Global genetic modifiers of fetal hemoglobin in sickle cell disease: Systematic review and meta-analysis.

Genetic Association Studies in Hepatocellular Carcinoma: Systematic Meta‐Analyses, a Comprehensive Field Synopsis, and Epidemiological Evidence

ABSTRACT Associations between various genetic variants and the risk of hepatocellular carcinoma (HCC) have been extensively explored but produced contradictory results. The aim of the present systematic meta‐analysis was to determine and validate genetic variants that are associated with HCC risk. Two‐step literature searches of PubMed, Embase, Web of Science, and Google Scholar databases and various meta‐analyses were performed, and a comprehensive field synopsis and epidemiological evidence were provided. A total of 20,081 publications were identified, of which 830 were deemed eligible for inclusion. Eventually, 36 variants in 27 genes were identified to be associated with HCC risk. Moreover, cumulative epidemiological evidence of an association was graded as moderate for nine variants in eight genes (ESR1 rs2234693, GRP78 rs430397, HLA‐DP rs3077, HLA‐DQ rs2856718, MnSOD rs4880, TNFα rs361525, HFE rs1800562 and rs1799945, and UGT1A7 High/Low) and strong for three variants in three genes (IL‐1B rs1143627, COL18A1 rs7499, and NQO1 rs1800566); HFE rs1800562 was deemed to have a false‐positive association. Thus, 11 variants in 11 genes were identified to be associated with HCC risk. This synopsis helps elucidate the mechanisms of carcinogenesis of HCC and provides insights into the early diagnosis and novel treatments of HCC by targeting those potential genes.

Association of germline ABCB1 and ERCC1 polymorphisms with CDK4/6 inhibitor-induced neutropenia in patients with breast cancer: a systematic review and meta-analysis

CDK4/6 inhibitors are standard-of-care for HR+/HER2− advanced breast cancer, but grade 3/4 neutropenia occurs in up to 60% of patients. Germline polymorphisms in ABCB1 , encoding the P-glycoprotein efflux transporter, have been investigated as predictors of CDK4/6 inhibitor–induced neutropenia, with conflicting results across populations. No meta-analysis has previously pooled these findings. PubMed, Scopus, and Web of Science were systematically searched. Studies reporting genotype-stratified grade 3/4 neutropenia in CDK4/6 inhibitor–treated patients were eligible. Four SNPs were analyzed: ABCB1 rs1128503, ABCB1 rs1045642, ERCC1 rs11615, and ERCC1 rs3212986. Odds ratios were pooled using Mantel-Haenszel weighting with random-effects (rs1128503, rs11615) or fixed-effect (rs1045642, rs3212986) models under dominant genetic models, stratified by ancestry. The protocol was registered in PROSPERO (CRD420261379298). Four studies (1,138 patients) were included. No SNP showed a significant overall association. However, significant ancestry-dependent heterogeneity was detected for two ABCB1 SNPs. For rs1045642, T-carrier status was significantly associated with increased neutropenia in European/Caucasian patients (pooled OR 1.62, 95% CI 1.05–2.52, p = 0.03, I 2 = 0%) but decreased risk in East Asians (OR 0.31, 95% CI 0.13–0.74, p = 0.009; subgroup difference p = 0.0009). For rs1128503, a concordant European trend was observed (OR 1.87, 95% CI 0.87–4.00, p = 0.11) with reversed direction in North African/Middle Eastern patients (OR 0.33, 95% CI 0.12–0.92, p = 0.03; subgroup difference p = 0.02). For ERCC1 rs11615, the inclusion of Wang 2024 nullified the previously borderline European signal (pooled OR 0.99, 95% CI 0.42–2.33, p = 0.98, I 2 = 75%), with subgroup differences no longer significant (p = 0.17). ERCC1 rs3212986 showed no association (OR 1.07, 95% CI 0.53–2.17, I 2 = 0%). These preliminary findings suggest that ABCB1 rs1045642 T-carrier status may be associated with CDK4/6 inhibitor–induced neutropenia in European/Caucasian patients, with a concordant trend for rs1128503 findings. Both associations appear ancestry-dependent, although the limited number of studies and single-study ancestry subgroups preclude definitive conclusions. ERCC1 rs11615, previously borderline in a single study, was not confirmed upon independent replication. Prospective validation in adequately powered, ancestry-stratified cohorts incorporating ABCB1 haplotype analysis and pharmacokinetic sampling is warranted. identifier CRD420261379298.

