Dataset Information

SHP-2 and PI3-kinase genes PTPN11 and PIK3R1 may influence serum apoB and LDL cholesterol levels in normal women.

ABSTRACT: Insulin regulates apoB metabolism via activation of PI3K or regulation of MTP via MAPK/ERK signalling. SHP-2 enhances both pathways through increased IRS-1 phosphorylation. We hypothesized that variants in the SHP-2 gene PTPN11 and PI3K p85alpha subunit gene PIK3R1 may influence fasting levels of plasma apoB and/or LDL cholesterol. We tested association of tagging SNPs (tSNPs) in each gene with serum lipids in a large sample of unselected population-based Caucasian female twins (n=2771, mean age 47.4+/-12.5 years) and then tested interaction between tSNPs in determining apoB and LDL levels. PTPN11 tSNP rs11066322 was associated with apoB (P=0.007) and rs11066320 was associated with LDL cholesterol (P=0.016). PIK3R1 tSNP rs251406 was associated with apoB (P=0.0003) and rs706713 was associated with LDL cholesterol (P=0.009). PTPN11 tSNP rs11066322 interacted with PIK3R1 tSNP rs251406 in determining serum apoB levels (P=0.012) and with PIK3R1 tSNP rs40318 in determining LDL cholesterol levels (P=0.009). Association of single tSNPs with both apoB and LDL cholesterol as well as interactions between the two genes suggest that variants influencing SHP-2 activity may modulate the acute pathway by which insulin regulates these lipids.

SUBMITTER: Jamshidi Y

PROVIDER: S-EPMC2084489 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

SHP-2 and PI3-kinase genes PTPN11 and PIK3R1 may influence serum apoB and LDL cholesterol levels in normal women.

Jamshidi Y Y Gooljar S B SB Snieder H H Wang X X Ge D D Swaminathan R R Spector T D TD O'Dell S D SD

Atherosclerosis 20070109 2

Insulin regulates apoB metabolism via activation of PI3K or regulation of MTP via MAPK/ERK signalling. SHP-2 enhances both pathways through increased IRS-1 phosphorylation. We hypothesized that variants in the SHP-2 gene PTPN11 and PI3K p85alpha subunit gene PIK3R1 may influence fasting levels of plasma apoB and/or LDL cholesterol. We tested association of tagging SNPs (tSNPs) in each gene with serum lipids in a large sample of unselected population-based Caucasian female twins (n=2771, mean age ...[more]

PMID: 17214991

Similar Datasets

Project description:Non-communicable diseases, including cardiovascular diseases (CVDs), are increasing in African populations. High serum low density lipoprotein cholesterol (LDL-cholesterol) levels are a known risk factor for CVDs in European populations, but the link remains poorly understood among Africans. This study investigated the associations between serum LDL-cholesterol levels and selected variants in the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and low density lipoprotein receptor adaptor protein 1 (LDLRAP1) genes in some selected African populations. Nineteen SNPs were selected from publicly available African whole genome sequence data based on functional prediction and allele frequency. SNPs were genotyped in 1000 participants from the AWI-Gen, study selected from the extremes of LDL-cholesterol level distribution (500 with LDL-cholesterol>3.5 mmol/L and 500 with LDL-cholesterol<1.1 mmol/L). The minor alleles at five of the six associated SNPs were significantly associated (P<0.05) with lower LDL-cholesterol levels: LDLRAP1 rs12071264 (OR 0.56, 95% CI: 0.39-0.75, P = 2.73x10-4) and rs35910270 (OR 0.78, 95% CI: 0.64-0.94, P = 0.008); APOB rs6752026 (OR 0. 55, 95% CI: 0.41-0.72, P = 2.82x10-5); LDLR: rs72568855 (OR 0.47, 95% CI: 0.27-0.82, P = 0.008); and PCSK9 rs45613943 (OR = 0.72, 95% CI: 0.58-0.88, P = 0.001). The minor allele of the sixth variant was associated with higher LDL-cholesterol levels: APOB rs679899 (OR 1.41, 95% CI: 1.06-1.86, P = 0.016). A replication analysis in the Africa America Diabetes Mellitus (AADM) study found the PCSK9 variant to be significantly associated with low LDL-cholesterol levels (Beta = -0.10). Since Africans generally have lower LDL-cholesterol levels, these LDL-cholesterol associated variants may be involved in adaptation due to unique gene-environment interactions. In conclusion, using a limited number of potentially functional variants in four genes, we identified significant associations with lower LDL-cholesterol levels in sub-Saharan Africans.

