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Serotonin toxicity results from serotonin excess in the central nervous system from serotonergic drugs. Previous studies suggest an association between T102C polymorphism of the serotonin 2A (5-hydroxytryptamine 2A) receptor gene and serotonergic adverse effects with serotonergic drugs. We aimed to determine whether there is an association between the T102C polymorphism and serotonin toxicity in patients taking serotonergic drug overdoses. Ninety-five patients presenting with serotonergic drug overdoses were examined for serotonin toxicity and had blood collected for DNA analysis. A diagnosis of serotonin toxicity was made in 14 patients (15%) based on the Hunter Serotonin Toxicology Criteria. Four of the 14 patients (29%) with serotonin toxicity had the C/C genotype compared with 20/81 (25%) without serotonin toxicity. There were no differences in age or sex, but the median defined daily dose taken by patients with serotonin toxicity was 27 (14-84) compared with 18 (2-136) in patients without serotonin toxicity (P=0.06). There was no association between serotonin toxicity and the T102C polymorphism in patients taking a serotonergic drug overdose. [ABSTRACT FROM AUTHOR]

As a result of genome-wide association studies in larger sample sets, there has been an increase in identifying genes that influence susceptibility to individual immune-mediated diseases, as well as evidence that some genes are associated with more than one disease. In this study, we tested 17 single nucleotide polymorphisms (SNP) from 16 gene regions that have been reported in several autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), ankylosing spondylitis (AS) and Crohn's disease (CD) to determine whether the variants are also associated with type 1 diabetes (T1D). In up to 8010 cases and 9733 controls we found some evidence for an association with T1D in the regions containing genes: 2q32/STAT4, 17q21/STAT3, 5p15/ERAP1 (ARTS1), 6q23/TNFAIP3 and 12q13/KIF5A/PIP4K2C with allelic P-values ranging from 3.70 × 10−3 to 3.20 × 10−5. These findings extend our knowledge of susceptibility locus sharing across different autoimmune diseases, and provide convincing evidence that the RA/SLE locus 6q23/TNFAIP3 is a newly identified T1D locus.Genes and Immunity (2009) 10, 188–191; doi:10.1038/gene.2008.99; published online 25 December 2008 [ABSTRACT FROM AUTHOR]

Genome-wide association studies provide insight into multigenic diseases through the identification of susceptibility genes and etiological pathways. In addition, the identification of shared variants among autoimmune disorders provides insight into common disease pathways. We previously reported an association of a nonsynonymous single nucleotide polymorphism (SNP) rs763361/Gly307Ser in the immune response gene CD226 on chromosome 18q22 with type 1 diabetes (T1D) susceptibility. Here, we report efforts toward identifying the causal variant by exonic resequencing and tag SNP mapping of the 18q22 region in both T1D and multiple sclerosis (MS). In addition to the analysis of newly available samples in T1D (2088 cases and 3289 controls) and autoimmune thyroid disease (AITD) (821 cases and 1920 controls), resulting in strong support for the Ser307 association with T1D (P=3.46 × 10−9) and continued potential evidence for AITD (P=0.0345), we provide evidence for association of Gly307Ser with MS (P=4.20 × 10−4) and rheumatoid arthritis (RA) (P=0.017). The Ser307 allele of rs763361 in exon 7 of CD226 predisposes to T1D, MS, and possibly AITD and RA, and based on the tag SNP analysis, could be the causal variant.Genes and Immunity (2009) 10, 5–10; doi:10.1038/gene.2008.82; published online 30 October 2008 [ABSTRACT FROM AUTHOR]

Alterations in the secretion of adipokines may explain the link between obesity, type 2 diabetes (T2DM) and coronary artery disease (CAD). These conditions have been associated with variation in the adiponectin gene, although evidence for this relationship has been variable, with differences found even in similar samples. This study aims to clarify these inconsistencies by determining the impact of identified adiponectin gene ( ADIPOQ) variants (−11391G>A,−1377C>G[promoter] and +45T>G[exon 2] and +276G>T[intron 2]) on the prospective risk of CAD and T2DM in healthy men, and on adverse metabolic markers, in myocardial infarct survivors and controls from different parts of Europe. The hazard ratio for cardiovascular disease varied across the −11391GG/GA/AA(p = 0.03) and −11371CC/CG/GG(p = 0.05) genotypes only. In contrast, only the +45T>G variant (3.80[1.76-8.24]) was associated with T2DM, while two haplotypes (p < 0.05) and +276G>T(p = 0.01) increased risk in interaction with obesity. The variants were associated with a number of biomarkers in Southern but not Northern Europe (p = 0.01), despite no significant differences in allele or haplotype frequencies (p > 0.44). A risk haplotype could not be identified in either sample. Adiponectin gene variants are hence currently poor markers for the development of T2DM and CAD. Their influence on risk depends significantly on interactions that are not currently understood with either genetic variation elsewhere or the environment of the sample studied. [ABSTRACT FROM AUTHOR]

