Genetic Variants of rs1275988 and rs2586886 in TWIK-Related Acid-Sensitive K+ Channel-1 Gene as Potential Risk Factors for Obese Patients with Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) is a prevalent sleep disorder characterized by recurrent upper airway collapse during sleep, leading to intermittent hypoxia, hypercapnia, and fragmented sleep. These physiological disturbances contribute to cardiovascular and cerebrovascular morbidity. While obesity is a well-established risk factor for OSA, the genetic underpinnings of this association remain incompletely understood. Recent evidence highlights the role of potassium channels in respiratory regulation and metabolic processes, prompting investigation into the TWIK-related acid-sensitive K+ channel-1 (TASK-1, encoded by KCNK3) gene. This study explores the association between two single nucleotide polymorphisms (SNPs) in the TASK-1 gene—rs1275988 and rs2586886—and the risk of severe OSA in obese individuals.
Study Design and Participant Characteristics
The study enrolled 335 participants from the Center for Hypertension at the People’s Hospital of Xinjiang Uygur Autonomous Region, China, between April and December 2016. Participants were stratified into two groups: 164 individuals with severe OSA (apnea-hypopnea index [AHI] ≥30 events/hour) and 171 non-OSA controls (AHI <5 events/hour). Polysomnography (PSG) confirmed OSA severity, and exclusion criteria eliminated confounding factors such as central sleep apnea, chronic respiratory diseases, malignancies, and secondary hypertension.
Demographic and clinical data revealed significant differences between groups. Severe OSA patients were predominantly male (86% vs. 52.6% in controls), with higher rates of smoking (53.7% vs. 26.9%) and alcohol consumption (51.2% vs. 31.6%). Obesity metrics, including body mass index (BMI ≥28 kg/m²), waist circumference (110 cm vs. 100 cm), and neck circumference (44 cm vs. 40 cm), were markedly elevated in the severe OSA group. Additionally, severe OSA patients exhibited dyslipidemia, with higher triglyceride (1.96 mmol/L vs. 1.45 mmol/L) and total cholesterol levels (4.62 mmol/L vs. 4.27 mmol/L), alongside reduced high-density lipoprotein (0.90 mmol/L vs. 1.00 mmol/L).
Genetic Analysis and SNP Selection
The TASK-1 gene was selected for its role in respiratory chemosensitivity, hypoxia response, and lipid metabolism regulation. Two SNPs—rs1275988 and rs2586886—were chosen based on their functional relevance, linkage disequilibrium patterns (r² >0.8), and minor allele frequency (≥0.05). Genotyping was performed using kompetitive allele-specific PCR, with 10% of samples reanalyzed for quality control. Hardy-Weinberg equilibrium testing validated genotype distributions for rs2586886 but not rs1275988 in the total population.
Key Findings in the Total Population
Initial analysis of the entire cohort showed no significant differences in genotype distributions, allele frequencies, or genetic models (recessive and dominant) for either SNP between severe OSA and control groups. For rs1275988, the GG genotype prevalence was 60.7% in OSA vs. 55.6% in controls (P=0.251), while the G allele frequency was 77.3% vs. 72.2% (P=0.131). Similarly, rs2586886 showed GG genotype rates of 57.6% vs. 54.9% (P=0.213), with G allele frequencies of 75.8% vs. 71.6% (P=0.234). These results suggested that TASK-1 polymorphisms alone did not independently predict OSA risk in the general population.
Stratification by Obesity Status
Given the known interaction between KCNK3 and obesity, participants were stratified by BMI (≥28 kg/m² vs. <28 kg/m²). Striking differences emerged in the obese subgroup:
- rs1275988: The GG genotype was significantly more prevalent in severe OSA (57.5% vs. 41% in non-OSA; P=0.014). The G allele frequency was 75.5% vs. 59% (P=0.006), and the recessive model (GG+GA vs. AA) showed a 93.4% vs. 76.9% distribution (P=0.005).
- rs2586886: Similarly, the GG genotype dominated in severe OSA (56.1% vs. 41%; P=0.026), with a G allele frequency of 74.5% vs. 59% (P=0.011). The recessive model revealed 92.9% vs. 76.9% (P=0.009).
In non-obese individuals (BMI <28 kg/m²), no significant associations were observed for either SNP. This stratification underscored obesity as a critical effect modifier, amplifying the genetic risk conferred by TASK-1 variants.
Logistic Regression Analysis
Simple logistic regression in obese individuals identified the GG genotype as a significant risk factor for OSA:
- rs1275988: Odds ratio (OR)=4.902 (95% CI: 1.582–15.186; P=0.006).
- rs2586886: OR=4.420 (95% CI: 1.422–13.734; P=0.010).
Multivariate analysis adjusted for sex, smoking, alcohol use, lipid levels, and BMI confirmed the interaction between rs1275988 and obesity. The combination of GG genotype and BMI ≥28 kg/m² drastically elevated OSA risk (OR=8.916; 95% CI: 4.506–17.645; P<0.001). Male sex and elevated total cholesterol also independently predicted severe OSA.
Mechanistic Insights and Biological Plausibility
TASK-1 channels, expressed in brainstem respiratory neurons, regulate neuronal excitability in response to pH and oxygen fluctuations—hallmarks of OSA pathophysiology. Intermittent hypoxia and hypercapnia in OSA may dysregulate TASK-1 activity, impairing ventilatory control. Additionally, KCNK3 variants influence adipocyte thermogenesis and lipid metabolism, potentially exacerbating obesity-driven airway collapsibility. The GG genotype may enhance channel sensitivity to metabolic stressors, creating a feedforward loop between obesity and respiratory dysfunction.
Limitations and Future Directions
The study’s focus on severe OSA cases limits generalizability to milder forms. Absence of arterial blood gas data during sleep precluded direct correlation between genotype and nocturnal hypoxemia/hypercapnia. Furthermore, the candidate-gene approach may overlook other SNPs within KCNK3 or interacting loci. Future research should validate these findings in diverse populations, incorporate functional studies to elucidate TASK-1 channel dynamics, and explore therapeutic strategies targeting potassium channels in OSA management.
Conclusion
This study identifies rs1275988 and rs2586886 in the TASK-1 gene as potential genetic risk factors for severe OSA in obese individuals. The GG genotype of both SNPs synergizes with elevated BMI to substantially increase OSA susceptibility, highlighting the interplay between genetic predisposition and metabolic factors. These findings advance our understanding of OSA pathogenesis and pave the way for personalized risk stratification and targeted interventions in high-risk populations.
doi.org/10.1097/CM9.0000000000000401
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