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Conventional and Mendelian randomization analyses suggest no association between lipoprotein(a) and early atherosclerosis: the Young Finns Study.

ABSTRACT: Lipoprotein(a) [Lp(a)] is an established risk factor for coronary disease and stroke, but mechanisms underlying this association are unknown. We examined the association of Lp(a) with early atherosclerosis by using conventional epidemiologic analysis and a Mendelian randomization analysis. The latter utilized genetic variants that are associated with Lp(a) to estimate causal effect.A prospective population-based cohort study of 939 men and 1141 women was conducted. Lp(a) was measured repeatedly at mean ages 17 and 38 years. Measurements of carotid intima-media thickness (IMT) and brachial flow-mediated dilation (FMD) at mean ages 32 and 38 years were used to determine the level and 6-year progression of subclinical atherosclerosis. Lp(a)-related genetic variant, rs783147, was identified by a genome wide association analysis (P = 3.1 × 10???), and a genetic score was constructed based on 10 Lp(a)-related variants. Mendelian randomization test was performed using a two-stage instrumental variables analysis.rs783147 and the genetic score were strong instruments for nonconfounded Lp(a) levels (F-statistics 269.6 and 446.0 in the first-stage instrumental variable analysis). However, Lp(a) levels were not associated with the levels of or change in IMT or FMD in any of the conventional and instrumental variables tests. The null finding was observed both with rs783147 and the genetic score as instruments and remained unchanged after adjustment for clinical characteristics, such as age, sex, HDL and LDL cholesterol, ApoB, systolic and diastolic blood pressure, diabetes and smoking.Data from conventional and Mendelian randomization analyses provide no support for early atherogenic effects of increased Lp(a) levels.

SUBMITTER: Kivimaki M

PROVIDER: S-EPMC3106966 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Conventional and Mendelian randomization analyses suggest no association between lipoprotein(a) and early atherosclerosis: the Young Finns Study.

Kivimäki Mika M Magnussen Costan G CG Juonala Markus M Kähönen Mika M Kettunen Johannes J Loo Britt-Marie BM Lehtimäki Terho T Viikari Jorma J Raitakari Olli T OT

International journal of epidemiology 20101114 2

<h4>Background</h4>Lipoprotein(a) [Lp(a)] is an established risk factor for coronary disease and stroke, but mechanisms underlying this association are unknown. We examined the association of Lp(a) with early atherosclerosis by using conventional epidemiologic analysis and a Mendelian randomization analysis. The latter utilized genetic variants that are associated with Lp(a) to estimate causal effect.<h4>Methods</h4>A prospective population-based cohort study of 939 men and 1141 women was conduc ...[more]

PMID: 21078622

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Project description:BACKGROUND:High levels of plasma homocysteine occur almost uniformly in patients with end-stage renal disease (ESRD). IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a common cause of ESRD in young adults. Here, we aimed to detect whether homocysteine was elevated and associated with clinical-pathologic manifestations of IgAN patients and tested its causal effects using a two-sample Mendelian randomization (MR) approach. METHODS:For observational analysis, 108 IgAN patients, 30 lupus nephritis (LN) patients, 50 minimal change disease (MCD) patients, and 206 healthy controls were recruited from April 2014 to April 2015. Their plasma homocysteine was measured and clinical-pathologic manifestations were collected from medical records. For MR analysis, we further included 1686 IgAN patients. The missense variant methylenetetrahydrofolate reductase C677T (rs1801133) was selected as an instrument, which was genotyped by TaqMan allele discrimination assays. RESULTS:Majority of IgAN patients (93.52%, 101/108) showed elevated levels of plasma homocysteine (>10 ?mol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 ?mol/L, Z?=?-5.29, P?<?0.01) and in healthy controls (median: 18.32 vs. 10.00 ?mol/L, Z?=?-8.76, P?<?0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 ?mol/L, Z?=?-1.32, P?=?0.19). Significant differences were observed in sub-groups of IgAN patients according to quartiles of plasma homocysteine for male ratio (22.22% vs. 51.85% vs. 70.37% vs. 70.37%, ??=?14.29, P?<?0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 ?mol/L, ??=?34.06, P?<?0.01), estimated glomerular filtration rate (median: 100.52 vs. 74.23 vs. 52.68 vs. 42.67 mL·min·1.73 m, ??=?21.75, P?<?0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, ??=?2.97, P?=?0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, ??=?11.47, P?<?0.01), and pathologic tubular atrophy and interstitial fibrosis (T) (T0/T1/T2: 62.96%/33.33%/3.70% vs. 29.63%/40.74%/29.63% vs. 24.00%/48.00%/28.00% vs. 14.81%/37.04%/48.15%, ??=?17.66, P?<?0.01). The coefficient of each rs1801133-T allele on homocysteine levels after controlling age and sex was 7.12 (P?<?0.01). MR estimates showed causal positive effects of homocysteine on serum creatine (??=?0.76, P?=?0.02), systolic blood pressure (??=?0.26, P?=?0.02), diastolic blood pressure (??=?0.20, P?=?0.01), and pathologic T lesion (??=?0.01, P?=?0.01) in IgAN. CONCLUSIONS:By observational and MR analyses, consistent results were observed for associations of plasma homocysteine with serum creatinine, blood pressures, and pathologic T lesion in IgAN patients.

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Conventional and Mendelian randomization analyses suggest no association between lipoprotein(a) and early atherosclerosis: the Young Finns Study.

Publications

Conventional and Mendelian randomization analyses suggest no association between lipoprotein(a) and early atherosclerosis: the Young Finns Study.

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