Prevalence and correlates of restless legs syndrome in men living with HIV

Background Data on the prevalence and correlates of restless legs syndrome (RLS) in people with HIV are limited. This study sought to determine the prevalence of RLS, associated clinical correlates, and characterize sleep-related differences in men with and without HIV. Methods Sleep-related data were collected in men who have sex with men participating in the Multicenter AIDS Cohort Study (MACS). Demographic, health behaviors, HIV status, comorbidities, and serological data were obtained from the MACS visit coinciding with sleep assessments. Participants completed questionnaires, home polysomnography, and wrist actigraphy. RLS status was determined with the Cambridge-Hopkins RLS questionnaire. RLS prevalence was compared in men with and without HIV. Multinomial logistic regression was used to examine correlates of RLS among all participants and men with HIV alone. Sleep-related differences were examined in men with and without HIV by RLS status. Results The sample consisted of 942 men (56% HIV+; mean age 57 years; 69% white). The prevalence of definite RLS was comparable in men with and without HIV (9.1% vs 8.7%). In multinomial regression, HIV status was not associated with RLS prevalence. However, white race, anemia, depression, and antidepressant use were each independently associated with RLS. HIV disease duration was also associated with RLS. Men with HIV and RLS reported poorer sleep quality, greater sleepiness, and had worse objective sleep efficiency/ fragmentation than men without HIV/RLS. Conclusions The prevalence of RLS in men with and without HIV was similar. Screening for RLS may be considered among people with HIV with insomnia and with long-standing disease

Novel genes for familial combined hyperlipidemia.

Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90095-1679, USA. Familial combined hyperlipidemia (FCHL) is a complex genetic disorder of unknown etiology. Recently, 'modifier' genes of the FCHL phenotype, such as the apolipoprotein AI-CIII-AIV gene cluster and LPL, have been identified in several populations. A 'major' gene for FCHL has been identified in a Finnish isolate which maps to a region syntenic to murine chromosome 3 where a locus for combined hyperlipidemia has been identified. We review these and other recent studies which indicate that FCHL is genetically heterogeneous. Publication Types: Review Review, Tutoria

Linkage of a candidate gene locus to familial combined hyperlipidemia: lecithin:cholesterol acyltransferase on 16q.

Department of Microbiology and Molecular Genetics, Molecular Biology Institute, University of California, Los Angeles, 90095-1679, USA. Familial combined hyperlipidemia (FCHL) is a common lipid disorder characterized by elevated levels of plasma cholesterol and triglycerides that is present in 10% to 20% of patients with premature coronary artery disease. To study the pathophysiological basis and genetics of FCHL, we previously reported recruitment of 18 large families. We now report linkage studies of 14 candidate genes selected for their potential involvement in the aspects of lipid and lipoprotein metabolism that are altered in FCHL. We used highly polymorphic markers linked to the candidate genes, and these markers were analyzed using several complementary, nonparametric statistical allele-sharing linkage methodologies. This current sample has been extended over the one in which we identified an association with the apolipoprotein (apo) AI-CIII-AIV gene cluster. We observed evidence for linkage of this region and FCHL (P<0.001), providing additional support for its involvement in FCHL. We also identified a new locus showing significant evidence of linkage to the disorder: the lecithin:cholesterol acyltransferase (LCAT) locus (P<0.0006) on chromosome 16. In addition, analysis of the manganese superoxide dismutase locus on chromosome 6 revealed a suggestive linkage result in this sample (P<0.006). Quantitative traits related to FCHL also provided some evidence of linkage to these regions. No evidence of linkage to the lipoprotein lipase gene, the microsomal triglyceride transfer protein gene, or several other genes involved in lipid metabolism was observed. The data suggest that the lecithin:cholesterol acyltransferase and apolipoprotein AI-CIII-AIV loci may act as modifying genes contributing to the expression of FCHL

Abstract # 2036 Recent stimulant use and leukocyte gene expression in methamphetamine users with treated HIV infection

The use of stimulants such as methamphetamine may accelerate HIV disease progression, but scant research has examined stimulant-associated pathophysiologic alterations in treated HIV. In a sample of 55 HIV-positive, methamphetamine-using sexual minority men with a viral load less than 200 copies/mL, 27 participants with a urine sample that was reactive for recent stimulant use (Stimulant Tox+) were compared to 28 who tested negative in urine for stimulants (Stimulant Tox−). Analyses employed the false discovery rate (FDR) under the Benjamini-Hochberg procedure with a 10% cut-off. Stimulant Tox+ participants did not differ from those who were Stimulant Tox− on demographic and clinical characteristics. However, Stimulant Tox+ participants reported more days using methamphetamine in the past 30 days (10.7 versus 4.0; p < 0.01). RNA sequencing provided evidence for differential expression of 32 genes and perturbation of 168 pathways in recent stimulant users. Most notably, we observe upregulation single genes linked to HIV latency (i.e., CD274 and FCGR2A) in Stimulant Tox+ participants. Pathway analyses indicated that recent stimulant use was associated with two-directional perturbation of gene sets governing HIV latency, immune activation, inflammation, neuroendocrine hormone regulation, and neurotransmitter synthesis. Stimulant Tox+ participants also displayed significantly higher log10 TNF-alpha plasma levels (Mean = 1.74 versus 1.63; p = 0.023). Further research is needed to examine these mechanisms whereby stimulant use may contribute to HIV persistence and disease progression

Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A

OBJECTIVE: To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesity, hyperlipidemia and insulin resistance, using a 10 cM genome-wide scan. DESIGN: Plasma leptin and soluble tumor necrosis factor receptor superfamily members 1A and 1B (sTNFRSF1A and sTNFRSF1B, also known as sTNFR1 and sTNFR2) were analyzed as unadjusted and adjusted quantitative phenotypes of adiposity, in addition to body mass index (BMI), in multipoint and single-point analyses. In the second stage of analysis, an important chromosome 1 positional candidate gene, the leptin receptor (LEPR), was studied. SUBJECTS: Eighteen Dutch pedigrees with familial combined hyperlipidemia (FCH) (n=198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity. RESULTS: Multipoint analysis of the genome scan data identified linkage (log of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1S3728 and D1S1665, flanking the leptin receptor (LEPR) gene by approximately 9 and 3 cM, respectively, The LOD score decreased to 1.8 with age- and gender-adjusted leptin levels. Notably, BMI also mapped to this region with an LOD score of 1.2 (adjusted BMI: LOD 0.5). Two polymorphic DNA markers in LEPR and their haplotypes revealed linkage to unadjusted and adjusted BMI and leptin, and an association with leptin levels was found as well. In addition, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma concentrations of soluble TNFRSF1A. BMI gave a LOD score of 0.6. Moreover, a chromosome 10 q-ter locus, AFM198ZB, showed linkage with adjusted BMI (LOD 3.3), CONCLUSION: These data provide evidence that a human chromosome 1 locus, harboring the LEPR gene, contributes to plasma leptin concentrations, adiposity and body weight in humans affected with this insulin resistant dyslipidemic syndrome, Navel loci on chromosome 8 and 10 qter need further study

Identification of TNFRSF-1B as a novel modifier gene in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) is the most commonly inherited hyperlipidemia in man, with a frequency of +/-1% in the general population and similar to 10% in myocardial infarction survivors. A genomic scan in 18 Dutch FCHL families resulted in the identification of several loci with evidence for linkage. One of these regions, 1p36,2, contains TNFRSF1B which encodes one of the tumor necrosis factor receptors. An intron 4 polymorphic CA-repeat was used to confirm linkage to FCHL. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function (P = 0,032), and, borderline, with apolipoprotein B levels (P = 0.064). Furthermore, in a case-control study, association was demonstrated since the overall CA-repeat genotype distribution was significantly different among 40 unrelated FCHL patients and 48 unrelated healthy spouse controls (P = 0.029), This difference was due to a significant increase in allele CA271 homozygotes in the FCHL patients (P = 0,019), Mutation analysis of exon 6 in 73 FCHL family members demonstrated the presence of a single nucleotide polymorphism with two alleles, coding for methionine (196M) and arginine (196R), Complete linkage disequilibrium between CA267, CA271 and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype, In conclusion, TNFRSF1B was found to be associated with susceptibility to FCHL, Our data suggest that an as yet unknown disease-associated mutation, linked to alleles 196M and CA271, plays a role in the pathophysiology of FCHL

Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies

&lt;p&gt;&lt;b&gt;Background&lt;/b&gt; &lt;br&gt;Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.&lt;/br&gt;&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods&lt;/b&gt; &lt;br&gt;We assessed the −1131T&#x3E;C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20 842 patients with coronary heart disease, 35 206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12 785 incident cases of coronary heart disease during 2·79 million person-years at risk). We analysed −1131T&#x3E;C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy.&lt;/br&gt;&lt;/p&gt; &lt;p&gt;&lt;b&gt;Findings&lt;/b&gt; &lt;br&gt;The minor allele frequency of −1131T&#x3E;C was 8% (95% CI 7—9). −1131T&#x3E;C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3·5% [95% CI 2·6—4·6]; 0·053 mmol/L [0·039—0·068]), lower apolipoprotein AI (1·3% [0·3—2·3]; 0·023 g/L [0·005—0·041]), and higher apolipoprotein B (3·2% [1·3—5·1]; 0·027 g/L [0·011—0·043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16·0% (95% CI 12·9—18·7), or 0·25 mmol/L (0·20—0·29), higher (p=4·4×10−24). The odds ratio for coronary heart disease was 1·18 (95% CI 1·11—1·26; p=2·6×10−7) per C allele, which was concordant with the hazard ratio of 1·10 (95% CI 1·08—1·12) per 16% higher triglyceride concentration recorded in prospective studies. −1131T&#x3E;C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12·2 nmol/L [95% CI 7·7—16·7]; p=9·3×10−8) and smaller HDL particle size (0·14 nm [0·08—0·20]; p=7·0×10−5), factors that could mediate the effects of triglyceride.&lt;/br&gt;&lt;/p&gt; &lt;p&gt;&lt;b&gt;Interpretation&lt;/b&gt; &lt;br&gt;These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease.&lt;/br&gt;&lt;/p&gt; &lt;p&gt;&lt;b&gt;Funding&lt;/b&gt; &lt;br&gt;British Heart Foundation, UK Medical Research Council, Novartis.&lt;/br&gt;&lt;/p&gt