LPA genetic variation is associated with type 2 diabetes after adjustment for lipoprotein(a) concentration: results of the Aragon Workers’ health study
The findings suggest that common LPA variation represented by the 15-SNV genetic score may contribute to T2D risk through mechanisms not fully captured by circulating Lp(a) concentration alone.
Abstract
Epidemiological and Mendelian randomization studies have reported an inverse relationship between lipoprotein(a) [Lp(a)] concentration and type 2 diabetes (T2D), although findings have not been uniform across studies. We hypothesized that genetic variation at the
LPA
locus may contribute to T2D development beyond circulating Lp(a) concentration alone, and therefore aimed to investigate the association between common
LPA
variation and incident T2D.
We analysed 5058 male participants from the Aragon Workers’ Health Study with approximately 15 years of follow-up. T2D was defined as the presence of antidiabetic treatment or HbA1c ≥ 6.5%. Common
LPA
single-nucleotide variants (SNVs) with a minor allele frequency ≥ 1% were selected. Several weighted
LPA
genetic scores were constructed, with the 15-SNV score defined as the primary
LPA
genetic score and alternative and more restricted scores evaluated in sensitivity analyses. Associations of single
LPA
variants and
LPA
genetic scores with incident T2D were assessed using multivariable logistic regression models adjusted for age, body mass index, ln-transformed Lp(a), and a T2D polygenic risk score. False discovery rate correction was applied to account for multiple testing. Robustness was assessed using leave-one-out analyses and Cox proportional hazards models.
Among 4744 participants free of T2D at baseline, 578 (12.2%) developed incident T2D. Baseline Lp(a) concentrations were lower in participants who developed incident T2D than in those who remained free of T2D (12.6 [5.0–32.5] versus 17.0 [6.1–40.0] mg/dL;
p
< 0.001). No individual
LPA
SNV remained significantly associated with incident T2D. In contrast, the primary 15-SNV
LPA
genetic score was associated with incident T2D after adjustment for measured baseline Lp(a) concentration (odds ratio per one-standard-deviation increase 1.17, 95% confidence interval 1.07–1.29;
p
= 0.001). The 13-SNV, 12-SNV, 10-coding/splice, and 2-SNV raising-Lp(a) scores were also significantly associated with incident T2D after false discovery rate correction. The association with the 15-SNV
LPA
genetic score was supported by leave-one-out and Cox analyses.
A 15-SNV
LPA
genetic score was associated with incident T2D after adjustment for measured baseline Lp(a) concentration and a T2D polygenic risk score. These findings suggest that common
LPA
variation represented by the 15-SNV genetic score may contribute to T2D risk through mechanisms not fully captured by circulating Lp(a) concentration alone.
Background: Lipoprotein(a) [Lp(a)] is a genetically determined, pro-atherogenic lipoprotein enriched in oxidized phospholipids and increasingly recognized as a key potential contributor to residual cardiovascular and inflammatory risk. However, data on its distribution and cardiometabolic associations in Middle Eastern populations remain limited. This study aimed to evaluate the prevalence of elevated Lp(a) and its association with type 2 diabetes (T2D), systemic inflammation, and ethnic variation in a multiethnic cohort. Methods: In this cross-sectional study, data from 2083 adults aged ≥ 18 years residing in Kuwait were collected through the Kuwait Diabetes Epidemiology Program (KDEP) at Dasman Diabetes Institute between 2011 and 2014 using random sampling. Plasma Lp(a) concentrations, cardiometabolic parameters, and high-sensitivity C-reactive protein (CRP) were measured. Elevated Lp(a) was defined as ≥ 50 mg/dL according to established clinical guidelines. Associations of elevated Lp(a) with T2D and CRP were assessed using multivariable Poisson regression models to estimate adjusted prevalence ratios. Results: The overall prevalence of elevated Lp(a) was 41.2%, exceeding global estimates. Significant ethnic variation was observed, with Arabs exhibiting the highest prevalence. After adjustment for potential confounders, individuals with T2D had a higher prevalence of elevated Lp(a) (APR = 1.166) and diabetes status significantly modified the association between CRP and elevated Lp(a) interaction (APR = 1.015), thus supporting a link between Lp(a) and systemic inflammation. Conclusions: Elevated Lp(a) was highly prevalent in this multiethnic Middle Eastern population and was independently associated with T2D and systemic inflammation. These findings support the emerging concept that Lp(a) may function as a molecular-inflammatory mediator potentially contributing to residual cardiovascular risk and highlight the importance of incorporating Lp(a) assessment into cardiometabolic risk stratification, particularly in high-risk populations.
Mohammad G. Qaddoumi, A. Albatineh, I. Alkhairi et al.· Biomedicines· 0 citations
New SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population are identified, including a missense variant in an olfactory receptor gene linked to MCP-1, which may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.
J. Leite, G. F. L. Pascoal, G. B. S. Duarte et al.· Frontiers in Immunology· 0 citations
OBJECTIVE
Treatment response in type 2 diabetes (T2D) varies widely among individuals. This study aimed to quantify the contributions of clinical characteristics and genetic predisposition as measured through partitioned polygenic risk scores (pPRS) to variation in glycemic response to glucose-lowering therapies.
