Clarifying complex inheritance: apolipoprotein C3 and atherosclerosis.

PURPOSE OF REVIEW: To describe some steps in the progress in the molecular biology of a peptide, apolipoprotein C3; its gene mutations that render individuals susceptible or resistant to developing hyperlipidaemia and atherosclerosis. RECENT FINDINGS: Data that lead to the development of a new therapeutic agent volanesorsen. SUMMARY: The agent blocks the function of the mRNA of apolipoprotein C3 and successfully treats severe hypertriglyceridaemia in phase 3 trials (Ionis Pharmaceuticals).

The effect of manual and mechanical stimulation on oxytocin release and milking characteristics in Holstein cows milked 3 times daily.

Prestimulation administered to a cow before attachment of the milking unit has historically been performed manually. Development of innovative milking technology has allowed manual stimulation to be replaced by mechanical forms of stimulation. Holstein cows (n=30) were enrolled in a crossover design to determine the effect of manual stimulation (forestripping and drying) and high-vibration pulsation on oxytocin profiles, milk yield, milk flow rates, incidence of delayed milk ejection causing bimodal milk flow curves, and residual milk in Holstein cows milked 3 times daily (3×). All cows were subjected to all treatments. Cows received manual (forestripping and drying) or mechanical (high-vibration pulsation) stimulation along with lag times of 0, 30, or 90 s for 21 consecutive milkings. Forestripping involved the manual removal of 2 streams of milk from each teat and drying of the teats. High-vibration pulsation involved increasing the pulsation cycles from 60 to 300 pulses/min and reducing the vacuum in the pulsation chamber to 20 kPa. The 5 treatments were (1) immediate attachment of the milking machine under normal pulsation (T0); (2) dip plus forestrip and drying with 30-s lag time (FD30); (3) dip plus forestrip and drying with 90-s lag time (FD90); (4) high-vibration pulsation for 30 s (HV30); and (5) high-vibration pulsation for 90 s (HV90). Milk yield per milking averaged 14.0 kg and was significantly different among treatments; however, the maximum difference detected among treatments was 0.8 kg/milking. Milking unit on-time, which represents the time when the milking unit is under normal pulsation and harvesting milk (excluding the high-vibration pulsation time of 30 or 90 s), was shortest (245 s) for cows subjected to 90 s of high-vibration pulsation (HV90) and ranged from 256 to 261 s for all other treatments. Milk harvest may have begun during high-vibration pulsation; however, only 0.13 and 0.32 kg of milk was harvested during high-vibration pulsation for HV30 and HV90, respectively. The incidence of bimodal milk curves was lowest for FD90 (7%) and highest for T0 (21%). The somatic cell count was <72×10(3) cells/mL for all treatments. Residual milk obtained by giving 10 IU of oxytocin in the jugular vein followed by 2 min of milking unit attachment represented 12 to 14% of the total milk and did not differ among treatments. Endogenous oxytocin profiles peaked between 12.4 and 18.3 pg/mL for all treatments, and the peak occurred sooner in manually stimulated cows; however, we detected no difference in oxytocin concentration beyond 2 min after milking unit attachment. High-vibration pulsation elicited a similar oxytocin release when taking the start time of stimulation from manual stimulation or high vibration into consideration. Forestripping for visual observation of milk combined with the use of high-vibration stimulation may reduce variation in the milking routine. A predetermined lag time with minimal variation may be achieved via the time spent in high-vibration stimulation instead of a lag period dictated by milking personnel.

Linkage and association between distinct variants of the APOA1/C3/A4/A5 gene cluster and familial combined hyperlipidemia.

OBJECTIVE: Combined hyperlipidemia is a common disorder, characterized by a highly atherogenic lipoprotein profile and a substantially increased risk of coronary heart disease. The purpose of this study was to establish whether variations of apolipoprotein A5 (APOA5), a newly discovered gene of lipid metabolism located 30 kbp downstream of the APOA1/C3/A4 gene cluster, contributes to the transmission of familial combined hyperlipidemia (FCHL). METHODS AND RESULTS: We performed linkage and association tests on 128 families. Two independent alleles, APOA5c.56G and APOC3c.386G, of the APOA1/C3/A4/A5 gene cluster were overtransmitted in FCHL (P=0.004 and 0.007, respectively). This was paired with reduced transmission of the common APOA1/C3/A4/A5 haplotype (frequency 0.4461) to affected subjects (P=0.012). The APOA5c.56G genotype accounted for 7.3% to 13.8% of the variance in plasma triglyceride levels in probands (P<0.004). The APOC3c.386G genotypes accounted for 4.4% to 5.1% of the variance in triglyceride levels in FCHL spouses (P<0.007), suggesting that this allele marks a FCHL quantitative trait as well as representing a susceptibility locus for the condition. CONCLUSIONS: A combined linkage and association analysis establishes that variation at the APOA1/C3/A4/A5 gene cluster contributes to FCHL transmission in a substantial proportion of northern European families.

