The rs2736100 within the telomerase reverse transcriptase gene and rs16847897 within the telomerase RNA component gene moderate the association between internalizing mental disorders and telomere length attrition among HIV+ children and adolescents in Uganda
The rs2736100 within the telomerase reverse transcriptase gene and rs16847897 within the telomerase RNA component gene moderate the association between internalizing mental disorders and telomere length attrition among HIV+ children and adolescents in Uganda
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DOI：
10.21203/rs.2.16324/v1
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发表时间：
2019-10
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通讯作者：
A. Kalungi;E. Kinyanda;J. Womersley;M. Joloba;W. Ssembajjwe;R. Nsubuga;P. Kaleebu;J. Levin;M. Kidd;S. Seedat;S. Hemmings
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作者：
A. Kalungi;E. Kinyanda;J. Womersley;M. Joloba;W. Ssembajjwe;R. Nsubuga;P. Kaleebu;J. Levin;M. Kidd;S. Seedat;S. Hemmings
背景 内化性精神障碍 (IMD) 与端粒长度 (TL) 加速磨损有关。然而，这种关联尚未在遗传变异的背景下进行研究。一项大型全基因组荟萃分析表明，多个位点影响平均 TL，特别是端粒酶逆转录酶 (TERT) 和端粒酶 RNA 成分 (TERC) 基因内的单核苷酸多态性。据报道，溶质载体家族 6 成员 4 基因 (SLC6A4) 和色氨酸羟化酶 2 (TPH2) 基因的遗传变异可调节社会环境与 TL 之间的关联。 SLC6A4 编码血清素转运蛋白 (5-HTT)，这是一种从突触回收血清素的蛋白质，而 TPH2 编码色氨酸羟化酶 2，这是一种催化血清素生物合成中限速反应的酶。这项病例对照研究使用线性回归模型来调查乌干达 HIV+ 儿童（7-11 岁）和青少年（12-17 岁）中 TERT、TERC、SLC6A4 和 TPH2 基因中选定的多态性对 IMD 和相对 TL (rTL) 之间关联的调节作用。研究的多态性为：rs2736100、rs7726159、rs10069690 和 rs2853669 (TERT)； rs12696304、rs16847897 和 rs10936599 (TERC)； 5-HTTLPR、rs35531、5-HTTLPR/rs35531 和 STin2.VNTR (SLC6A4) 以及 rs1843809、rs1386494 和 rs34517220 (TPH2)。结果 在基线时，与地点、年龄、性别和社会经济状况匹配的对照相比，患有任何内化性精神障碍的 HIV+儿童和青少年的相对 TL 显着更长 (p = 0.001)。所研究的多态性对观察到的 IMD 和基线 rTL 之间的关联没有任何调节作用。 12 个月时，我们观察到基线病例和对照之间的 12 个月 rTL 没有统计学上的显着差异（p = 0.117），然而，在对每个选定的多态性的影响进行建模时，我们观察到 IMD 与 rs2736100 和 rs16847897 的相互作用显着影响 rTL（分别为 p = 0.007 和 p = 0.012）。结论 随着时间的推移，rs2736100 和 rs16847897 多态性调节了乌干达 HIV+ 儿童和青少年中 IMD 和 rTL 之间的关联。 rs2736100 的 T 等位基因和 rs16847897 的 C 等位基因与 IMD 病例中 rTL 加速损耗相关。这些等位基因与 IMD 相互作用以调节 rTL 的机制需要进一步研究。
Background Internalizing mental disorders (IMDs) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the context of genetic variation. A large genome-wide meta-analysis has implicated several loci that affect mean TL, in particular single nucleotide polymorphisms within the telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) genes. Genetic variations in the solute carrier family 6 member 4 gene (SLC6A4) and the tryptophan hydroxylase 2 (TPH2) genes have also been reported to moderate the association between social environment and TL. The SLC6A4 codes for the serotonin transporter (5-HTT), a protein that recycles serotonin from synapses while the TPH2 codes for tryptophan hydroxylase 2, an enzyme that catalyzes the rate-limiting reaction in serotonin biosynthesis. This case-control study used linear regression models to investigate the moderating effects of selected polymorphisms in TERT, TERC, SLC6A4 and TPH2 genes on the association between IMDs and relative TL (rTL), among Ugandan HIV+ children (7-11 years) and adolescents (12-17 years). Investigated polymorphisms were: rs2736100, rs7726159, rs10069690, and rs2853669 (TERT); rs12696304, rs16847897 and rs10936599 (TERC); 5-HTTLPR, rs35531, 5-HTTLPR/rs35531 and STin2.VNTRs (SLC6A4) and rs1843809, rs1386494, and rs34517220 (TPH2). Results At baseline, HIV+ children and adolescents with any internalizing mental disorder had significantly longer relative TL compared to controls matched for site, age, sex and socio-economic status (p = 0.001). None of the polymorphisms investigated had any moderating effect on the observed association between IMDs and baseline rTL. At 12 months, we observed no statistically significant difference in 12-month rTL between baseline cases and controls (p = 0.117), however, on modeling the effects of each of the selected polymorphisms, we observed that the interaction of IMDs and each of rs2736100 and rs16847897 significantly influenced rTL (p = 0.007 and p = 0.012 respectively). Conclusions The rs2736100 and rs16847897 polymorphisms moderate the association between IMDs and rTL among Ugandan HIV+ children and adolescents over time. The T-allele for rs2736100 and a C-allele for rs16847897 are associated with accelerated rTL attrition among cases of IMDs. The mechanisms under which these alleles interact with IMDs to moderate rTL require further investigations.