Abstract Background Host genetic factors contribute to the heterogeneity of clinical outcomes in Coronavirus Disease 2019 (COVID-19). Interleukin-8 (IL-8) and its receptor IL-8R1 (CXCR1) play key roles in inflammatory responses and cytokine-mediated tissue damage during severe SARS-CoV-2 infection. This study investigated the association of IL-8 rs4073 and rs2227306, as well as IL-8R1 rs2234671 polymorphisms, with COVID-19 mortality in an Iranian population. Methods A total of 328 hospitalized COVID-19 patients, including 178 recovered and 150 deceased individuals, were enrolled. Genotyping of IL-8 rs4073, IL-8 rs2227306, and IL-8R1 rs2234671 polymorphisms was performed using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), and selected samples were confirmed by Sanger sequencing. Genotype and allele frequencies were compared between groups, and logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multilocus genotype combination analysis was also conducted. Results The IL-8R1 rs2234671 polymorphism showed a significant association with COVID-19 mortality. Carriers of the G allele exhibited an increased risk of death compared with CC homozygotes under codominant, dominant, overdominant, and log-additive inheritance models (all P < 0.05). The strongest association was observed under the dominant model (OR = 3.29, 95% CI = 1.55–6.99, P = 0.0014). In contrast, IL-8 rs4073 and rs2227306 polymorphisms showed no statistically significant associations with mortality when analyzed individually. Multilocus genotype combination analysis suggested that specific combinations involving IL-8R1 rs2234671 may influence clinical outcomes, although these findings require further validation. Conclusions Our findings indicate that the IL-8R1 rs2234671 polymorphism is associated with COVID-19 mortality in the studied Iranian population, supporting the importance of IL-8/CXCR1-mediated inflammatory pathways in disease progression. Although individual IL-8 polymorphisms were not significantly associated with mortality, combined genetic effects may contribute to outcome variability. However, the proposed functional mechanisms remain to be experimentally validated. Larger multi-ethnic studies and functional investigations are needed to validate these associations and clarify their biological significance. Clinical trial number Not applicable.
Abstract Ischemic heart disease (IHD) is the leading cause of death worldwide and arises from a complex interplay of genetic, environmental, and lifestyle factors. Apolipoprotein E (ApoE), encoded by the APOE gene on chromosome 19q13.3, is a central regulator of lipid metabolism and one of the most extensively studied genetic determinants of cardiovascular risk. The three major APOE isoforms, ε2, ε3, and ε4, defined by the rs429358 and rs7412 single nucleotide polymorphisms, exert distinct effects on low-density lipoprotein cholesterol (LDL-C) levels, atherosclerotic plaque formation, and vascular inflammation. This review aimed to synthesise current evidence on APOE polymorphisms and their association with IHD, with particular attention to South Asian and Pakistani populations. A narrative literature search was conducted in PubMed, Scopus, and Google Scholar for studies published between 1990 and 2024, using the terms APOE polymorphism, ischemic heart disease, coronary artery disease, apolipoprotein E SNP, and cardiovascular genetics. The APOE ε4 allele was consistently associated with elevated total cholesterol and LDL-C levels, increased atherosclerotic burden, and higher IHD risk across multiple populations, whereas the ε2 allele was generally protective, with the notable exception of rare ε2/ε2 homozygotes who may develop type III hyperlipoproteinemia. Promoter-region polymorphisms, including rs405509, rs769446, and rs449647, were found to further modulate APOE expression and may independently influence lipid profiles and plaque stability. In a premature coronary artery disease cohort, the ε3/ε4 genotype (18.9% versus 10.2% in controls; p = 0.001) and the ε4 allele (11.1% versus 7.0%; p = 0.007) were significantly more frequent in patients than controls. South Asian populations, including Pakistanis, exhibited a lower ε4 allele frequency than Western populations yet remained disproportionately susceptible to IHD, suggesting that additional genetic and environmental factors substantially contribute to regional cardiovascular risk. APOE polymorphisms are important modulators of IHD risk through their effects on lipid metabolism, inflammation, and endothelial function. Although incorporating APOE genotyping into risk stratification holds promise, current evidence—particularly the absence of large-scale, longitudinal data in Pakistani populations—does not yet justify its routine clinical use for personalised prevention. Adequately powered, population-specific genotyping studies linked to long-term clinical outcomes are therefore needed before such applications can be realised.
