Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) < P(overall) < 1.6 x 10(-23); odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 x 10(-5)) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at > or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.     

A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus

We identified and replicated an association between ITGAM (CD11b) at 16p11.2 and risk of systemic lupus erythematosus (SLE) in 3,818 individuals of European descent. The strongest association was at a nonsynonymous SNP, rs1143679 (P = 1.7 x 10(-17), odds ratio = 1.78). We further replicated this association in two independent samples of individuals of African descent (P = 0.0002 and 0.003; overall meta-analysis P = 6.9 x 10(-22)). The genetic association between ITGAM and SLE implicates the alpha(M)beta2-integrin adhesion pathway in disease development.     

Vernix caseosa as a multi-component defence system based on polypeptides, lipids and their interactions

Vernix caseosa is a white cream-like substance that covers the skin of the foetus and the newborn baby. Recently, we discovered antimicrobial peptides/proteins such as LL-37 in vernix, suggesting host defence functions of vernix. In a proteomic approach, we have continued to characterize proteins in vernix and have identified 20 proteins, plus additional variant forms. The novel proteins identified, considered to be involved in host defence, are cystatin A, UGRP-1, and calgranulin A, B and C. These proteins add protective functions to vernix such as antifungal activity, opsonizing capacity, protease inhibition and parasite inactivation. The composition of the lipids in vernix has also been characterized and among these compounds the free fatty acids were found to exhibit antimicrobial activity. Interestingly, the vernix lipids enhance the antimicrobial activity of LL-37 in vitro, indicating interactions between lipids and antimicrobial peptides in vernix. In conclusion, vernix is a balanced cream of compounds involved in host defence, protecting the foetus and newborn against infection.     

Effect of nonprotein thiols on protein synthesis in isolated rat hepatocytes

The ability of nonprotein thiols to modulate rates of protein synthesis was investigated in isolated rat hepatocytes. Addition of cysteine stimulates protein labelling by [¹⁴C] Leucine. Glutahione depletion, induced by in vivod administration of L-buthionine sulfoximine and diethylmaleate, did not alter the effect of cysteine, although it decreased the rate of protein synthesis by 32%. The effect of cysteine on protein synthesis does not seem to be related to a perturbatin of the redox state of the NAD⁺/NADH system or to changes in the rate of gluconeogenic pathway. The following observations indicate that cysteine may stimulate protein syntheis by increasing intracellular levels of aspartate: 1. Amino-oxyacetate, an inhibitor of pyridoxyal-dependent enzymes, inhibits protein labelling and decreases aspartate cellular content, whereas most amino acids accumulate or remain unchanged; 2. Cysteine, in the absence or in the presence of amino-ocycetate, stimulates protein labelling and induces aspartate accumulation, although mot amino acids diminish or remain unchanged.     

Glucose formation from methylglyoxal in hepatocytes from streptozotocin-induced diabetic mice: the effect of insulin

Acetol and methylglyoxal are intermediates of the intrahepatic metabolism of acetone leading to pyruvate formation. In hepatocytes prepared from fasted streptozotocin-induced diabetic mice, net glucose production could be measured from methylglyoxal but not from acetone or acetol. Insulin increased glucose formation from methylglyoxal in a concentration-dependent manner, whereas it was ineffective when pyruvate was used as substrate. Drug oxidation, as evidenced byp-aminophenol formation from aniline, was enhanced by methylglyoxal, and insulin proved to be stimulatory in this case as well. It is concluded that insulin might be involved in the regulation of glucose formation from methylglyoxal, but its mode of action is not yet clear.     

Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy.

Congestive heart failure (CHF) can result from various disease states with inadequate cardiac output. CHF due to dilated cardiomyopathy (DCM) is a familial disease in 20-30% of cases and is associated with mutations in genes encoding cytoskeletal, contractile or inner-nuclear membrane proteins. We show that mutations in the gene encoding giant-muscle filament titin (TTN) cause autosomal dominant DCM linked to chromosome 2q31 (CMD1G; MIM 604145). Titin molecules extend from sarcomeric Z-discs to M-lines, provide an extensible scaffold for the contractile machinery and are crucial for myofibrillar elasticity and integrity. In a large DCM kindred, a segregating 2-bp insertion mutation in TTN exon 326 causes a frameshift, truncating A-band titin. The truncated protein of approximately 2 mD is expressed in skeletal muscle, but western blot studies with epitope-specific anti-titin antibodies suggest that the mutant protein is truncated to a 1.14-mD subfragment by site-specific cleavage. In another large family with DCM linked to CMD1G, a TTN missense mutation (Trp930Arg) is predicted to disrupt a highly conserved hydrophobic core sequence of an immunoglobulin fold located in the Z-disc-I-band transition zone. The identification of TTN mutations in individuals with CMD1G should provide further insights into the pathogenesis of familial forms of CHF and myofibrillar titin turnover.     

Discovery of a cool planet of 5.5 Earth masses through gravitational microlensing

In the favoured core-accretion model of formation of planetary systems, solid planetesimals accumulate to build up planetary cores, which then accrete nebular gas if they are sufficiently massive. Around M-dwarf stars (the most common stars in our Galaxy), this model favours the formation of Earth-mass (M(o)) to Neptune-mass planets with orbital radii of 1 to 10 astronomical units (au), which is consistent with the small number of gas giant planets known to orbit M-dwarf host stars. More than 170 extrasolar planets have been discovered with a wide range of masses and orbital periods, but planets of Neptune's mass or less have not hitherto been detected at separations of more than 0.15 au from normal stars. Here we report the discovery of a 5.5(+5.5)(-2.7) M(o) planetary companion at a separation of 2.6+1.5-0.6 au from a 0.22+0.21-0.11 M(o) M-dwarf star, where M(o) refers to a solar mass. (We propose to name it OGLE-2005-BLG-390Lb, indicating a planetary mass companion to the lens star of the microlensing event.) The mass is lower than that of GJ876d (ref. 5), although the error bars overlap. Our detection suggests that such cool, sub-Neptune-mass planets may be more common than gas giant planets, as predicted by the core accretion theory.