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1.  The MAP2K5-linked SNP rs2241423 is associated with BMI and obesity in two cohorts of Swedish and Greek children 
BMC Medical Genetics  2012;13:36.
Background
Recent genome-wide association studies have identified a single nucleotide polymorphism within the last intron of MAP2K5 associated with a higher body mass index (BMI) in adults. MAP2K5 is a component of the MAPK-family intracellular signaling pathways, responding to extracellular growth factors such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF). In this study, we examined the association of this variant in two cohorts of children from Sweden and Greece.
Methods
We examine the association of rs2241423 to BMI in a cohort of 474 Swedish children admitted for treatment of childhood obesity and 519 children matched for gender, ethnicity and socioeconomic background from the Stockholm area, as well as a cross-sectional cohort of 2308 Greek school children (Healthy Growth Study). Children were genotyped using a predesigned TaqMan polymorphism assay. Logistic regression was used to test for an association of rs2241423 to obesity in the cohort of Swedish children. Linear regression was used to test for an association of rs2241423 to BMI z-score and phenotypic measurements of body adiposity in the cohort of Greek children. Models were adjusted for age and gender. In the cohort of Greek children the model was also adjusted for stage of pubertal development.
Results
The minor allele of rs2241423, allele A, was associated with a protective effect against obesity in the cohort of Swedish children (p = 0.029, OR = 0.79 (95% CI: 0.64–0.98)), and with a lower BMI z-score in the cohort of Greek children (p = 0.028, β = −0.092). No association to phenotypic measurements of body fat distribution could be observed in our study.
Conclusions
rs2241423 was associated with BMI and obesity in two independent European cohorts suggesting a role for MAP2K5 in early weight regulation.
doi:10.1186/1471-2350-13-36
PMCID: PMC3459804  PMID: 22594783
Obesity; MAP2K5; Childhood obesity; Genetics; rs2241423
2.  Genetic and expression studies of SMN2 gene in Russian patients with spinal muscular atrophy type II and III 
BMC Medical Genetics  2011;12:96.
Background
Spinal muscular atrophy (SMA type I, II and III) is an autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron gene (SMN1). SMN2 is a centromeric copy gene that has been characterized as a major modifier of SMA severity. SMA type I patients have one or two SMN2 copies while most SMA type II patients carry three SMN2 copies and SMA III patients have three or four SMN2 copies. The SMN1 gene produces a full-length transcript (FL-SMN) while SMN2 is only able to produce a small portion of the FL-SMN because of a splice mutation which results in the production of abnormal SMNΔ7 mRNA.
Methods
In this study we performed quantification of the SMN2 gene copy number in Russian patients affected by SMA type II and III (42 and 19 patients, respectively) by means of real-time PCR. Moreover, we present two families consisting of asymptomatic carriers of a homozygous absence of the SMN1 gene. We also developed a novel RT-qPCR-based assay to determine the FL-SMN/SMNΔ7 mRNA ratio as SMA biomarker.
Results
Comparison of the SMN2 copy number and clinical features revealed a significant correlation between mild clinical phenotype (SMA type III) and presence of four copies of the SMN2 gene. In both asymptomatic cases we found an increased number of SMN2 copies in the healthy carriers and a biallelic SMN1 absence. Furthermore, the novel assay revealed a difference between SMA patients and healthy controls.
Conclusions
We suggest that the SMN2 gene copy quantification in SMA patients could be used as a prognostic tool for discrimination between the SMA type II and SMA type III diagnoses, whereas the FL-SMN/SMNΔ7 mRNA ratio could be a useful biomarker for detecting changes during SMA pharmacotherapy.
doi:10.1186/1471-2350-12-96
PMCID: PMC3146920  PMID: 21762474
3.  The obesity gene, TMEM18, is of ancient origin, found in majority of neuronal cells in all major brain regions and associated with obesity in severely obese children 
BMC Medical Genetics  2010;11:58.
Background
TMEM18 is a hypothalamic gene that has recently been linked to obesity and BMI in genome wide association studies. However, the functional properties of TMEM18 are obscure.
Methods
The evolutionary history of TMEM18 was inferred using phylogenetic and bioinformatic methods. The gene's expression profile was investigated with real-time PCR in a panel of rat and mouse tissues and with immunohistochemistry in the mouse brain. Also, gene expression changes were analyzed in three feeding-related mouse models: food deprivation, reward and diet-induced increase in body weight. Finally, we genotyped 502 severely obese and 527 healthy Swedish children for two SNPs near TMEM18 (rs6548238 and rs756131).
