a dose-dependent effect: underweight in carriers of duplication and obesity in carriers of deletion. KCTD13 was identified as a possible candidate gene for BMI alteration on proximal syndromes, whereas SH2B1 gene was identified as candidate for distal syndromes. The results shown in this paper suggest that syndromic patients could constitute a reliable model to evaluate hypothalamic satiety and obesity disorders as well as generate a wide expectation for primary prevention of comorbidities. Furthermore, 16p13.2p12.3 showed to be an important region on the regulation of body fatness.

Association study of six single nucleotide polymorphisms with obesity in two independent Iberian samples

Several BMI associated-loci conferring susceptibility to obesity have been identified. Summarizing all these risk-associated variations into a genetic risk-score (GRS) may improve predictive power and cumulative effect on obesity risk. In this study, we investigate the reproducibility in two independent samples of the association and weighted GRS previously proposed for six SNPs as predictors for obesity susceptibility. A case-control study was performed using one sample comprising 346 unrelated Portuguese children [6–12 years-old; 191 controls and 155 obese], and a second sample comprising 332 unrelated Spanish adults [18–60 years-old; 217 controls and 115 obese]. Polymorphisms located on FTO, TFAP2B, SEC16B, ETV5, and SH2B1 genes were genotyped by allelic discrimination TaqMan assays.After Bonferroni corrections we found nominal significant associations of the rs17817449 FTO polymorphism with BMI (p = 0.023), Z-score (p = 0.009), weight (p = 0.020), and waist circumference (p = 0.022) in the Portuguese children. A nominal association was also observed with risk of obesity (p = 0.027). The same polymorphism was found significantly associated with obesity (p = 0.0005) in Spanish adults. Nominal association with risk of obesity was also found for rs7634510 ETV5 polymorphism (p = 0.011). No further associations were observed for the other polymorphisms. Our results failed to replicate a previously proposed GRS predicting high susceptibility to childhood obesity. Nonetheless, we highlight the role of the rs17817449 FTO polymorphism on obesity in both Portuguese and Spanish samples, as well as the rs7634510 ETV5 polymorphism in adults.

Association of SH2B1 gene polymorphism with overweight and obesity

To investigate the association of SH2B1 gene rs7359397 polymorphism with overweight and obesity, as well as some related metabolic indicators in Northwest Chinese. Based on the cohort of China National Diabetes and Metabolic disorders Study(2007-2008)in Shanxi province, totally 1 210(including 635 overweight and 167 obese)males and 1 711(including 781 overweight and 212 obese)females were participated in this study. Matrix assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF MS)was adopted as the genotyping method. After adjusting for age, the single nucleotide polymorphism rs7359397 of SH2B1 was found to be associated with overweight and obesity in males. The correlation with overweight accords with the dominant(P=0.02), overdominant(P=0.03), and log-additive models(P=0.025), while the correlation with obesity accords with the dominant(P=0.007 8), overdominant(P=0.008 1), and log-additive models(P=0.015). rs7359397 showed to have a significant association with body mass index, body fat percentage, fasting serum insulin, homeostasis model assessment of insulin resistance in males; and high density lipoprotein-cholesterol in females(P<0.05). The results show that SH2B1 rs7359397 polymorphism is associated with overweight, obesity, and related metabolic indicators in males of the population studied. (Chin J Endocrinol Metab, 2017, 33: 1038-1042) Key words: Single nucleotide polymorphism; Overweight; Obesity; SH2B1 gene; Insulin

Evidence for Association between SH2B1 Gene Variants and Glycated Hemoglobin in Nondiabetic European American Young Adults: The Add Health Study.

Glycated hemoglobin (HbA1c) is used to classify glycaemia and type 2 diabetes (T2D). Body mass index (BMI) is a predictor of HbA1c levels and T2D. We tested 43 established BMI and obesity loci for association with HbA1c in a nationally representative multiethnic sample of young adults from the National Longitudinal Study of Adolescent to Adult Health [Add Health: age 24-34 years; n = 5641 European Americans (EA); 1740 African Americans (AA); 1444 Hispanic Americans (HA)] without T2D, using two levels of covariate adjustment (Model 1: age, sex, smoking, and geographic region; Model 2: Model 1 covariates plus BMI). Bonferroni adjustment was made for 43 SNPs and we considered P < 0.0011 statistically significant. Means (SD) for HbA1c were 5.4% (0.3) in EA, 5.7% (0.4) in AA, and 5.5% (0.3) in HA. We observed significant evidence for association with HbA1c for two variants near SH2B1 in EA (rs4788102, P = 2.2 × 10(-4) ; rs7359397, P = 9.8 × 10(-4) ) for Model 1. Both results were attenuated after adjustment for BMI (rs4788102, P = 1.7 × 10(-3) ; rs7359397, P = 4.6 × 10(-3) ). No variant reached Bonferroni-corrected significance in AA or HA. These results suggest that SH2B1 polymorphisms are associated with HbA1c, largely independent of BMI, in EA young adults.