Anna D. Argoty-Pantoja

High blood pressure (BP) represents a major cause of life‐threatening cardiovascular conditions. GWAS have identified >2000 BP‐associated signals. BP‐GWAS usually analyze each BP trait individually. However, multi‐trait GWAS may yield novel loci and improve polygenic risk scores (PRS) prediction. We explored whether multi‐trait BP‐GWAS can: (i) find novel loci undetected by single‐trait GWAS; (ii) increase heritability estimates; (iii) improve PRS prediction of hypertension within the Lifelines Cohort Study. We investigate the utility of multi‐trait GWAS approaches of correlated BP traits (systolic BP, diastolic BP, pulse pressure). We tested two multi‐trait methods inputting results from the latest N > 1 million single‐trait BP‐GWAS: (a) Multi‐Trait Analysis of GWAS (MTAG); (b) genomic structural equation modeling (GenomicSEM); and compared results with single‐trait results. We only identified one novel locus from multi‐trait GWAS: ZNF268 . Neither heritability estimates nor PRS performance improved using multi‐trait GWAS. In this scenario of complete sample overlap across BP‐GWAS, we observed little gain in results from multi‐trait BP‐GWAS over single‐trait BP‐GWAS. Our findings quantify the limited benefit of multi‐trait methods under this specific setting. Future BP genetic discoveries are more likely to come from larger GWAS adding new cohort data. However, conclusions may differ for other traits, depending on trait‐specific genetic architecture.

Genetic predisposition and alcohol consumption are risk factors for increased blood pressure (BP), but their interactions influencing BP remain understudied. We conducted population-specific and cross-population meta-analyses of genome-wide gene-alcohol (GxAlc) interactions affecting BP in >1.1M individuals from multiple populations. We identified 46 GxAlc interaction loci for BP, including 21 from one-degree-of-freedom interaction tests (PGxAlc<5x10-8; or <0.05/Meff, Meff independent BP associations at P<10-5), and 25 from two-degree-of-freedom tests of main and interaction effects (PGxAlc<0.05/M2df, M2df independent 2df-associations at P2df<5x10-8), including 7 novel and 39 known BP loci. The 12q24 locus highlights the genetic effect of BRAP-rs11066001 on BP, being ~6 times larger in current drinkers than in non-drinkers. Gene prioritization with 46 GxAlc loci identified 15 genes with ≥3 lines of evidence (location, literature, druggability, functional/regulatory annotation, or pathway analyses). Several loci showed sex- and population-specific effects and revealed biological pathways of alcohol’s influence on BP, suggesting mechanisms underlying alcohol-induced hypertension.

Introduction: Genome-wide association studies (GWAS) for kidney function have mainly focused on creatinine-based glomerular filtration rate (eGFR _crea ), which is affected by variation in muscle mass. Moreover, the genetic basis of the sexual dimorphism of chronic kidney disease is underexplored. Methods: We performed a GWA meta-analysis for creatinine clearance (CrCl), a muscle mass-independent kidney function phenotype, in 58,976 individuals of European descent from the Lifelines Cohort Study. Results: We identified 16 independent loci with 21 genome-wide significant lead single nucleotide polymorphisms (SNPs) associated with CrCl, two of which had not been reported previously in kidney function GWASs: rs146465192, located near the RP1-249F5.3 gene (effect allele frequency (EAF) = 0.01, P = 3.38 × 10 ⁻⁹ ) and rs117014836, located near the AGPAT4 gene (EAF = 0.02, P = 5.42 × 10 ⁻⁹ ). Both SNPs were also associated with eGFR _crea in Lifelines (rs146465192: P = 1.34 × 10 ⁻⁸ ; rs117014836: P = 3.64 × 10 ⁻⁷ ), but not in previously published eGFR GWASs. In silico follow-up analyses revealed that rs146465192 was associated with plasma IGF2R (β = -0.519, P = 1.40 × 10 ^-6 ), while rs117014836 was associated with blood expression levels of AGPAT4 (eQTL P = 6.54 × 10 ^-6 ). Furthermore, we identified two female-specific CrCl loci (t-statistic P < 0.004): rs8002366 ( GPC6 ) and rs12908437 ( IGF1R ), associated with GPC6 expression in kidney (eQTL P = 8.38 × 10 ^-10 ) and IGF1R expression in blood (eQTL P = 2.62 × 10 ^-6 ), respectively. Conclusion: This first large-scale GWAS of CrCl revealed two new genetic variants among both sexes and two female-specific variants influencing kidney function. Lay summary: Kidney function is a complex phenotype influenced by many different factors, including genetics. Earlier genetic studies often used the creatinine-based estimated glomerular filtration rate (eGFRcrea) as the measure of kidney function. However, eGFRcrea is influenced not just by kidney function but also by an individual’s muscle mass, which may distort the results. Therefore, in this study we used creatinine clearance (CrCl), a measure of kidney function independent of muscle mass, to look for genes in a European-ancestry population. We identified 16 genetic regions; two of which had not been found before. We also found two additional regions that were only related to CrCl in females. This shows the added value of investigating CrCl and suggests sex-based differences in how genetics affect kidney function.

