The vasopressor action of the renin-angiotensin system in the rat snake, Ptyas korros

The pressor actions of homologous kidney extract and human angiotensins I and II were studied in the conscious rat snake, Ptyas korros. A converting enzyme inhibitor (captopril), an angiotensin II analogue ([Sar¹, Ala⁸]ANG II), an α-adrenergic receptor antagonist (phentolamine), and a catecholamine releaser (reserpine) were used to elucidate their actions. It was found that captopril attenuated the pressor effects of the kidney extract and angiotensin I but not that of angiotensin II. [Sar¹, Ala⁸]ANG II and phentolamine both significantly attenuated, but did not completely inhibit the vasopressor actions of the kidney extract and angiotensins I and II. However, reserpine administration did not reduce the action of angiotensin II. These findings suggest that the renin-angiotensin system in snakes is similar to those present in mammals and other nonmammalian species, except for the mechanism of angiotensin II action. In the present study, angiotensin II was found to act partly through the α-adrenergic receptor which is not as specific as that in mammals and thus may respond to an agonist other than its usual ones, and partly through the vascular angiotensin II receptor.     

Association of a polymorphism in the lipin 1 gene with systolic blood pressure in men

BACKGROUND: Lipin 1 plays a role in abdominal obesity, insulin resistance, and hypertriglyceridemia. The gene is located at 2p25.1, a susceptibility locus for hypertension. We studied the association of tagging single-nucleotide polymorphisms (SNPs) in the lipin 1 (LPIN1) gene with hypertension and blood pressure. METHODS: Twelve tagging SNPs from the HapMap database were genotyped using Sequenom MassArray in 268 hypertensive subjects and 407 normotensive controls, of whom 268 matched the cases in age and sex. RESULTS: None of the tagging SNPs were found to be associated with hypertension after correcting for multiple testing, although carriers of the minor allele of rs10520097 had nominally lower odds for hypertension (P = 0.014). After excluding subjects who were on antihypertensive medications, the minor allele of rs10495584 was nominally associated with lower mean systolic and diastolic blood pressures in men (121.1 +/- 14.2 and 76.3 +/- 10.2 mm Hg vs. 127.4 +/- 15.2 and 80.1 +/- 10.5 mm Hg, P = 0.002 and 0.007, respectively), but not in women (P > 0.05). The association of rs10495584 with systolic blood pressure in men remained significant after correcting for multiple testing and adjustment for age, waist circumference, insulin resistance, triglyceride, and high-density lipoprotein (HDL) cholesterol (beta = -0.158, P = 0.005). An analysis of statistically similar SNPs (ssSNPs) in the regions surrounding rs10495584 suggested that its effect may be caused by its high linkage disequilibrium (LD) with the SNP, rs11524, in which the major allele forms an exonic splicing silencer sequence. CONCLUSION: Our study provides further evidence that lipin 1 may play a role in blood pressure regulation, especially in men.     

Whole exome sequencing identifies a novel mutation in the transglutaminase 6 gene for spinocerebellar ataxia in a Chinese family

Li M, Pang SYY, Song Y, Kung MHW, Ho S‐L, Sham P‐C. Whole exome sequencing identifies a novel mutation in the transglutaminase 6 gene for spinocerebellar ataxia in a Chinese family. Autosomal dominant spinocerebellar ataxias (SCA) constitute a heterogeneous group of inherited disorders. The transglutaminase 6 (TGM6) gene was recently suggested as a SCA causative gene in Chinese SCA families. In this study, two affected members of a three‐generation Chinese family with SCA characterized by progressive cerebellar ataxia and lower limb pyramidal signs were subjected to whole exome sequencing. Through bioinformatics analysis of the sequence variants in these two individuals, we identified a novel mutation in the TGM6 gene (c.1528G>C) which showed perfect co‐segregation with disease phenotype in all nine members of this family. This finding confirms that mutations in TGM6 gene represent an important cause of SCA in Chinese. This study also shows that whole exome sequencing of a small number of affected individuals, leveraged on bioinformatics analysis, can be an efficient strategy for identifying causative mutations in rare Mendelian disorders.     

Comparative genomic hybridization: comparison between esophageal squamous cell carcinoma and gastric cardia adenocarcinoma from a high-incidence area for both cancers in Henan, northern China

Esophageal squamous cell carcinoma (SCC) remains the leading cause of cancer related deaths in Linzhou (formerly Linxian), the highest incidence area for esophageal cancer (EC) in Henan, northern China. In China, gastric cardia adenocarcinoma (GCA) shares very similar geographic distribution with SCC, suggesting the possibility of similar risk factors involved in SCC and GCA carcinogenesis in these areas. However, the underlying genetic alterations for esophageal and gastric cardia carcinogenesis, especially for the molecular difference between SCC and GCA, are largely unknown. The present study was thus undertaken to determine the difference in chromosomal aberrations in SCC (n = 37) and GCA (n = 31) using the comparative genomic hybridization method (CGH). All the patients were from Linzhou, Henan, a high-risk geographic region for both SCC and GCA. CGH results showed that chromosomal aberrations with different degrees were identified both in SCC and GCA. In SCC, chromosomal profile of DNA copy number was characterized by most frequently detected gains at 8q (29/37, 78%), 3q (24/37, 65%) and 5p (19/37, 51%); and frequently detected losses at 3p (21/37, 57%), 8p and 9q (14/37, 38%). In GCA, the frequently detected gains were identified at 20q (13/31, 42%), 6q (12/31, 39%) and 8q (11/31, 35%); the DNA copy number losses in GCA occurred frequently at 17p (17/31, 55%), 19p (15/31, 48%) and 1p (14/31, 45%). Statistically, there were evident differences between SCC and GCA in DNA copy number gains at 8q, 3q, 5p and 20q (P < 0.05) and in losses at 3p, 8p, 5q, 17p and 18q (P < 0.05). Gains at 8q were frequently observed in both SCC and GCA. Gains at 3q and 8p were frequently observed in TNM stage III of both SCC and GCA. The present CGH results provide candidate regions that may contain specific related genes involved in SCC and GCA in the Linzhou population. Gains at 8q, 3q and 5p and losses at 3p, 8p and 9q were specifically implicated in SCC; gains at 20q, 6q and 8q and losses at 17p, 19p and 1p were specifically implicated in GCA; gains at 8q were implicated in both SCC and GCA.     

Ascertainment Through Family History of Disease Often Decreases the Power of Family-based Association Studies

Selection of cases with additional affected relatives has been shown to increase the power of the case-control association design. We investigated whether this strategy can also improve the power of family-based association studies that use the transmission disequilibrium test (TDT), while accounting for the effects of residual polygenic and environmental factors on disease liability. Ascertainment of parent-offspring trios conditional on the proband having affected first-degree relatives almost always reduced the power of the TDT. For many disease models, this reduction was quite considerable. In contrast, for the same sample size, designs that analyzed more than one affected offspring per family often improved power when compared to the standard parent-offspring trio design. Together, our results suggest that (1) residual polygenic and environmental influences should be considered when estimating the power of the TDT for studies that ascertain families with multiple affected relatives; (2) if trios are selected conditional on having additional affected offspring, then it is important to genotype and include in the analysis the additional siblings; (3) the ascertainment strategy should be considered when interpreting results from TDT analyses. Our analytic approach to estimate the asymptotic power of the TDT is implemented online at http://pngu.mgh.harvard.edu/∼purcell/gpc/. Edited by David Allison     

Phenotypic and population differences in the association between CILP and lumbar disc disease

Background

Lumbar disc disease (LDD) is one of the leading causes of disability in the working‐age population. A functional single‐nucleotide polymorphism (SNP), +1184T→C, in exon 8 of the cartilage intermediate layer protein gene (CILP) was recently identified as a risk factor for LDD in the Japanese population (odds ratio (OR) 1.61, 95% CI 1.31 to 1.98), with implications for impaired transforming growth factorβ1 signalling.

Aim

To validate this finding in two different ethnic cohorts with LDD.

Methods

This SNP and flanking SNPs were analysed in 243 Finnish patients with symptoms of LDD and 259 controls, and in 348 Chinese subjects with MRI‐defined LDD and 343 controls.

Results and conclusion

The results showed no evidence of association in the Finnish (OR = 1.35, 95% CI 0.97 to 1.87; p = 0.14) or the Chinese (OR = 1.05, 95% CI 0.77 to 1.43; p = 0.71) samples, suggesting that cartilage intermediate layer protein gene is not a major risk factor for symptoms of LDD in Caucasians or in the general population that included individuals with or without symptoms.Lumbar disc disease (LDD) is one of the leading causes of disability in the working‐age population. Radiological changes indicative of LDD are common, but only a proportion develops complications such as disc herniation and sciatica. Although the aetiology of LDD is not well understood, there is strong evidence for the involvement of both genetic and environmental factors.^1,2A recent study reported an association between LDD and a functional single‐nucleotide polymorphism (SNP) (rs2073711), +1184T→C, in exon 8 of the cartilage intermediate layer protein gene (CILP) in a Japanese group (odds ratio (OR) 1.61, 95% CI 1.31 to –1.98).³ The allelic change resulted in amino acid substitution Ile395Thr. CILP is expressed widely in intervertebral discs and its expression increases as disc degeneration progresses.³ CILP interacts directly with transforming growth factor (TGF)β1, inhibiting the TGFβ1‐mediated induction of extracellular matrix proteins such as aggrecan and collagen II.³ Functional studies showed that the C allele (coding for Thr395) increased binding and inhibition of TGFβ1, suggesting that regulation of TGFβ1 signalling by CILP plays a crucial role in the aetiology and pathogenesis of LDD.³Argument for a causal role would be strengthened if the same association could be replicated in a distinct population, and in clinical cases of LDD defined by MRI changes indicative of LDD in general. Therefore, we investigated the association between CILP polymorphisms and LDD in a Finnish sample with symptoms of LDD, and in a Chinese sample with only MRI‐defined LDD. These samples were informative in previous studies demonstrating association of LDD with the vitamin D receptor gene⁴ and the Gln326Trp (Trp2) allele of COL9A2⁵ in Chinese and the Arg103Trp (Trp3) allele of COL9A3 in Finns.⁶ Thus, the Chinese sample is comparable with the Finnish dataset, and a correlation can then be drawn with the Japanese dataset.     

Smoldering multiple myeloma: present position and potential promises

Since smoldering multiple myeloma (SMM) was first described over three decades ago based on a case series of six patients, its definition and our understanding of the entity have evolved considerably. The risk of progression to symptomatic myeloma (MM) varies greatly among individuals diagnosed with myeloma precursor disease. Epidemiologic, molecular, flow cytometric and radiological techniques have demonstrated that this transformation to MM from precursor states is not sudden but rather a continuous overlapping series of events with evidence of end‐organ damage that could manifest in the earliest stages of disease. Contemporary antimyeloma therapies can yield rapid, deep, and durable responses with manageable toxicities, and molecular‐cell‐based measures are now available to rule out minimal residual disease. With this information, clinical studies with correlative measures can now be developed to test the fundamental hypothesis that intervention in early myeloma may provide a measurable clinical benefit to patients by either delaying progression or eradicating plasma cell clones.