Genetic study of common variants at the Apo E, Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes and coronary artery disease (CAD): variation in LIPC gene associates with clinical outcomes in patients with established CAD.

BACKGROUND: Current evidence demonstrates that positive family history and several alterations in lipid metabolism are all important risk factors for coronary artery disease (CAD). All lipid abnormalities themselves have genetic determinants. Thus, objective of this study was to determine whether 6 genetic variants potentially related to altered lipid metabolism were associated with CAD and with lipid abnormalities in an Italian population. These genetic variables were: apolipoprotein E (Apo E), Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and the hepatic lipase (LIPC) genes. Furthermore, an 8 years prospective analysis of clinical cardiovascular events was related to the various genetic markers. METHODS: 102 subjects with established coronary artery disease and 104 unrelated normal subjects were studied. CAD Patients were followed up for 8 years, and clinical CAD outcomes (a second coronary angioplasty (PTCA), myocardial infarction, coronary artery by-pass graft (CABG), cardiovascular deaths), available from 60 subjects, were related to the genetic variants by multiple regression analysis. Results. Of the six lipid loci studied (for a total of 11 polymorphisms) only the apolipoprotein E, Apo B and LIPC polymorphisms distinguished between case and controls. However, multivariate analysis accounting for clinical and metabolic predictors of CAD showed that only the ApoB Xba1 and ApoE4 polymorphism associated with CAD in this Italian population. When lipid parameters were related to genotypes, the ApoE, ApoB, and LIPC gene polymorphisms were associated to various markers of dyslipidaemia in the CAD patients, confirming previous reports. When the occurrence of a second cardiovascular event was related to genotypes, an independent role was observed for the LIPC gene T202T variant. CONCLUSIONS: variation in LIPC (hepatic lipase) gene associates with clinical outcomes in Italian patients with established CAD. Further studies on the LIPC gene in CAD patients are warranted, in particular looking at the possible influences on clinical outcomes.

Confirmed locus on chromosome 11p and candidate loci on 6q and 8p for the triglyceride and cholesterol traits of combined hyperlipidemia.

UNLABELLED: Background- Combined hyperlipidemia is a common disorder characterized by a highly atherogenic lipoprotein profile and increased risk of coronary heart disease. The etiology of the lipid abnormalities (increased serum cholesterol and triglyceride or either lipid alone) is unknown. METHODS AND RESULTS: We assembled 2 large cohorts of families with familial combined hyperlipidemia (FCHL) and performed disease and quantitative trait linkage analyses to evaluate the inheritance of the lipid abnormalities. Chromosomal regions 6q16.1-q16.3, 8p23.3-p22, and 11p14.1-q12.1 produced evidence for linkage to FCHL. Chromosomes 6 and 8 are newly identified candidate loci that may respectively contribute to the triglyceride (logarithm of odds [LOD], 1.43; P=0.005) and cholesterol (LOD, 2.2; P=0.0007) components of this condition. The data for chromosome 11 readily fulfil the guidelines required for a confirmed linkage. The causative alleles may contribute to the inheritance of the cholesterol (LOD, 2.04 at 35.2 cM; P=0.0011) component of FCHL as well as the triglyceride trait (LOD, 2.7 at 48.7 cM; P=0.0002). CONCLUSIONS: Genetic analyses identify 2 potentially new loci for FCHL and provide important positional information for cloning the genes within the chromosome 11p14.1-q12.1 interval that contributes to the lipid abnormalities of this highly atherogenic disorder.

The human type-C retrovirus, in Blacks from the Caribbean region, and relationship to adult T-cell leukemia/lymphoma

Type-C RNA tumour viruses have been implicated in the etiology of naturally occurring leukemias and lymphomas of animals. Human T-cell leukimia/lymphoma virus (HTLV) is the first human virus of this class consistently identified in association with a specific type of human leukemia/lymphoma. The isolation of HTLV was made possible by the ability to grow mature T-cell in tissue culture usually with T-cell growth factor (TCGF). We now report a cluster usually with T-cell leukemia/lymphoma among Blacks from the Caribbean in which all eight cases are positive for HLV virus and/or antibody. These patients have diseases that appears indistinguisable from Japanese adult T-cell leukemia/lymphoma which, as we have also reported, is associated with HTLV in over 90 percent of cases. The finding of HTLV antibodies in some of the normal population in the Caribbean and Japan, and the clustering of a specific form of T-cell leukemia/lyphoma in these virus-endemic areas, suggest that HTLV infection may be associated with the occurrence of a distinctive clinico-pathologic entity (Summary)