RESEARCH DESIGN AND METHOD
We analysed data from two population-based cohorts: the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) and the UK Biobank (UKBB). GoDARTS included 41 802 patients who initiated one of six major drug classes, of whom 11 615 had available genotype data. UKBB contributed 9371 individuals, including 8293 with genetic data. The primary outcome was glycaemic response, defined as the change in HbA1c 12 months after treatment initiation. Variables included demographic and clinical factors (age, sex, BMI, baseline HbA1c, kidney and liver function markers) and 14 pPRS representing T2D-related biological pathways. Linear regression models were fitted within each cohort and drug class (metformin, sulfonylureas, TZDs, DPP4i, SGLT2i, GLP-1RA), and effect estimates were combined using fixed-effect meta-analysis.
RESULT
Baseline HbA1c was most strongly associated with glycemic response (p < 0.001). Older age was consistently associated with greater HbA1c reduction, while BMI and total cholesterol demonstrated drug-class-specific associations, with higher BMI associated with improved response to TZDs and higher total cholesterol generally associated with poorer glycaemic outcomes. Meta-analysis across GoDARTS and UK Biobank showed that higher overall T2D genetic risk was associated with greater HbA1c reduction with sulfonylureas (β = -0.46 mmol/mol, p = 0.013). Specific genetic profiles were also associated with drug responses, including β-cell function clusters with sulfonylureas (β = -0.57, p = 0.002), obesity-related variants with GLP-1RA (β = -1.49, p = 0.04), liver-lipid variants with SGLT2 inhibitors (β = -0.84, p = 0.05), and bilirubin pPRS with DPP-4 inhibitors (β = -0.69, p = 0.006).
CONCLUSION
Both clinical and genetic factors significantly contribute to inter-individual variability in T2D drug response. Partitioned PRSs provide mechanistic insights into drug-specific pathways and have the potential to inform precision prescribing and optimise therapeutic outcomes in routine diabetes care.
S. Garg, R. Kitchen, R. Gupta et al.· Diabetes, obesity and metabo...· 0 citations
This study aimed to investigate the relationships between visit-to-visit variability in HbA1c and fasting plasma glucose (FPG) and atherosclerotic markers in persons with type 2 diabetes mellitus (T2DM), employing epidemiological analyses and Mendelian randomization (MR) techniques. Between January 2001 and December 2020, 2290 persons with T2DM (1307 men and 983 women) who underwent evaluation for atherosclerosis screening were enrolled in a management program at a medical center in Taiwan. To assess potential causal relationships among the coefficient of variation (CV) of HbA1c (HbA1c-CV), FPG-CV, and markers of atherosclerosis, we conducted a 2-stage multivariable regression analysis using 22 and 21 single nucleotide polymorphisms as instrumental variables for HbA1c and FPG, respectively. A total of 2290 individuals with T2DM were included, with a mean age of 61.79 years, and 57% were male. In the epidemiological analysis, after multivariable adjustment, the odds ratios for an ankle–brachial index (ABI) < 0.9 in the third and fourth quartiles compared with the first quartile were 3.15 (95% confidence interval [CI]: 1.80–5.50) and 4.29 (95% CI: 2.44–7.56), respectively, for FPG-CV, and 1.67 (95% CI: 1.06–2.62) and 1.65 (95% CI: 1.01–2.70), respectively, for HbA1c-CV. In the MR analysis, comparing the fourth quartile with the first quartile, the odds ratios for ABI < 0.9 and brachial–ankle pulse wave velocity (baPWV) ≥ 1800 cm/s were 2.78 (95% CI: 1.84–4.19) and 1.58 (95% CI: 1.23–2.02), respectively, for the unweighted genetic risk score predicting FPG-CV. Epidemiological and MR analyses provide evidence that FPG variability is significantly associated with atherosclerosis, as indicated by the ABI.
Tsai-Chung Li, Chia-Ing Li, Chiu-Shong Liu et al.· Medicine· 0 citations
Prospective studies have demonstrated an inverse association between lipoprotein(a) [Lp(a)] levels and the risk for type 2 diabetes, although the mechanisms underlying this relationship remain unclear. We examined the associations of Lp(a) with incident type 2 diabetes, fasting serum insulin, and fasting plasma glucose, in the prospective Young Finns Study cohort.
Lp(a) measurements were first available in Young Finns Study participants in 1986 (N = 2 464). For type 2 diabetes analyses, the baseline was defined as the 2001 follow-up study (participants aged 24–39 years) when data on both Lp(a) and diabetes status were available (N = 2 263). The association between Lp(a) levels and incident type 2 diabetes was examined using the Fine-Gray model. Associations with fasting insulin and glucose were analyzed using repeated-measures linear regression, utilizing data from 1986, 2001, 2007, 2011, and 2018.
During the mean follow-up period of 16.6 years from 2001, 144 participants (6.4%) developed type 2 diabetes. 2001 log
e
-transformed Lp(a) (at 24–39 years of age) was associated with a decreased risk of type 2 diabetes [hazard ratio per one-unit increase in log
e
-Lp(a): 0.83, 95% confidence interval 0.73–0.96] in the age- and sex-adjusted model. Additionally, longitudinal inverse associations were observed between Lp(a) and fasting insulin levels. Compared to the lowest Lp(a) quartile, mean fasting insulin was 0.079 standard deviation units lower in the highest quartile (
p
= 0.019, trend-
p
= 0.0093). Inverse associations between Lp(a) and fasting glucose were observed in males.
In the Young Finns Study, higher adult Lp(a) concentrations were prospectively associated with lower risk of incident type 2 diabetes. Longitudinal analyses further showed inverse associations between Lp(a) and fasting insulin, supporting a possible link between Lp(a), insulin metabolism, and diabetes risk.
M. Knuuti, N. Kartiosuo, K. Pahkala et al.· Cardiovascular Diabetology· 0 citations
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