Impact of genetic polymorphisms on the pathogenesis of achalasia: an age‐dependent paradigm?

Abstract  A wealth of evidence supports the concept that achalasia represents an autoimmune disorder in which a triggering factor (probably a virus) is the starter of an uncontrolled myenteric ganglionitis leading to neurodegeneration. The reasons whereby this process occurs only in some individuals and at the oesophageal level are unknown, but it is reasonable to assume that some genetic influence may affect the achalasia phenotype, making some individuals more or less susceptible to the disease. Association studies between achalasia and polymorphisms of genes involved in the regulation of immune responses may help to explain the complexity of achalasia pathogenesis and progression.     

The val66met polymorphism of brain‐derived neurotrophic factor is associated with human esophageal hypersensitivity

Background Recent evidence implicates brain‐derived neurotrophic factor (BDNF) in visceral hypersensitivity and pain in functional gastrointestinal disorders. We hypothesized that presence of the val66met polymorphism in the BDNF gene would be linked to increased esophageal sensitivity to electrical stimulation. Methods A total of 39 healthy volunteers (20 males, mean age 30) compliant with inclusion criteria after screening procedures were genotyped for BDNF polymorphisms and completed an Hospital Anxiety and Depression Scale (HADS) questionnaire. Sensory (ST) and pain (PT) thresholds in the proximal (PE) and distal (DE) esophagus were determined using electrical stimuli to a swallowed intraluminal catheter with bipolar electrodes by an investigator blinded to the subjects’ genotype. For comparison, somatic ST and PT (hand and foot) were also tested. HADS scores together with esophageal and somatic thresholds were then correlated with BDNF polymorphism status. Key Results Eleven of 39 (28%) volunteers had at least one Met allele (Met carriers). When compared with Val/Val, Met carriers had lower esophageal PT (Median PT [mA]: Val/Val vs Met carriers, PE; 49.4 vs 44.3, P = 0.033, DE: 63.8 vs 55.4, P = 0.045) with higher proportion of Val/Val subjects in the upper quartile for PT in both PE (P = 0.021) and DE (P = 0.033), yet similar somatic PT (Median PT [mA] Hand; 33.6 vs 38.0, P = 0.22, Foot; 44.7 vs 44.0, P = 0.48). Sensitivity results were independent of anxiety (P = 0.66) and depression (P = 0.33) scores. Conclusions & Inferences val66met BDNF polymorphisms are associated with increased esophageal sensitivity to experimental electrical stimulation. Thus, BDNF genotype may be a useful biomarker for electrical sensitivity in the healthy human esophagus.     

CXCL10 haplotypes and multiple sclerosis: association and correlation with clinical course

CXCL10 (interferon- γ -inducible protein-10) levels are increased in cerebrospinal fluid of multiple sclerosis (MS) patients with symptomatic attacks of inflammatory demyelination, supporting a role for this molecule in MS pathogenesis. Two hundred and twenty-six patients with MS and 235 controls were genotyped for G  →  C and T  →  C single nucleotide polymorphisms (SNPs) in exon 4 of CXCL10 gene. Haplotypes were tested for association and correlated with clinical variables. The two SNPs studied were in complete linkage disequilibrium. None of the determined haplotypes was associated with MS. However, carriers of the GGTT haplotype (defined as wild type, according to the sequence in National Centre for Biotechnology Information (NCBI) database) had a significantly lower progression index than non-carriers ( P  = 0.016). Furthermore, amongst patients who had an initial relapsing remitting (RR) course of the disease, the time between onset and second episode was significantly longer in GGTT carriers ( P  = 0.021). Considering secondary progressive (SP)–MS patients, the time between the initial RR form and the subsequent worsening to SP was longer in this group ( P  = 0.08). Therefore, the GGTT haplotype of the CXCL10 gene is not a susceptibility factor for the development of MS, but is probably to influence the course of MS, possibly contributing to slow down the progression of the disease.     

The role of NrCAM in neural development and disorders--beyond a simple glue in the brain

NrCAM is a neuronal cell adhesion molecule of the L1 family of immunoglobulin super family. It plays a wide variety of roles in neural development, including cell proliferation and differentiation, axon growth and guidance, synapse formation, and the formation of the myelinated nerve structure. NrCAM functions in cell adhesion and modulates signaling pathways in neural development through multiple molecular interactions with guidance and other factors. Alterations in NrCAM structure/expression are associated with psychiatric disorders such as autism and drug addiction and with tumor progression. The mechanisms of NrCAM participation in development and how these might be perturbed in disorders are reviewed.     

云南少数民族和汉族特发性癫痫CLCN2基因多态性研究

目的检测云南省5种独有少数民族(基诺族、阿昌族、布朗族、佤族、拉祜族)与汉族人群特发性癫痫与电压门控氯通道-2基因CLCN2基因多态性是否相关。方法采用PCR、单碱基延伸(SNap shot)等技术,应用病例-对照法检测云南少数民族特发性癫痫患者92例及其未发病亲属170例、云南汉族特发性癫痫患者107例及63例健康人群外周血CLCN2基因多态性。统计少数民族与汉族人群中rs13099401、rs4912540两个位点的基因型、等位基因频率,分别用χ2等检验进行统计分析。结果 CLCN2基因rs13099401位点基因型频率分布在少数民族病例组与汉族病例、对照组之间有统计学差异(χ2=6.828,P=0.033;χ2=9.246,P=0.010,均P<0.05);基因型CC与非CC型在少数民族病例组与汉族对照组间有统计学差异(χ2=9.245,OR=3.26,P=0.002,P<0.01)。rs4912540位点基因型频率在各组间无统计学差异(P>0.05)。结论 CLCN2基因位点rs13099401可能是云南少数民族特发性癫痫患者的相关性位点,基因型CC为汉族特发性癫痫发作的一个保护性因素;rs4912540与云南人群特发性癫痫无显著相关性。     

汉族人血小板膜糖蛋白Ⅱb/Ⅲa基因多态性与脑梗死的关系

目的 探讨汉族人群中血小板膜糖蛋白Ⅱb/Ⅲa基因多态性与脑梗死的关系.方法 临床筛选121例实验病例,分为两组:脑梗死组75例,对照组46例.均提取基因组DNA,PCR扩增目的 基因片段,并将扩增产物送生物公司测序,确定有无Ⅱb/Ⅲa基因多态性存在.最后进行统计学分析.结果 在所有人选人群中仅发现1例脑梗死患者存在基凶多态性,无临床及统计学意义.结论 在汉族人群中,Ⅱb/Ⅲa基因多态性出现频率太低,与脑梗死发病无关.

Abstract：

Objective To discuss the relationship between genetic polymorphisms of the platelet glycoprotein receptor Ⅱb/Ⅲa and cerebral infarction.Methods 121 cases were divided into 2 groups:75 cases in the cerebral infarction group and 46 cases in the control group.Existence of the polymorphisms of receptor Ⅱb/Ⅲa was detected by PCR and sequencing in production of amplification.Results The polymorphisms of receptor Ⅱb/Ⅲa were found only in 1 cerebral infarction patient and had no clinical and statistical significance.Conclusions The frequency of occurrence of genetic polymorphisms of the platelet glycoprotein receptor Ⅱb/Ⅲa may be too few in Han people,and has no raltionship of cerebral infarction.