Context-Dependent Associations of the APOA1 rs670 Polymorphism with Apolipoprotein A1 and HDL Cholesterol: A Systematic Review and Meta-Analysis

The APOA1 rs670 (−75 G>A) polymorphism has been implicated in lipid metabolism and susceptibility to metabolic syndrome (MetS). However, individual studies have reported inconsistent associations with circulating apolipoprotein A1 (Apo A1) and lipid parameters, and no meta-analysis has comprehensively evaluated these associations stratified by metabolic disorder status. We therefore quantified the associations between APOA1 rs670 and serum Apo A1 and lipid parameters, and determined whether these associations are modified by metabolic disorder status. PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched from inception to March 2026. Eligible studies reported APOA1 rs670 genotype data with quantitative lipid measurements. Forty studies involving 22,175 participants met the inclusion criteria. Pooled effect sizes were estimated as standardized mean differences (SMDs) with 95% confidence intervals (CIs) using random-effects models. This review was registered in PROSPERO (CRD420261333145). A allele carriers had significantly higher serum Apo A1 (SMD, 0.20; p < 0.001) and HDL-C levels (SMD, 0.14; p < 0.001) than GG homozygotes. Subgroup analyses stratified by metabolic disorder status revealed that the associations with Apo A1 (SMD, 0.53 vs. 0.11) and HDL-C (SMD, 0.23 vs. 0.08) were substantially stronger among individuals with metabolic disorders than among metabolically healthy individuals. No significant associations were observed for LDL-C or triglyceride levels. The APOA1 rs670 polymorphism is associated with higher circulating Apo A1 and HDL-C levels, with stronger associations in individuals with metabolic disorders. These findings suggest that metabolic status modifies the phenotypic effects of rs670 on the Apo A1–HDL pathway.

Association between the PNPLA3 I148M (rs738409) polymorphism and risk of metabolic dysfunction-associated steatotic liver disease: a meta-analysis (2015-2025).

BACKGROUND Metabolically-dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and is strongly influenced by genetic susceptibility. Among the identified genetic variants, the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 (I148M) polymorphism has been consistently associated with hepatic steatosis and disease progression. However, previous meta-analyses included fewer studies, limited ethnic diversity, and insufficient investigation of between-study heterogeneity. This study aimed to comprehensively evaluate the association between the PNPLA3 rs738409 polymorphism and MASLD susceptibility. METHODS A systematic literature search was conducted in PubMed, Embase, Scopus, Web of Science, and Google Scholar to identify eligible case-control studies published between 2015 and 2025. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under allelic, dominant, homozygous, heterozygous, and combined genotype models using random-effects meta-analysis. Between-study heterogeneity was assessed using the I² statistic, and ethnicity-based subgroup analyses were performed to investigate potential sources of heterogeneity. RESULTS Forty-one studies comprising 9,064 patients with MASLD and 10,894 controls were included. The G allele was significantly associated with increased susceptibility to MASLD (OR = 1.70, 95% CI: 1.49-1.93). Individuals carrying the GG genotype had approximately a twofold higher risk of MASLD (OR = 2.00, 95% CI: 1.65-2.42), whereas the CC genotype showed a protective association (OR = 0.51, 95% CI: 0.44-0.59). Significant associations were also observed for the CG genotype (OR = 1.22, 95% CI: 1.08-1.38) and the dominant model (CG + GG vs. CC) (OR = 2.64, 95% CI: 1.86-3.75). Although substantial between-study heterogeneity was observed (I² = 66%-96%), ethnicity-based subgroup analyses explained part of the variability while demonstrating consistent associations across major ethnic populations. CONCLUSIONS This updated meta-analysis confirms that the PNPLA3 rs738409 (I148M) polymorphism is a major genetic susceptibility factor for MASLD across diverse populations. Although ethnicity contributes to between-study heterogeneity, the association remains robust across populations. These findings support the incorporation of PNPLA3 into multifactorial risk assessment models and provide an updated evidence base for future precision medicine approaches in MASLD.

LPA genetic variation is associated with type 2 diabetes after adjustment for lipoprotein(a) concentration: results of the Aragon Workers’ health study

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.

Meta-analysis of 49(cid:0)549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels