👤 Jeanette N McClintick

Both lipoprotein(a) [Lp(a)] and peripheral artery disease (PAD) are associated with ischaemic events. We sought to assess the association between Lp(a) and major adverse cardiovascular events (MACE) and major lower extremity events (MALE) among patients with baseline PAD. The Mass General Brigham (MGB) Lp(a) registry includes all individuals with Lp(a) measured at two tertiary care centres from 2000 to 2019. Those with PAD were grouped according to Lp(a) percentile: 1st-25th [Q1, Lp(a) ≤ 14 nmol/L], 26th-50th (Q2, 14-<42 nmol/L), 51st-75th (Q3, 42-<132 nmol/L), and 76th-100th (Q4, 132-855 nmol/L). Outcomes were MACE [composite of cardiovascular (CV) death, myocardial infarction, or coronary revascularization] and MALE (composite of peripheral revascularization, acute limb ischaemia, or major lower extremity amputation). Cox proportional hazard modelling was used to assess the association between Lp(a) and the outcomes of interest after adjusting for traditional risk factors. Among 3757 individuals with PAD [39% female, median age 68 (IQR: 58-77)], individuals with Lp(a) levels in the third and fourth quartiles had a 24 and 30% increased hazard of MACE, respectively [adj. hazard ratio (HR): 1.24, P = 0.005; adj. HR: 1.30, P = 0.001] when compared with those in the first quartile. Individuals in the fourth quartile had a 19% greater hazard of MALE (adj. HR: 1.19, P = 0.043). Elevated Lp(a) in patients with PAD was associated with an increased risk of both MACE and MALE. Accordingly, measurement of Lp(a) may convey important prognostic value and allow for further risk stratification within this high-risk population. Show less

Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk. We carried out a genome-wide association study (GWAS) on a case-control sample drawn from the families in the Collaborative Study on the Genetics of Alcoholism. The cases all met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition; controls all consumed alcohol but were not dependent on alcohol or illicit drugs. To prioritize among the strongest candidates, we genotyped most of the top 199 single nucleotide polymorphisms (SNPs) (p < or = 2.1 x 10(-4)) in a sample of alcohol-dependent families and performed pedigree-based association analysis. We also examined whether the genes harboring the top SNPs were expressed in human brain or were differentially expressed in the presence of ethanol in lymphoblastoid cells. Although no single SNP met genome-wide criteria for significance, there were several clusters of SNPs that provided mutual support. Combining evidence from the case-control study, the follow-up in families, and gene expression provided strongest support for the association of a cluster of genes on chromosome 11 (SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS, and OSBPL5) with alcohol dependence. Several SNPs nominated as candidates in earlier GWAS studies replicated in ours, including CPE, DNASE2B, SLC10A2, ARL6IP5, ID4, GATA4, SYNE1, and ADCY3. We have identified several promising associations that warrant further examination in independent samples. Show less

The current study examined the effects of operant ethanol (EtOH) self-administration on gene expression kin the nucleus accumbens (ACB) and amygdala (AMYG) of inbred alcohol-preferring (iP) rats. Rats self-trained on a standard two-lever operant paradigm to administer either water-water, EtOH (15% v/v)-water, or saccharin (SAC; 0.0125% g/v)-water. Animals were killed 24 h after the last operant session, and the ACB and AMYG dissected; RNA was extracted and purified for microarray analysis. For the ACB, there were 513 significant differences at the p<0.01 level in named genes: 55 between SAC and water; 215 between EtOH and water, and 243 between EtOH and SAC. In the case of the AMYG (p<0.01), there were 48 between SAC and water, 23 between EtOH and water, and 63 between EtOH and SAC group. Gene Ontology (GO) analysis indicated that differences in the ACB between the EtOH and SAC groups could be grouped into 15 significant (p<0.05) categories, which included major categories such as synaptic transmission, cell and ion homeostasis, and neurogenesis, whereas differences between the EtOH and water groups had only 4 categories, which also included homeostasis and synaptic transmission. Several genes were in common between the EtOH and both the SAC and water groups in the synaptic transmission (e.g., Cav2, Nrxn3, Gabrb2, Gad1, Homer1) and homeostasis (S100b, Prkca, Ftl1) categories. Overall, the results suggest that changes in gene expression in the ACB of iP rats are associated with the reinforcing effects of EtOH. Show less