Association between Single Nucleotide Polymorphisms in Gamma-Aminobutyric Acid B Receptor, Insulin Receptor Substrate-1, and Hypocretin Neuropeptide Precursor Genes and Susceptibility to Obstructive Sleep Apnea Hypopnea Syndrome in a Chinese Han Population

Abstract

Objective: To investigate genotype-phenotype changes between rs29230 in γ-aminobutyric acid B receptor (GABBR1), rs1801278 in insulin receptor substrate-1 (IRS-1), and rs9902709 in hypocretin neuropeptide precursor (HCRT) and obstructive sleep apnea hypopnea syndrome (OSAHS) in Chinese Han individuals. Materials and Methods: A total of 130 patients with OSAHS and 136 age- and gender-matched healthy controls were enrolled in this study. A brief description of DNA extraction and genotyping is given. Multivariate unconditional logistic regression analysis adjusted for gender and age was used to estimate the associations of single nucleotide polymorphisms (SNPs) rs29230 (GABBR1), rs1801278 (IRS-1), and rs9902709 (HCRT) with OSAHS risk. Subgroup analysis was performed to evaluate differences in these SNPs among subgroups according to gender, body mass index (BMI), and severity of disease. Results: Genotype and allele frequencies of rs29230 were significantly different between cases and controls (p = 0.0205 and p = 0.0191, respectively; odds ratio = 0.493, 95% confidence interval = 0.271-0.896), especially for male patients (p = 0.0259 and p = 0.0202, respectively). Subgroup analysis according to BMI also revealed a significant allele difference for rs29230 between cases and controls in the overweight subgroup (p = 0.0333). Furthermore, allele and genotype frequencies of rs1801278 showed significant differences between cases and controls (p = 0.0488 and p = 0.0471, respectively). However, no association was observed between rs9902709 and OSAHS risk (p = 0.2762), and no differences were identified in other subgroups. Conclusion: In this study, there was an association between variants of rs29230 and rs1801278 and OSAHS risk in the Chinese Han population but not for rs9902709.

Characterization of Genetic and Phenotypic Heterogeneity of Obstructive Sleep Apnea Using Electronic Health Records

“…The authors observed an effect primarily in men indicating the C allele at rs29230 (reported in the literature on the alternative strand) was increased in OSA patients 61 . A subsequent candidate gene study conducted in 266 individuals from China confirmed an association between the C allele at rs29230 and risk for OSA defined as AHI≥5 in patients with no evidence of underlying confounding comorbid conditions, while additionally controlling for differences in BMI between cases and controls 62 . The GABBR1 gene encodes a receptor for the main inhibitory neurotransmitter in humans, gamma-aminobutyric acid (GABA).…”

“…The GABBR1 gene encodes a receptor for the main inhibitory neurotransmitter in humans, gamma-aminobutyric acid (GABA). GABA(B) receptors are expressed in hypoglossal motorneurons innervating the tongue, which are important for inhibiting tongue movement 62 . It is possible that variation in GABBR1 influences risk for OSA by affecting activity of the encoded receptor resulting in dysfunction of the hypoglossal motoneurons 61; 62 .…”

“…GABA(B) receptors are expressed in hypoglossal motorneurons innervating the tongue, which are important for inhibiting tongue movement 62 . It is possible that variation in GABBR1 influences risk for OSA by affecting activity of the encoded receptor resulting in dysfunction of the hypoglossal motoneurons 61; 62 . Notably, the functional consequences of the rs29230 missense variant on GABBR1 , depending on the isoform, varies across numerous in silico prediction algorithms and is reported by some software to be possibly damaging and others benign (see Ensembl Variant Effect Predictor for the range of consequences, https://uswest.ensembl.org/index.html).…”

Role of Gabaergic System Genetic Polymorphisms in the Development of Obstructive Sleep Apnea Syndrome in Asthma Patients

“…Гомозиготный по делеции генотип (DD) чаще встречался у больных с СОАС (81% против 65%, p=0,1), тогда как гетерозиготный генотип являлся протективным. Вне зависимости от пола среди носителей генотипа DD отмечался более высокий ИАГ, по сравнению с носителями ID генотипа (2, Нам не удалось воспроизвести ассоциацию полиморфизма гена первой субъединицы метаботропных ГАМК-рецептров rs29230 с СОАС, прежде выявленную в китайской популяции [11], даже при анализе в подгруппах в зависимости от пола и наличия ожирения. Вместе с тем, полученные данные в целом согласуются с выдвинутой гипотезой о негативной роли ГАМК в патогенезе СОАС.…”

“…Также было замечено, что прием габапентина -препарата, стимулирующего выработку ГАМК, приводит к существенному увеличению частоты ночных апноэ-гипопноэ у пожилых людей [12]. Среди детей, больных СОАС, была найдена повышенная концентрация ГАМК в утренней моче [8], а исследование 2016 года, проведенное в КНР, обнаружило полиморфизм гена первой субъединицы метаботропных ГАМК-рецепторов GABBR1, значимо ассоциированный с СОАС [11].…”