Results
TMEM18 was found to be remarkably conserved and present in species that diverged from the human lineage over 1500 million years ago. The TMEM18 gene was widely expressed and detected in the majority of cells in all major brain regions, but was more abundant in neurons than other cell types. We found no significant changes in the hypothalamic and brainstem expression in the feeding-related mouse models. There was a strong association for two SNPs (rs6548238 and rs756131) of the TMEM18 locus with an increased risk for obesity (p = 0.001 and p = 0.002).
Conclusion
We conclude that TMEM18 is involved in both adult and childhood obesity. It is one of the most conserved human obesity genes and it is found in the majority of all brain sites, including the hypothalamus and the brain stem, but it is not regulated in these regions in classical energy homeostatic models.
doi:10.1186/1471-2350-11-58
PMCID: PMC2858727  PMID: 20380707
4.  The common FTO variant rs9939609 is not associated with BMI in a longitudinal study on a cohort of Swedish men born 1920-1924 
BMC Medical Genetics  2009;10:131.
Background
Common FTO (fat mass and obesity associated) gene variants have recently been strongly associated with body mass index and obesity in several large studies. Here we set out to examine the association of the FTO variant rs9939609 with BMI in a 32 year follow up study of men born 1920-1924. Moreover, we analyzed the effect of physical activity on the different genotypes.
Methods
The FTO rs9936609 was genotyped using an Illumina golden gate assay. BMI was calculated using standard methods and body fat was estimated by measuring skinfold thickness using a Harpenden caliper. Physical activity was assessed using a four question medical questionnaire.
Results
FTO rs9939609 was genotyped in 1153 elderly Swedish men taking part of a population-based cohort study, the ULSAM cohort. The risk of obesity and differences in BMI according to genotype at the ages of 50, 60, 70, 77 and 82 were investigated. We found no increased risk of obesity and no association with BMI at any age with the FTO rs9939609 variant. We found however interaction between physical activity at the age of 50 years and genotype on BMI levels (p = 0.039) and there was a clear trend towards larger BMI differences between the TT and AA carriers as well as between AT and AA carriers in the less physically active subjects.
Conclusion
Here we found that the well established obesity risk allele for a common variant in FTO does not associate with increased BMI levels in a Swedish population of adult men which reached adulthood before the appearance of today's obesogenic enviroment. There is an interaction between physical activity and the effect of the FTO genotype on BMI levels suggesting that lack of physical activity is a requirement for an association of FTO gene variants to obesity.
doi:10.1186/1471-2350-10-131
PMCID: PMC2797506  PMID: 20003232
5.  Association between a rare SNP in the second intron of human Agouti related protein gene and increased BMI 
BMC Medical Genetics  2009;10:63.
Background
The agouti related protein (AGRP) is an endogenous antagonist of the melanocortin 4 receptor and is one of the most potent orexigenic factors. The aim of the present study was to assess the genetic variability of AGRP gene and investigate whether the previously reported SNP rs5030980 and the rs11575892, a SNP that so far has not been studied with respect to obesity is associated with increased body mass index (BMI).
Methods
We determined the complete sequence of the AGRP gene and upstream promoter region in 95 patients with severe obesity (BMI > 35 kg/m2). Three polymorphisms were identified: silent mutation c.123G>A (rs34123523) in the second exon, non-synonymous mutation c.199G>A (rs5030980) and c.131-42C>T (rs11575892) located in the second intron. We further screened rs11575892 in a selected group of 1135 and rs5030980 in group of 789 participants from the Genome Database of Latvian Population and Latvian State Research Program Database.
Results
The CT heterozygotes of rs11575892 had significantly higher mean BMI value (p = 0.027). After adjustment for age, gender and other significant non-genetic factors (presence of diseases), the BMI levels remained significantly higher in carriers of the rs11575892 T allele (p = 0.001). The adjusted mean BMI value of CC genotype was 27.92 ± 1.01 kg/m2 (mean, SE) as compared to 30.97 ± 1.03 kg/m2 for the CT genotype. No association was found between rs5030980 and BMI.
Conclusion
This study presents an association of rare allele of AGRP polymorphism in heterozygous state with increased BMI. The possible functional effects of this polymorphism are unclear but may relate to splicing defects.
doi:10.1186/1471-2350-10-63
PMCID: PMC2714840  PMID: 19602223

Results 1-5 (5)