LPA kringle IV type 2 is associated with type 2 diabetes in a Chinese population with very high cardiovascular risk

Muhanhali, Dilidaer; Zhai, Tianyu; Ling, Yan; Gao, Xin

doi:10.1194/jlr.p082792

Cited by 20 publications

(7 citation statements)

References 26 publications

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“…The Lp(a) concentration is strongly genetically determined by the copy number variant kringle IV type 2 (KIV-2) and several single nucleotide polymorphisms in the LPA gene region [39]. Mendelian Randomization studies reported that genetic variants which lead to elevated Lp(a) levels were associated with higher CHD risk [39,40] and lower T2D risk [39][40][41][42]. The results of these Mendelian Randomization studies strongly point at causality.…”

Section: Importance Of Single Pathways For T2d and Chd Development Inmentioning

confidence: 99%

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Huth

Bauer

Zierer

et al. 2020

Cardiovasc Diabetol

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Background: Biomarkers may contribute to our understanding of the pathophysiology of various diseases. Type 2 diabetes (T2D) and coronary heart disease (CHD) share many clinical and lifestyle risk factors and several biomarkers are associated with both diseases. The current analysis aims to assess the relevance of biomarkers combined to pathway groups for the development of T2D and CHD in the same cohort. Methods: Forty-seven serum biomarkers were measured in the MONICA/KORA case-cohort study using clinical chemistry assays and ultrasensitive molecular counting technology. The T2D (CHD) analyses included 689 (568) incident cases and 1850 (2004) non-cases from three population-based surveys. At baseline, the study participants were 35-74 years old. The median follow-up was 14 years. We computed Cox regression models for each biomarker, adjusted for age, sex, and survey. Additionally, we assigned the biomarkers to 19 etiological pathways based on information from literature. One age-, sex-, and survey-controlled average variable was built for each pathway. We used the R 2 PM coefficient of determination to assess the explained disease risk. Results: The associations of many biomarkers, such as several cytokines or the iron marker soluble transferrin receptor (sTfR), were similar in strength for T2D and CHD, but we also observed important differences. Lipoprotein (a) (Lp(a)) and N-terminal pro B-type natriuretic peptide (NT-proBNP) even demonstrated opposite effect directions. All pathway variables together explained 49% of the T2D risk and 21% of the CHD risk. The insulin-like growth factor binding protein 2 (IGFBP-2, IGF/IGFBP system pathway) best explained the T2D risk (about 9% explained risk, independent of all other pathway variables). For CHD, the myocardial-injury-and lipid-related-pathways were most important and both explained about 4% of the CHD risk. Conclusions: The biomarker-derived pathway variables explained a higher proportion of the T2D risk compared to CHD. The ranking of the pathways differed between the two diseases, with the IGF/IGFBP-system-pathway being most strongly associated with T2D and the myocardial-injury-and lipid-related-pathways with CHD. Our results help to better understand the pathophysiology of the two diseases, with the ultimate goal of pointing out targets for lifestyle intervention and drug development to ideally prevent both T2D and CHD development.

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Section: Importance Of Single Pathways For T2d and Chd Development Inmentioning

confidence: 99%

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Huth

Bauer

Zierer

et al. 2020

Cardiovasc Diabetol

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“…isoform size and risk of T2D were also reported [30] though we were unable to investigate the role of Lp(a) isoform size as these data are not available in the UK Biobank, which is among the limitations of the current study.…”

Section: Discussionmentioning

confidence: 90%

Associations of Very Low Lipoprotein(a) Levels With Risks Of New-Onset Diabetes And Non-Alcoholic Liver Disease

Yeung

Said

Vegte

et al. 2023

Preprint

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Aim We aimed to study the association of very low serum Lipoprotein(a) [Lp(a)] concentrations with new-onset type 2 diabetes (T2D) and non-alcoholic liver disease (NAFLD) in the context of lipid-lowering medication usage in the UK Biobank, a large prospective population cohort. We tested the association for potential causality between genetically determined Lp(a) concentrations and disease outcomes using a Mendelian randomization (MR) strategy. Methods Using an extended biomarker dataset, we identified 47,840 participants with very low Lp(a) concentrations (<3.8 nmol/L) from a total of 449,026 participants. With a median follow-up of 12.4 years (interquartile range 11.5-13.1), we assessed the risk of new-onset cardiometabolic diseases in these participants stratified by usage of lipid-lowering medication using Cox proportional hazards models. We performed two sample MR analyses to test causal relationship between genetically predicted Lp(a) and T2D and NAFLD. Results Compared to participants with Lp(a) within the standard reportable range of 3.8-189 nmol/L, participants with very low Lp(a) (<3.8 nmol/L) were at increased risk of developing both T2D (HR 1.07; 95% CI 1.01-1.12) and NAFLD (HR 1.36; 95% CI 1.26-1.46) as opposed to decreased risk for coronary artery disease. The risk for new-onset T2D was higher in participants using lipid-lowering medication (fully adjusted HR 1.16; 95% CI 1.06-1.26). On the other hand, there was higher risk of NAFLD in participants not on lipid-lowering medication (HR 1.39; 95%CI 1.27-1.51). There was no evidence for causal links between genetically predicted Lp(a) and T2D or NAFLD in two sample MR analyses. Conclusions Very low Lp(a) was associated with higher risks of T2D and NAFLD in a prospective analysis of the UK Biobank. These associations were influenced by lipid lowering medication usage. MR analyses did not support causality for these inverse associations.

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“…At present, most of the studies on LPA SNPs focus on the risk of CHD and atherosclerosis 30 . The prediction of future MACEs by SNPs is only seen in a few articles, and most of them focus on the European population 31 .…”

Section: Discussionmentioning

confidence: 99%

Elevated lipoprotein(a) and genetic polymorphisms in the LPA gene may predict cardiovascular events

Huang

et al. 2022

Sci Rep

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Elevated lipoprotein(a) [Lp(a)] is a risk factor for coronary heart disease (CHD), but there are few studies on the prediction of future cardiovascular events by Lp(a) and its LPA single nucleotide polymorphisms (SNPs). The aim of this study was to investigate whether elevated Lp(a) and its SNPs can predict cardiovascular events. We evaluated whether Lp(a) and LPA SNPs rs6415084 and rs12194138 were associated with the incidence rate and severity of CHD. All participants were followed up for 5 years. Elevated Lp(a) is an independent risk factor for the risk and severity of CHD (CHD group vs. control group: OR = 1.793, 95% CI: 1.053–2.882, p = 0.043; multiple-vessel disease group vs. single-vessel disease group: OR = 1.941, 95% CI: 1.113–3.242, p = 0.027; high GS group vs. low GS group: OR = 2.641, 95% CI: 1.102–7.436, p = 0.040). Both LPA SNPs were risk factors for CHD, and were positively associated with the severity of CHD (LPA SNPs rs6415084: CHD group vs. control group: OR = 1.577, 95% CI: 1.105–1.989, p = 0.004; multiple-vessel disease group vs. single-vessel disease group: OR = 1.613, 95% CI: 1.076–2.641, p = 0.030; high GS group vs. low GS group: OR = 1.580, 95% CI: 1.088–2.429, p = 0.024; LPA SNPs rs12194138: CHD group vs. control group: OR = 1.475, 95% CI: 1.040–3.002, p = 0.035; multiple-vessel disease group vs. single-vessel disease group: OR = 2.274, 95% CI: 1.060–5.148, p = 0.038; high GS group vs. low GS group: OR = 2.067, 95% CI: 1.101–4.647, p = 0.021). After 5 years of follow-up, elevated Lp(a) and LPA SNPs rs6415084 and rs12194138 can independently predict cardiovascular events. The increase of serum Lp(a) and LPA SNPs rs6415084 and rs12194138 are associated with increased prevalence and severity of CHD, and can independently predict cardiovascular events.

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LPA kringle IV type 2 is associated with type 2 diabetes in a Chinese population with very high cardiovascular risk

Cited by 20 publications

References 26 publications

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease—a comparison in the MONICA/KORA study

Associations of Very Low Lipoprotein(a) Levels With Risks Of New-Onset Diabetes And Non-Alcoholic Liver Disease

Elevated lipoprotein(a) and genetic polymorphisms in the LPA gene may predict cardiovascular events

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