Ng Soo Khai, Burdon Kathryn P, Fitzgerald Jude T, Zhou Tiger, Fogarty Rhys, Souzeau Emmanuelle, Landers John, Mills Richard A, Casson Robert J, Ridge Bronwyn, Graham Stuart L, Hewitt Alex W, Mackey David A, Healey Paul R, Wang Jie Jin, Mitchell Paul, MacGregor Stuart, Craig Jamie E
Department of Ophthalmology Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia 2Ophthalmic Research Laboratories, South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia.
Department of Ophthalmology Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia 3Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Invest Ophthalmol Vis Sci. 2016 Jun 1;57(7):3416-21. doi: 10.1167/iovs.16-19401.
Many genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at the 9p21 glaucoma locus (CDKN2B/CDKN2B-AS1) to be significantly associated with primary open-angle glaucoma (POAG), with association being stronger in normal tension glaucoma (NTG) and advanced glaucoma. We aimed to determine whether any observed differences in genetic association at the 9p21 locus are influenced by sex.
Sex was assessed as a risk factor for POAG for 2241 glaucoma participants from the Australian and New Zealand Registry of Advanced Glaucoma, the Glaucoma Inheritance Study in Tasmania, and the Flinders Medical Centre. A total of 3176 controls were drawn from the Blue Mountains Eye Study and South Australia: 1523 advanced POAG and 718 nonadvanced POAG cases were genotyped along with 3176 controls. We selected 13 SNPs at the 9p21 locus, and association results were subanalyszd by sex for high-tension glaucoma (HTG) and NTG. Odds ratios (ORs) between sexes were compared.
A sex bias was present within advanced NTG cases (57.1% female versus 42.9% male, P = 0.0026). In all POAG cases, the strongest associated SNP at 9p21 was rs1063192 (OR, 1.43; P = 4 × 10-18). This association was stronger in females (OR, 1.5; P = 5 × 10-13) than in males (OR, 1.35; P = 7 × 10-7), with a statistically significant difference in female to male OR comparison (P = 1.0 × 10-2). An NTG to HTG subanalysis yielded statistically significant results only in females (OR, 1.63; P = 1.5 × 10-4) but not in males (OR, 1.15; P = 2.8 × 10-1), with a statistically significant difference in female to male OR comparison (P = 1.4 × 10-4).
This study demonstrated that female sex is a risk factor for developing advanced NTG. The stronger genetic signals at the 9p21 locus among females may contribute at least in part to the observed sex bias for NTG.
许多全基因组关联研究已确定9p21青光眼位点（CDKN2B/CDKN2B-AS1）的常见单核苷酸多态性（SNP）与原发性开角型青光眼（POAG）显著相关，在正常眼压性青光眼（NTG）和晚期青光眼患者中这种相关性更强。我们旨在确定9p21位点观察到的遗传关联差异是否受性别影响。
在澳大利亚和新西兰晚期青光眼登记处、塔斯马尼亚青光眼遗传研究以及弗林德斯医疗中心的2241例青光眼患者中，将性别作为POAG的一个风险因素进行评估。总共从蓝山眼研究和南澳大利亚选取了3176名对照：1523例晚期POAG患者和718例非晚期POAG患者以及3176名对照进行基因分型。我们在9p21位点选择了13个SNP，并按性别对高眼压性青光眼（HTG）和NTG进行关联结果的亚组分析。比较了不同性别的优势比（OR）。
晚期NTG患者中存在性别偏差（女性占57.1%，男性占42.9%，P = 0.0026）。在所有POAG患者中，9p21位点关联最强的SNP是rs1063192（OR，1.43；P = 4×10-18）。这种关联在女性中（OR，1.5；P = 5×10-13）比男性中（OR，1.35；P = 7×10-7）更强，女性与男性OR比较有统计学显著差异（P = 1.0×10-2）。NTG与HTG的亚组分析仅在女性中产生了统计学显著结果（OR，1.63；P = 1.5×10-4），而在男性中未产生（OR，1.15；P = 2.8×10-1），女性与男性OR比较有统计学显著差异（P = 1.4×10-4）。
本研究表明女性是发生晚期NTG的一个风险因素。女性中9p21位点更强的遗传信号可能至少部分导致了观察到的NTG性别偏差。