Project description:Background: Almonds may increase circulating HDL cholesterol when substituted for a high-carbohydrate snack in an isocaloric diet, yet little is known about the effects on HDL biology and function.Objective: The objective was to determine whether incorporating 43 g almonds/d in a cholesterol-lowering diet would improve HDL subspecies and function, which were secondary study outcomes.Methods: In a randomized, 2-period, crossover, controlled-feeding study, a diet with 43 g almonds/d (percentage of total energy: 51% carbohydrate, 16% protein, and 32% total and 8% saturated fat) was compared with a similar diet with an isocaloric muffin substitution (58% carbohydrate, 15% protein, and 26% total and 8% saturated fat) in men and women with elevated LDL cholesterol. Plasma HDL subspecies and cholesterol efflux from J774 macrophages to human serum were measured at baseline and after each diet period. Diet effects were examined in all participants (n = 48) and in normal-weight (body mass index: <25; n = 14) and overweight or obese (?25; n = 34) participants by using linear mixed models.Results: The almond diet, compared with the control diet, increased ?-1 HDL [mean ± SEM: 26.7 ± 1.5 compared with 24.3 ± 1.3 mg apolipoprotein A-I (apoA-I)/dL; P = 0.001]. In normal-weight participants, the almond diet, relative to the control diet, increased ?-1 HDL (33.7 ± 3.2 compared with 28.4 ± 2.6 mg apoA-I/dL), the ?-1 to pre-?-1 ratio [geometric mean (95% CI): 4.3 (3.3, 5.7) compared with 3.1 (2.4, 4.0)], and non-ATP-binding cassette transporter A1 cholesterol efflux (8.3% ± 0.4% compared with 7.8% ± 0.3%) and decreased pre-?-2 (3.8 ± 0.4 compared with 4.6 ± 0.4 mg apoA-I/dL) and ?-3 (23.5 ± 0.9 compared with 26.9 ± 1.1 mg apoA-I/dL) HDL (P < 0.05). No diet effects were observed in the overweight or obese group.Conclusions: Substituting almonds for a carbohydrate-rich snack within a lower-saturated-fat diet may be a simple strategy to maintain a favorable circulating HDL subpopulation distribution and improve cholesterol efflux in normal-weight individuals with elevated LDL cholesterol. This trial was registered at clinicaltrials.gov as NCT01101230.

Project description:ObjectiveA significant proportion of persons with metabolic syndrome (MetS), prediabetes, or type 2 diabetes (T2D) do not develop atherosclerotic cardiovascular disease (ASCVD).We sought to determine whether discordantly normal apolipoprotein B (ApoB) relative to elevated LDL-C may help to explain heterogeneity in ASCVD risk among persons with metabolic disorders.MethodsThere were 278 Bogalusa Heart Study participants with MetS (n=95), prediabetes (n=233), or T2D (n=31) and LDL-C ≥100 mg/dL who were free of carotid plaque at baseline (2001-02) and underwent carotid ultrasound at follow-up (2013-16). Multivariable modified Poisson regression estimated the long-term absence of carotid plaque for lower ApoB, continuously and categorically.ResultsParticipants were on average 36.1 years old at baseline, 61.5% were women, and 31.7% were black. A total of 50.7% had discordantly normal ApoB (<90 mg/dL) and the mean ApoB and LDL-C concentrations were 91.6 mg/dL and 137.7 mg/dL, respectively. In addition to having higher HDL-C and lower triglyceride values, individuals with ApoB <90 were more likely to maintain persistent absence of plaque compared to those with ApoB ≥90 (73.1% versus 58.4%, p=0.01). Contrastingly, there was no significant difference in the proportion of individuals who remained free of plaque with increasing LDL-C (p=0.45). Independent of traditional risk factors including LDL-C, each 10 mg/dL lower ApoB (RR=1.11, 95% CI: 1.03-1.19) and ApoB <90 (RR=1.22, 95% CI: 1.00-1.43) were significantly associated with the persistent absence of carotid plaque.ConclusionsOne-half of young persons with metabolic disorders and elevated LDL-C had discordantly normal ApoB and a low burden of carotid atherosclerosis over 13 years, suggesting that ApoB better represents the atherogenic lipid burden compared to LDL-C in this patient population. These results suggest a utility for assessing whether routine ApoB measurement can improve ASCVD risk stratification in young persons with metabolic disorders who have high triglycerides and low HDL-cholesterol.

Dataset Information

SHP-2 and PI3-kinase genes PTPN11 and PIK3R1 may influence serum apoB and LDL cholesterol levels in normal women.

Publications

SHP-2 and PI3-kinase genes PTPN11 and PIK3R1 may influence serum apoB and LDL cholesterol levels in normal women.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets