Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism

Chronic fatigue syndrome (CFS) is characterized by idiopathic fatigue of greater than 6 months' duration with postexertional exacerbation and many other symptoms. A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS. A total of 248 patients with CFS defined by Centers for Disease Control criteria, and 248 controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G --> T, Ala-Ser(224)). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine(224) homozygosity among the CFS patients was noted, compared with controls (chi(2) = 5.31, P = 0.07). Immunoreactive-CBG (IR-CBG) levels were higher in Serine/Alanine (Ser/Ala) than Ala/Ala subjects and higher again in Ser/Ser subjects, this effect was strongest in controls; Ser/Ser: 46.1 +/- 1.8 (n = 31, P = 0.03) vs. Ser/Ala: 42.4 +/- 1.0 (n = 56, P = 0.05) vs. Ala/Ala: 40.8 +/- 1.7 mug/mL (n = 21). Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients, total cortisol: Ser/Ser: 13.3 +/- 1.4 (n = 34) vs. Ser/Ala: 14.0 +/- 0.7 (n = 66) vs. Ala/Ala: 15.4 +/- 1.0 (n = 23). Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions.

Genetic time-series analysis identifies a major QTL for in vivo alcohol metabolism not predicted by in vitro studies of structural protein polymorphism at the ADH1B or ADH1C loci

After ingestion of a standardized dose of ethanol, alcohol concentrations were assessed, over 3.5 hours from blood (six readings) and breath (10 readings) in a sample of 412 MZ and DZ twins who took part in an Alcohol Challenge Twin Study (ACTS). Nearly all participants were subsequently genotyped on two polymorphic SNPs in the ADH1B and ADH1C loci known to affect in vitro ADH activity. In the DZ pairs, 14 microsatellite markers covering a 20.5 cM region on chromosome 4 that includes the ADH gene family were assessed, Variation in the timed series of autocorrelated blood and breath alcohol readings was studied using a bivariate simplex design. The contribution of a quantitative trait locus (QTL) or QTL's linked to the ADH region was estimated via a mixture of likelihoods weighted by identity-by-descent probabilities. The effects of allelic substitution at the ADH1B and ADH1C loci were estimated in the means part of the model simultaneously with the effects sex and age. There was a major contribution to variance in alcohol metabolism due to a QTL which accounted for about 64% of the additive genetic covariation common to both blood and breath alcohol readings at the first time point. No effects of the ADH1B*47His or ADH1C*349Ile alleles on in vivo metabolism were observed, although these have been shown to have major effects in vitro. This implies that there is a major determinant of variation for in vivo alcohol metabolism in the ADH region that is not accounted for by these polymorphisms. Earlier analyses of these data suggested that alcohol metabolism is related to drinking behavior and imply that this QTL may be protective against alcohol dependence.

Radiocarbon variations from the southern hemisphere, 10,350-9700 cal BP

We have made AMS measurements on a series of 10-ring samples from a subfossil Huon pine log found in western Tasmania (42degreesS, 145degreesE). The results show a pronounced rise in Delta(14)C over the first 200 years, and a decrease over the following 160 years. Tree-ring width measurements indicate that this log (catalogue SRT-447) can be cross-dated with another subfossil log (SRT-416) for which a series of high-precision radiometric C-14 measurements have previously been made. When the two tree-ring series are thus aligned, SRT-447 is the older of the two logs, and there is a 139-year overlap. We then have a Huon pine floating chronology spanning 680 years, with C-14 measurements attached. The C-14 data sets agree well within the period of overlap indicated by the tree-rings. The C-14 variations from Huon pine show excellent agreement with those from German oak and pine for the period 10,350-9670 cal BP. Aligning the Huon pine C-14 Series with that from German oak and pine allows us to examine the inter-hemispheric offset in C-14 dates in the early Holocene. (C) 2004 Elsevier B.V. All rights reserved.

Climatic variability in the southwest Pacific during the Last Termination (20-10 kyr BP)

The degree to which palaeoclimatic changes in the Southern Hemisphere co-varied with events in the high latitude Northern Hemisphere during the Last Termination is a contentious issue, with conflicting evidence for the degree of 'teleconnection' between different regions of the Southern Hemisphere. The available hypotheses are difficult to test robustly, however, because there are few detailed palaeoclimatic records in the Southern Hemisphere. Here we present climatic reconstructions from the southwestern Pacific, a key region in the Southern Hemisphere because of the potentially important role it plays in global climate change. The reconstructions for the period 20-10 kyr BP were obtained from five sites along a transect from southern New Zealand, through Australia to Indonesia, supported by 125 calibrated C-14 ages. Two periods of significant climatic change can be identified across the region at around 17 and 14.2 cal kyr BP, most probably associated with the onset of warming in the West Pacific Warm Pool and the collapse of Antarctic ice during Meltwater Pulse-1A, respectively. The severe geochronological constraints that inherently afflict age models based on radiocarbon dating and the lack of quantified climatic parameters make more detailed interpretations problematic, however. There is an urgent need to address the geochronological limitations, and to develop more precise and quantified estimates of the pronounced climate variations that clearly affected this region during the Last Termination. (c) 2005 Elsevier Ltd. All rights reserved.