Punab A M, Grigorova M, Punab M, Adler M, Kuura T, Poolamets O, Vihljajev V, Žilaitienė B, Erenpreiss J, Matulevičius V, Laan M
Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Andrology Unit, Tartu University Clinics, Tartu, Estonia.
Andrology. 2015 May;3(3):512-9. doi: 10.1111/andr.12022. Epub 2015 Mar 26.
Luteinizing hormone (LH) is a pituitary heterodimeric glycoprotein essential in male and female reproduction. Its functional polymorphic variant (V-LH) is determined by two missense mutations (rs1800447, A/G, Trp8Arg; rs34349826, A/G, Ile15Thr) in the LH β-subunit encoding gene (LHB; 19q13.3; 1111 bp; 3 exons). Among women, V-LH has been associated with higher circulating LH and reduced fertility, but the knowledge of its effect on male reproductive parameters has been inconclusive. The objective of this study was to assess the effect of V-LH on hormonal, seminal and testicular parameters in the Baltic young men cohort (n = 986; age: 20.1 ± 2.1 years) and Estonian idiopathic infertility patients (n = 607; 35.1 ± 5.9 years). V-LH was detected by genotyping of the underlying DNA polymorphisms using PCR-RFLP combined with resequencing of a random subset of subjects. Genetic associations were tested using linear regression under additive model and results were combined in meta-analysis. No significant difference was detected between young men and infertility patients for the V-LH allele frequency (11.0 vs. 9.3%, respectively). V-LH was associated with higher serum LH in both, the young men cohort (p = 0.022, allelic effect = 0.26 IU/L) and the idiopathic infertility group (p = 0.008, effect = 0.59 IU/L). In meta-analysis, the statistical significance was enhanced (p = 0.0007, resistant to Bonferroni correction for multiple testing; effect = 0.33 IU/L). The detected significant association of V-LH with increased serum LH remained unchanged after additional adjustment for the SNPs previously demonstrated to affect LH levels (FSHB -211G/T, FSHR Asn680Ser, FSHR -29A/G). Additionally, a suggestive trend for association with reduced testicular volume was observed among young men, and with lower serum FSH among infertility patients. The V-LH carrier status did not affect sperm parameters and other circulating reproductive hormones. For the first time, we show a conclusive contribution of V-LH to the natural variance in male serum LH levels. Its downstream clinical consequences are still to be learned.
促黄体生成素（LH）是一种垂体异源二聚体糖蛋白，在男性和女性生殖中至关重要。其功能性多态变体（V-LH）由促黄体生成素β亚基编码基因（LHB；19q13.3；1111 bp；3个外显子）中的两个错义突变（rs1800447，A/G，Trp8Arg；rs34349826，A/G，Ile15Thr）决定。在女性中，V-LH与循环中促黄体生成素水平升高和生育力降低有关，但关于其对男性生殖参数影响的认识尚无定论。本研究的目的是评估V-LH对波罗的海年轻男性队列（n = 986；年龄：20.1±2.1岁）和爱沙尼亚特发性不育患者（n = 607；35.1±5.9岁）的激素、精液和睾丸参数的影响。通过使用PCR-RFLP对潜在的DNA多态性进行基因分型，并结合对随机抽取的受试者子集进行重测序来检测V-LH。在加性模型下使用线性回归测试遗传关联，并在荟萃分析中合并结果。在年轻男性和不育患者中，V-LH等位基因频率未检测到显著差异（分别为11.0%和9.3%）。在年轻男性队列（p = 0.022，等位基因效应 = 0.26 IU/L）和特发性不育组（p = 0.008，效应 = 0.59 IU/L）中，V-LH均与血清促黄体生成素水平升高有关。在荟萃分析中，统计学显著性增强（p = 0.0007，对多重检验的Bonferroni校正具有抗性；效应 = 0.33 IU/L）。在对先前证明会影响促黄体生成素水平的单核苷酸多态性（FSHB -211G/T、FSHR Asn680Ser、FSHR -29A/G）进行额外调整后，检测到的V-LH与血清促黄体生成素升高之间的显著关联保持不变。此外，在年轻男性中观察到与睾丸体积减小相关的提示性趋势，在不育患者中观察到与血清促卵泡生成素水平降低相关的提示性趋势。V-LH携带者状态不影响精子参数和其他循环生殖激素。我们首次表明V-LH对男性血清促黄体生成素水平的自然变异有决定性作用。其下游的临床后果仍有待了解。