Abstract Background Duchenne and Becker muscular dystrophies are allelic X-linked dystrophinopathies caused by DMD pathogenic variants. Accurate delineation of the variant spectrum is required for molecular diagnosis, reproductive counseling, and assessment of eligibility for mutation-specific therapies. Objective To analyze the DMD variation spectrum and evaluate the diagnostic performance and limitations of a sequential multiplex ligation-dependent probe amplification (MLPA)-first, exome sequencing (ES)-second testing strategy in a large single-center cohort of patients with Duchenne and Becker muscular dystrophies. Methods The 940 probands (924 males and 16 females, with ages ranging from birth to 54 years) underwent initial screening for large deletions and duplications using multiplex ligation-dependent probe amplification (MLPA), with negative cases and single exon cases subsequently analyzed by exome sequencing (ES) for small variants. Maternal segregation analysis was performed in 888 families for which maternal samples were available to determine whether the identified DMD variants were maternally inherited or presumed de novo. Results A DMD variant was identified in 921 of 940 genetically or pathologically confirmed cases (97.98%). Among the 921 molecularly diagnosed cases, large deletions, large duplications, small sequence variants, and complex structural variants accounted for 66.34% (611/921), 11.73% (108/921), 20.63% (190/921), and 1.30% (12/921), respectively. From 921 cases, twelve complex structural variants, including combined deletion-duplication events, discontinuous duplications, and inversions, were identified. The 16 females with heterozygous DMD variants showed variable findings, ranging from no reported symptoms to elevated creatine kinase CK levels and clinically manifesting dystrophinopathy. Nineteen patients with biopsy-supported dystrophinopathy remained molecularly unresolved. Conclusion The MLPA and ES strategy could identified DMD variants in most genetically or pathologically confirmed cases. These findings refine the contemporary DMD variant spectrum in a Chinese referral cohort and support molecular diagnosis, family-based interpretation, genetic counseling, and assessment of eligibility for mutation-specific therapies.
Abstract Charcot–Marie–Tooth disease (CMT) is the most common group of inherited peripheral neuropathies, and CMT1A is its most prevalent demyelinating subtype. It is most often caused by a recurrent ~ 1.4–1.5 Mb tandem duplication on chromosome 17p12 encompassing the PMP22 gene, resulting in increased PMP22 expression and a complex pathogenic cascade involving Schwann-cell proteostatic stress, impaired myelin and lipid homeostasis, metabolic dysfunction, and secondary axonal degeneration. Despite the relative genetic homogeneity of the primary defect, substantial inter- and intra-familial phenotypic variability is observed, suggesting contributions from genetic modifiers, regulatory elements, and epigenetic mechanisms. This narrative review synthesizes current evidence on the genetic, molecular, and regulatory architecture of CMT1A, with particular emphasis on distal regulatory elements controlling PMP22 expression, promoter-specific transcriptional regulation, and mechanisms contributing to phenotypic heterogeneity. We further examine the evolving therapeutic landscape, from symptomatic management toward disease-modifying and precision therapeutic strategies. Particular attention is given to approaches designed to reduce PMP22 expression, including synergistic pharmacological therapy, antisense oligonucleotides, RNA interference, AAV-mediated gene silencing, and experimental regulatory-element editing, as well as therapeutic strategies targeting downstream mechanisms such as axonal transport and neuromuscular function. Emerging biomarkers, particularly serum neurofilament light chain (NfL), may support exploratory treatment monitoring and patient stratification. However, their value as pharmacodynamic or surrogate endpoints for regulatory decision-making in CMT1A has not yet been established. We also discuss lessons from clinical trials, including the challenges posed by slow disease progression, placebo responses, and heterogeneous treatment effects. Finally, we propose a framework for future CMT1A trials incorporating appropriate patient stratification, extended follow-up, and multimodal clinical, biological, and digital outcome measures. Together, these developments support an increasingly individualized framework for CMT1A that integrates gene dosage, regulatory biology, genetic modifiers, biomarkers, and therapeutic response.
Polycystic ovary syndrome (PCOS) is a common multifactorial endocrine disorder with reproductive and metabolic manifestations. The contribution of variants involved in ovarian folliculogenesis and metabolic regulation remains incompletely understood in South Asian populations. This study investigated the association of follicle-stimulating hormone receptor (FSHR) rs6165 and adiponectin (ADIPOQ) rs2241766 polymorphisms with PCOS susceptibility in Pakistani women and evaluated their combined genetic contribution using a cumulative genetic risk score. A hospital-based case-control study included 55 PCOS patients (Rotterdam 2003 criteria) and 60 healthy controls. Genotyping of ADIPOQ rs2241766 was performed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), whereas FSHR rs6165 was genotyped using allele-specific PCR. Associations were evaluated using logistic regression under allelic and codominant models after adjustment for age and body mass index (BMI). A two-locus genetic risk score based on total risk alleles was constructed and categorized into tertiles. The FSHR rs6165 AG genotype was associated with significantly increased PCOS risk compared with AA homozygotes (adjusted odds ratio (OR) = 7.56, 95