The strong association between the angiotensin I-converting enzyme (ACE) gene I/D polymorphism with serum ACE activity appears lacking in Nigerians and Kenyans, but has not previously been well assessed in others of African origin. This study addressed this issue in an ethnically well defined black South African population. A putative association for the A22982G ACE gene variant, a QTL likely to impact on serum ACE activity, was also sought. Subjects were 200 healthy male black South African volunteers from the Xhosa ethnic group. Venous blood was obtained from all subjects for DNA extraction. ACE I/D and A22982G genotypes were determined and serum ACE activity measured. Age and blood pressure were recorded. For the group as a whole (mean ± SD age 38.5 ± 9.8 years, SBP 119.6 ± 14.1 mmHg, DBP 78.2 ± 10.1 mmHg) serum ACE activity was 38.2 ± 11.2 nmol ml−1min−1. ACE I/D genotype was not significantly associated with serum ACE activity. In contrast, the A22982G variant was significantly associated with serum ACE activity, being 35.9 ± 9.6, 38.1 ± 10.6 and 42.4 ± 15.3 nmol ml−1min−1 for AA, AG and GG genotypes respectively; p = 0.03 by ANOVA and p = 0.01 by linear trend. In keeping with the findings in some other African populations, the ACE I/D polymorphism is not strongly associated with serum ACE activity in Xhosa South Africans. As such, it cannot be used as a marker of ACE activity in these subjects. In this regard the use of the A22982G gene variant may be more appropriate. [ABSTRACT FROM AUTHOR]

Viruses of the family Potyviridae exhibited a robust single-nucleotide polymorphism profile at the between-species level, conforming to the neutral theory rule. However, the ratios of nonsynonymous to synonymous mutations ( Ka/ Ks) were relatively greater between-species than within-species in viral cistrons examined from members of the genus Potyvirus, indicating a relaxation on constraint. Judged by the McDonald and Kreitman’s test, the fixation frequencies for nonsynonymous mutations across the genomes of closely related potyviruses were greater than expected, suggesting population bottlenecks at speciation. These mutation patterns are best explained by a deleterious-compensatory model. [ABSTRACT FROM AUTHOR]

We have previously shown that the selection of haplotype tag single nucleotide polymorphisms (htSNPs) and their statistical analysis in a multi-locus transmission/disequilibrium test (TDT) results in a more cost-effective genotyping strategy in disease association studies of genes by minimising redundancy due to linkage disequilibrium between SNPs. Further savings can be achieved by the use of a two-stage genotyping strategy. This approach is illustrated here in conjunction with the multi-locus TDT in determining whether common alleles of the immune regulatory genes RANK and its ligand TRANCE (RANKL) are associated with type 1 diabetes (T1D). A saving of approximately 75% of potential genotyping reactions could be made with minimal loss of power. There was little evidence from our analysis for association between the TRANCE and RANK genes and T1D in the populations tested.Genes and Immunity (2004) 5, 301-305. doi:10.1038/sj.gene.6364064 Published online 18 March 2004 [ABSTRACT FROM AUTHOR]

In 1474 healthy Caucasoid men aged 45-65 y, insulin-like growth factor II (IGF2) Apal AA homozygotes showed a mean body weight 4 kg lower than Apal GG homozygotes (77.6 ± 10.9 kg vs 81.6 ± 11.5 kg, P = 0.003) with heterozygotes (GA) intermediate (80.1±11.9 kg). The mean serum IGF-II concentration in 44 Apal AA individuals was significantly higher than in 48 Apal GG individuals (683.3±146.9 ng/ml vs 614.0±124.0 ng/ml, P=0.01). An INS Pst1 polymorphism showed no association with weight and it was also found to be in minimal linkage disequilibrium with the IGF2 Apal site (coefficient 0.016). The IGF2 Apal AA genotype is therefore associated with lower mean body weight but higher serum IGF-II concentrations than the GG genotype. Apal GG homozygotes incur a 1.67-fold risk of pathological Body Mass index (BMI) (> 30 kg/m²) compared with AA homozygotes. [ABSTRACT FROM AUTHOR]

A common polymorphism, rs7566605, 10 kb upstream of the insulin-induced gene 2 transcription start site has been associated with obesity in Caucasian and African-American populations, with the hypothesis that an alteration in gene expression results in elevated plasma triglyceride levels. The goal of this study was to verify the findings in a cohort of 2721 healthy Caucasian men (second Northwick Park Heart Study), and a separate study of 747 type 2 diabetic patients from Caucasian, Afro-Caribbean and Indian groups (University College London Diabetes and Cardiovascular Disease Study). The rs7566605 single-nucleotide polymorphism (SNP) was not related to plasma triglyceride levels in either study, and we found no association with body mass index or obesity in either cohort, despite having the power to detect the previously reported effect. This suggests that, at the least, the true size of the effect on obesity of this SNP is likely to be considerably less than reported previously. [ABSTRACT FROM AUTHOR]

Background and aims: An important part is played by inflammation in intracranial aneurysm formation. The hypothesis that there is an association of the proinflammatory cytokine interleukin-6 (IL-6) genotypes (-572G>C and -174G>C) with intracranial aneurysms was tested. Methods: IL-6 genotypes were determined in 91 Caucasian patients with aneurysms and compared with 2720 healthy UK controls. Results: For both polymorphisms, the distribution of the genotypes and estimated allele frequency were different between the control group and the aneurysm group. For -572G>C, a higher frequency of the C allele (p =0.001) and more people homozygous for the C allele were found among those with aneurysms than among the controls (4.4% v 0.3%, p = 0.001 ). For -174G>C, more people homozygous for the C allele were found among the controls than among those with aneurysm (18% v 7%, p = 0.007). The 572C/174G haplotype was associated with an increased risk of aneurysms, with the relative risk compared with the common haplotype being 1.89 and that for the -572G/174C haplotype being 0.58 (p<0.0005). Conclusion: This is the first, study to show that IL-6 promoter polymorphisms are associated with intracranial aneurysmal disease. Whether this association is with the development, progression or rupture of such aneurysms, or represents survivor bias, is unclear. [ABSTRACT FROM AUTHOR]

Abstract: Lipoprotein associated phospholipase A2 (Lp-PLA2) modulates low-density lipoprotein (LDL) oxidation by hydrolysing oxidised phospholipids present on particle surfaces. We investigated whether Lp-PLA2 activity and PLA2G7 A379V genotype were related to mediators of atherosclerosis in a diabetic study. Plasma Lp-PLA2 activity (taken in men only) and A379V genotype were investigated with regards to metabolic syndrome (MS), UKPDS risk score, and oxidised LDL (oxLDL/LDL), in a cohort of Caucasian men and women (n =783, age 62.5±13.7 years). After adjustment for type of diabetes, CHD status, and statin use, those individuals with features defining the MS (WHO guidelines) had higher Lp-PLA2 activity (35.6±11.9nmol/min/ml) compared to those without (33.0±10.8nmol/min/ml) (p =0.02). Quartiles of UKPDS coronary heart disease (CHD) risk score were also positively associated with Lp-PLA2 activity (p =0.006, p =0.004 linear trend). Those men in the highest quartile of oxLDL/LDL level had the lowest Lp-PLA2 activity (31.3±10.5nmol/min/ml) when compared to the middle two (32.3±9.8 and 35.9±10.9nmol/min/ml, respectively) and lowest quartile (35.6 ±12.5nmol/min/ml; p =0.03, p =0.004 linear trend). There was no significant association between A379V genotype and Lp-PLA2 enzyme activity (p =0.34) or oxLDL/LDL (p =0.32). Lp-PLA2 activity is an independent predictor of CHD risk and MS in a sample of subjects with diabetes mellitus. The association of Lp-PLA2 activity with oxLDL/LDL suggests that Lp-PLA2 may be a modulating factor in the process of atherosclerosis. [Copyright &y& Elsevier]