The Hirschsprung's–multiple endocrine neoplasia connection

The risk of patients with Hirschsprung's disease later developing multiple endocrine neoplasia remains a matter of concern. The multiple endocrine neoplasia 2–Hirschsprung's disease association has been shown to cosegregate in Hirschsprung's disease patients with both short- and long-segment aganglionosis, although patients with long-segment aganglionosis a to carry the greatest risk. The Hirschsprung's disease–medullary thyroid carcinoma relationship also appears to be bi-directional, and activation or suppression of the rearranged during transfection gene appeared to vary over succeeding generations within the same family. Rearranged during transfection gene variations are associated with both conditions. The cosegregation of Hirschsprung's disease and multiple endocrine neoplasia 2 is particularly interesting as it involves both “switch off” and “switch on” of the rearranged during transfection proto-oncogene in the same patient. This cosegregation mostly relates to the cysteine-rich area on RET-620 (the “Janus gene”). The mechanism whereby rearranged during transfection influences gene activation in multiple endocrine neoplasia 2 is complex, but genetic variations impair the rearranged during transfection tyrosine kinase response to tyrosine kinase activation, thus appearing to dictate downstream signaling cascade responses. Better understanding of the RET-620 relationship allows for a more cost-effective method of identifying those at risk by focusing rearranged during transfection gene testing to this specific area as a “hot spot”. The clinical awareness of possible medullary thyroid carcinoma has led to timely intervention and early treatment of this chemo- and radioresistant tumor with poor prognosis. Establishment of “risk” by genetic testing has become a classic model of molecular medicine being integrated into patient care and offering rearranged during transfection-directed prophylactic surgical management. In addition, novel approaches to treatment based on this genetic knowledge have already shown early promise in randomized clinical trials

Fat Mass and Obesity-Associated (FTO) Gene Polymorphisms Are Associated with Physical Activity, Food Intake, Eating Behaviors, Psychological Health, and Modeled Change in Body Mass Index in Overweight/Obese Caucasian Adults

The fat mass and obesity-associated (FTO) gene is currently recognized as the most robust predictor of polygenic obesity. We investigated associations between the FTO rs1421085 and rs17817449 polymorphisms and the FTO rs1421085–rs17817449 haplotype and dietary intake, eating behavior, physical activity, and psychological health, as well as the effect of these associations on BMI. N = 133 treatment seeking overweight/obese Caucasian adults participated in this study. Genotyping was performed from whole blood samples. Weight and height was measured and a non-quantified food frequency questionnaire was completed to assess food group intake. Validated questionnaires were completed to assess physical activity (Baecke questionnaire), psychological health (General Health questionnaire, Rosenburg self-esteem scale and Beck Depression Inventory), and eating behavior (Three Factor Eating questionnaire). The risk alleles of the FTO polymorphisms were associated with poorer eating behaviors (higher hunger, internal locus for hunger, and emotional disinhibition scores), a higher intake of high fat foods and refined starches and more depressive symptoms. The modeled results indicate that interactions between the FTO polymorphisms or haplotypes and eating behavior, psychological health, and physical activity levels may be associated with BMI. The clinical significance of these results for implementation as part of weight management interventions needs further investigation

Mutational analysis of the solute carrier family 11 member 1 gene (SLC11A1) implicated in iron transport

Thesis (PhD)--University of Stellenbosch, 2003.ENGLISH ABSTRACT: The solute carrier family 11 member 1 gene (SLC11A 1) is a divalent metal ion transporter with various pleiotropic effects on macrophage function. This gene that regulates iron, and is also regulated by cellular iron levels, has previously been linked to many infectious and autoimmune diseases. In this analysis, in vitro studies using the luciferase reporter system as well as case-control association studies were applied to investigate the significance of SLC11 A1 allelic variation in patients with diverse disease phenotypes. For in vitro studies, five different SLC11A 1 promoter constructs were generated, followed by transfection into U937 and THP-1 cells. The inserted fragments included two previously described alleles (alleles 2 and 3), two novel alleles identified in this study (alleles 8 and 9) and a C to T point mutation at nucleotide position -237 in the presence of allele 3. The most striking finding was the opposite effect observed for allele 3 in the presence of the -237C~ T polymorphism, similar to that of allele 2. Although the SLC11A 1 gene has previously been implicated in iron transport, we have demonstrated, for the first time, that the various alleles investigated cause differential expression of the gene upon iron loading. Association studies were performed by investigating diseases including oesophageal cancer (DC), inflammatory bowel disease (lBO) and hereditary haemochromatosis (HH) (or primary iron overload). Significant associations (P<O.05) were observed with allele 3 for all three conditions investigated only after stratification according to the presence of the -237C~ T polymorphism. Re-assessment of the promoter alleles according to expression profiles determined by the in vitro studies, showed statistically significant associations for allele 3 with DC and primary iron overload, compared with the respective population-matched control groups. Additionally, several novel variants were identified in exon 2 (112G~A, 148deIGACCAGCCC, 157insGACCAGCCCAG) and intron 1 (IVS1-28C~T), with variant IVS1-28C~T occurring at a significantly increased frequency in patients with DC compared with population-matched controls (P<O.05). Investigation of the SLC11A 1 gene in individuals presenting with iron overload in the absence of homozygosity for the HFE C282Y mutation, provided further support for the importance of sequence variation in the promoter region of the SLC11A 1 gene in modified risk of iron-related disorders. Genes related to iron homeostasis, including HFE, SLC11A3, HAMP and DCYTB, were investigated in individuals with similar criteria and potential disease-causing mutations were identified in 11% White and 45% Black South African patients. The possible significance of the SLC11A3 and DCYTB genes in iron overload in the Black South African population, and the possible involvement of the DCYTB gene in iron overload in general, are demonstrated for the first time. This study contributed to a better understanding of the function of the SLC11A 1 gene in relation to iron metabolism. The involvement of SLC11A 1 in a range of disease phenotypes including cancer and inflammatory conditions that may involve iron dysregulation, can probably be explained by interaction with external factors such as infectious agents that may affect cellular iron status. Our findings provide both in vivo and in vitro evidence that iron dysregulation mediated by allelic effects of SLC11A 1 may underlie disease susceptibility to infectious and autoimmune conditions.AFRIKAANSE OPSOMMING: Die opgeloste stof draer familie 11 deel 1 geen (SLC11 A 1) is 'n divalente metaal ioon vervoerder met verskeie pleiotropiese effekte op makrofaagfunksie. Die geen, wat yster reguleer en ook deur sellulêre ystervlakke gereguleer word, is voorheen verbind met verskeie infektiewe en outo-immune siektes. In hierdie studie is in vitro analises, deur middel van die lusiferase verklikker sisteem, asook gevalle-kontrole assosiasie studies gebruik om die rol van SLC11A 1 alleel variasie in pasiënte met diverse siektefenotipes te ondersoek. Vyf verskillende SLC11A 1 promotor variante is geskep vir in vitro studies en gevolg deur transfeksie in U937 en THP-1 sellyne. Die ingevoegde fragmente het twee voorheen beskryfde allele (allele 2 en 3), twee nuwe allele wat in hierdie studie geïdentifiseer is (allele 8 en 9) en In C na T puntmutasie by nukleotied posisie -237 in die teenwoordigheid van alleel 3 ingesluit. Die opvallendste bevinding was die teenoorgestelde effek wat waargeneem is wanneer alleel 3 in die teenwoordigheid van die -237C~ T polimorfisme voorkom, soortgelyk aan alleel 2 uitdrukking. Alhoewel die SLC11A1 geen voorheen geïmpliseer is in yster vervoer, is daar vir die eerste keer aangetoon dat na yster lading, die verskillende allele differensiële uitdrukking van die geen veroorsaak. Verskeie siektes, insluitend slukderm kanker (OC), inflammatoriese dermsiekte (lBO) en oorerflike hemochromatose (HH) (of primêre ysteroorlading), is ondersoek deur middel van assosiasie studies. Betekenisvolle verskille (P<O.05) is waargeneem vir alleel 3 tussen die kontrole- en pasiëntgroepe in al drie siektes wat ondersoek is, maar slegs na stratifikasie volgens die teenwoordigheid van die -237C~ T polimorfisme. Na hersiening van die promotor allele volgens ekspressie profiele verkry met in vitro studies is statisties betekenisvolle assosiasie ook verkry vir alleel 3 met OC en primêre ysteroorlading in vergelyking met die onderskeie populasie kontrolegroepe. Verder is verskeie nuwe variante ook geïdentifiseer in ekson 2 (112G~A, 148deIGACCAGCCC, 157insGACCAGCCCAG) en intron 1 (IVS1- 28C~ T) en 'n statisties betekenisvolle verhoogde frekwensie van variant IVS1- 28C~ T is waargeneem in pasiënte met OC in vergelyking met die populasie kontrolegroep (P<O.05). Die belangrikheid van variasie in die promotor area van die SLC11A 1 geen as 'n modifiserende faktor in ysterverwante siektes, is verder ondersteun deur die SLC11A 1 geen in individue met ysteroorlading in die afwesigheid van homosigositeit vir die HFE C282Y mutasie te ondersoek. Ander gene geassosieerd met yster homeostase, insluitend HFE, SLC11A3, HAMP and DCYTB, is ondersoek in individue met soortgelyke seleksie kriteria en potensiële siekte-verwante mutasies is geïdentifiseer in 11% Wit en 45% Swart Suid-Afrikaanse pasiënte. Die moontlike belang van die SLC11A3 en DCYTB gene in ysteroorlading in die Swart Suid-Afrikaanse populasie en die moontlike betrokkenheid van die DCYTB geen in yster oorlading oor die algemeen, is vir die eerste keer aangetoon. Hierdie studie dra by tot 'n beter insig in die funksie van die SLC11A 1 geen ten opsigte van ystermetabolisme. Die betrokkenheid van SLC11A 1 in 'n reeks siekte fenotipes, wat insluit kanker en inflammatoriese toestande wat verband kan hou met 'n yster wanbalans, kan moontlik verklaar word deur interaksie met eksterne faktore soos infektiewe agente wat die sellulêre yster status kan beïnvloed. Ons bevindinge verskaf beide in vivo en in vitro getuienis dat yster wanbalans, wat bemiddel word deur alleliese effekte van SLC11A1, verantwoordelik mag wees vir vatbaarheid vir infektiewe en outoimmune siekte toestande

Fat mass and obesity-associated (FTO) gene polymorphisms are associated with physical activity, food intake, eating behaviors, psychological health, and modeled change in body mass index in overweight/obese caucasian adults

Please cite as follows: Harbron, J., Van der Merwe, L., Zaahl, M. G., Kotze, M. J. & Senekal, M. 2014. Fat mass and obesity-associated (FTO) gene polymorphisms are associated with physical activity, food intake, eating behaviors, psychological health, and modeled change in body mass index in overweight/obese caucasian adults. Nutrients, 6(8):3130-3152, doi:10.3390/nu6083130.The original publication is available at http://www.mdpi.com/journal/nutrientsThe fat mass and obesity-associated (FTO) gene is currently recognized as the most robust predictor of polygenic obesity. We investigated associations between the FTO rs1421085 and rs17817449 polymorphisms and the FTO rs1421085–rs17817449 haplotype and dietary intake, eating behavior, physical activity, and psychological health, as well as the effect of these associations on BMI. N = 133 treatment seeking overweight/obese Caucasian adults participated in this study. Genotyping was performed from whole blood samples. Weight and height was measured and a non-quantified food frequency questionnaire was completed to assess food group intake. Validated questionnaires were completed to assess physical activity (Baecke questionnaire),psychological health (General Health questionnaire, Rosenburg self-esteem scale and Beck Depression Inventory), and eating behavior (Three Factor Eating questionnaire). The risk alleles of the FTO polymorphisms were associated with poorer eating behaviors (higher hunger, internal locus for hunger, and emotional disinhibition scores), a higher intake of high fat foods and refined starches and more depressive symptoms. The modeled results indicate that interactions between the FTO polymorphisms or haplotypes and eating behavior, psychological health, and physical activity levels may be associated with BMI. The clinical significance of these results for implementation as part of weight management interventions needs further investigation.http://www.mdpi.com/2072-6643/6/8/3130Publisher's versio

Fat Mass and Obesity-Associated (FTO) Gene Polymorphisms Are Associated with Physical Activity, Food Intake, Eating Behaviors, Psychological Health, and Modeled Change in Body Mass Index in Overweight/Obese Caucasian Adults

The fat mass and obesity-associated (FTO) gene is currently recognized as the most robust predictor of polygenic obesity. We investigated associations between the FTO rs1421085 and rs17817449 polymorphisms and the FTO rs1421085–rs17817449 haplotype and dietary intake, eating behavior, physical activity, and psychological health, as well as the effect of these associations on BMI. N = 133 treatment seeking overweight/obese Caucasian adults participated in this study. Genotyping was performed from whole blood samples. Weight and height was measured and a non-quantified food frequency questionnaire was completed to assess food group intake. Validated questionnaires were completed to assess physical activity (Baecke questionnaire), psychological health (General Health questionnaire, Rosenburg self-esteem scale and Beck Depression Inventory), and eating behavior (Three Factor Eating questionnaire). The risk alleles of the FTO polymorphisms were associated with poorer eating behaviors (higher hunger, internal locus for hunger, and emotional disinhibition scores), a higher intake of high fat foods and refined starches and more depressive symptoms. The modeled results indicate that interactions between the FTO polymorphisms or haplotypes and eating behavior, psychological health, and physical activity levels may be associated with BMI. The clinical significance of these results for implementation as part of weight management interventions needs further investigation