Single nucleotide polymorphisms (SNPs) in the serotonergic (5HT) system seem to have modulatory effects on depression and physical function. Preliminary evidence suggests that gene×environment interactions play a role in the development of depression, with somatic complaints serving as environmental stressors. We hypothesized that pain intensity may serve as a stress factor that modulates the association between SNPs in the 5HT system and depression. We investigated symptoms of pain, depression, physical functioning, and disability in 224 patients 6months after lumbar disc surgery. Associations between these variables and functional promoter SNPs in the serotonin receptor genes 5HTR1A (rs6295) and 5HTR2A (rs6311) were analyzed. For 5HTR2A, we found a significant gene×environment×sex interaction, as female patients carrying at least one A allele of the -1438A/G promoter SNP had significantly higher depression scores when confronted with severe pain compared to women harboring the GG genotype (P=.005). For 5HTR1A, patients homozygous for the -1019 G allele presented higher Beck Depression Inventory scores relative to the CG/CC group, indicating a major effect of this SNP on depression. Furthermore, women homozygous for either the 5HTR1A G allele or the 5HTR2A A allele had lower levels of physical functioning than patients with the other genotypes. These results suggest that 5HTR1A and 5HTR2A promoter variations have gender-dependent modulatory effects on depression and physical function in patients with pain. Furthermore, this study demonstrates that pain after lumbar surgery modulates the association between 5HT gene polymorphisms and depression.

Myelin protein zero (MPZ/P0) constitutes a major component of compact peripheral myelin. We report a family with a missense mutation, c.700G>T p.Asp234Tyr (deviant nomenclature: c.670G>T, p.Asp224Tyr), within the intracellular domain of myelin protein zero, who has distal sensorimotor symptoms, cramps, restless legs syndrome, neuropathic pain, and carpal tunnel syndrome. The index patient responded to intravenous immunoglobulin and immunosuppression, so there may be a possible secondary autoimmune process, probably triggered by altered antigen presentation due to mutated MPZ protein.

Mutations in the gene encoding smooth muscle cell alpha actin (ACTA2) have recently been shown to cause familial thoracic aortic aneurysms leading to type A dissections (TAAD) and predispose to premature stroke and coronary artery disease. In order to further explore the role of ACTA2 variations in the pathogenesis of TAAD, we sequenced the coding regions of this gene in 40 unrelated German patients with TAAD (with (n¼21) or without (n¼19) clinical features suggestive of Marfan syndrome). All patients had previously tested negative for mutations in the FBN1 and TGFBR2 genes. We identified three novel ACTA2 mutations and mapped them on a three-dimensional model of actin. Two mutations affect residues within (M49V) or adjacent to (R39C), the DNAse-I-binding loop within subdomain 2 of alpha actin. They were observed in families with recurrent aortic aneurysm (R39C) or aortic dissection (M49V). The third mutation causes an exchange in the vicinity of the ATP-binding site (G304R) in a patient thought to have isolated TAAD. None of the affected individuals had clinical features typical for Marfan syndrome, and no case of premature stroke or coronary artery disease was reported from the affected families. In conclusion, we underscore the role of ACTA2 mutations in nonsyndromic TAAD and suggest that ACTA2 should be included in the genes routinely investigated for syndromic and nonsyndromic TAAD. Detailed clinical investigations of additional families are warranted to further explore the full range of phenotypic signs associated with the three novel mutations described here.

BackgroundGhrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also indicates a role of ghrelin in cancer development.MethodsWe conducted a case-control study to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with colorectal cancer risk. Pairwise tagging was used to select the 11 polymorphisms included in the study. The selected polymorphisms were genotyped in 680 cases and 593 controls from the Czech Republic.ResultsWe found two SNPs associated with lower risk of colorectal cancer, namely SNPs rs27647 and rs35683. We replicated the two hits, in additional 569 cases and 726 controls from Germany.ConclusionA joint analysis of the two populations indicated that the T allele of rs27647 SNP exerted a protective borderline effect (Ptrend = 0.004).