Background: Dietary patterns impact blood pressure (BP) levels, but the potential impact of replacing specific types of fats with proteins or carbohydrates, in isocaloric models, on BP remains unclear. Objective: This study evaluates the longitudinal association between the substitution of different types of fats with proteins or carbohydrates and changes in BP in a Mexican population. Methods: We analyzed data from 1448 adults (mean age at baseline: 45 years; 73.3% women) from the Health Workers Cohort Study, followed over 13 years. Trained personnel measured systolic (SBP) and diastolic (DBP) blood pressure following standard procedures and techniques at baseline and follow-up. Macronutrient intake was assessed with a validated semi-quantitative food frequency questionnaire. Generalized Estimating Equations (GEE) for hypertension and fixed-effects linear regression for BP were conducted using isocaloric substitution models. Each estimate reflects the effect of a 3% energy substitution of specific fats for carbohydrates or proteins. Results: Substituting 3% of energy intake of polyunsaturated fat (PUFA) in place of vegetable protein (β = −2.94, 95% CI: −5.02, −0.86), animal protein (β = −2.68, 95% CI: −4.73, −0.63), low glycemic index (LGI) carbohydrates (β = −2.63, 95% CI: −4.40, −0.86), and high glycemic index (HGI) carbohydrates (β = −2.52, 95% CI: −4.31, −0.74) was associated with a significant reduction in SBP. Substituting 3% of the energy intake of PUFA in place of different types of carbohydrates was associated with lower odds of hypertension. PUFA was not associated with changes in DBP. Conclusions: Our findings suggest that exchanging PUFA for carbohydrates or proteins is associated with reduced SBP and a lower risk of hypertension, highlighting the importance of macronutrient composition independent of total energy intake and other fat types, which may have a substantial impact at the population level.

Background: The relationship between the dietary inflammatory index and blood pressure has been evaluated in European and American populations. This association remains unexplored in Mexico, where outcomes may differ due to the populace’s ancestral heritage and its diverse dietary habits. Methods: We used the Health Workers Cohort Study (2004 to 2018). DII intake was assessed using a food frequency questionnaire. Blood pressure was measured following standardized procedures and techniques. Fixed-effects linear regression and Cox regression models were utilized as the statistical approaches. Results: In the first approach, we observed a positive association between changes in DII intake and changes in both systolic (SBP β: 3.23, 95% CI 1.11, 5.34) and diastolic blood pressure (DBP β: 1.01, 95% CI −0.43, 2.44). When stratified by hypertension, these associations were magnified in participants with hypertension (SBP β: 6.26, 95% CI 2.63, 9.89; DBP β: 1.64, 95% CI −0.73, 4.02). In the second approach, interactions between sex and age categories were explored. Participants in the highest DII category were associated with an increased risk of hypertension, particularly among young women (HR: 3.16, 95% CI 1.19, 8.43). Conclusions: Results suggest that a pro-inflammatory diet is associated with an increase in blood pressure over time among Mexican population.

Osteoporosis is a globally relevant public health issue. Our study aimed to summarize the knowledge on the proteomic biomarkers for low bone mineral density over the last years. We conducted a systematic review following the PRISMA guidelines; the scoured databases were PubMed, Web of Sciences, Scopus, and EBSCO, from inception to 2 June 2023. A total of 610 relevant studies were identified and 33 were assessed for eligibility. Finally, 29 studies met the criteria for this systematic review. The risk of bias was evaluated using the Joanna Briggs Institute Critical Appraisal Checklist tool. From the studies selected, 154 proteins were associated with changes of bone mineral density, from which only 10 were reported in at least two articles. The protein–protein network analysis indicated potential biomarkers involved in the skeletal system, immune system process, regulation of protein metabolic process, regulation of signaling, transport, cellular component assembly, cell differentiation, hemostasis, and extracellular matrix organization. Mass spectrometry-based proteomic profiling has allowed the discovery of new biomarkers with diagnostic potential. However, it is necessary to compare and validate the potential biomarkers in different populations to determine their association with bone metabolism and evaluate their translation to the clinical management of osteoporosis.

The triglyceride-glucose index (TyG index) is an indicator of insulin resistance that has been studied recently. The relationship between insulin resistance and the risk of hypertension has been documented previously. However, there is limited knowledge regarding the association of the TyG index with hypertension incidence. This study aimed to evaluate the association of the TyG index with changes in blood pressure (BP) and hypertension incidence in Mexican adults. This analysis was performed using the Health Workers Cohort Study data. The TyG index was estimated as Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2] and divided into categories defined by tertiles. The analysis was conducted using fixed-effects linear regression models (n = 1,545) and Cox proportional hazards regression models (n = 1,113), adjusting for potential confounding variables. The incidence rates (95% CI) for the low, medium, and high categories of the TyG index were 22.1 (17.8, 27.5), 35.8 (30.1, 42.7), and 49.4 (42.1, 57.9), respectively. An increase in the levels of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was observed when changing from a low to a medium (DBP: β 2.55 mmHg, 95% CI 0.81, 4.29) and from a low to a high category of the TyG index (SBP: β 3.10 mmHg, 95% CI 1.16, 5.04; DBP: β 4.91 mmHg, 95% CI 2.88, 6.94). Furthermore, participants within the top category of the TyG index had a 56% higher risk of hypertension than those in the bottom category (HR = 1.56; 95% CI 1.18, 2.08). These results support the hypothesis that the TyG index is associated with high blood pressure in Mexican adults.