第五章 討論
第二節 研究限制
本研究有以下研究限制，第一為樣本數不足，全基因體關聯性研究需要更大 量的樣本數來提高統計檢定力(statistical power)，然而本研究已是目前從臺灣人 體生物資料庫能取得的最大樣本數，期許未來能招募到更多臺灣人口的基因訊息，
能有更大量的樣本數做研究分析。第二為樣本的健康問卷為自陳(self-report)資料，
樣本自己表示是否罹患類風濕性關節炎疾病，故可能存在患有此疾病者表示沒有 罹患此疾病，反之亦然。第三為無法確認因果關係，全基因體關聯性研究為觀察 性研究，無法確認研究所發現的單核苷酸多型性位點變異與類風濕性關節炎的因 果關係。
第三節 公共衛生與臨床意義
本研究進行的類風濕性關節炎全基因體關聯性研究提出了臺灣族群可能特 有的變異位點。目前已知的類風濕性關節炎相關位點多集中在歐洲族群樣本的研 究，即使在不同族群之間共享風險位點，不同族群間仍存在差異(Laufer et al., 2019)，這也支持需要對臺灣人口類風濕性關節炎風險位點進行更深入的分析。
透過全基因體關聯性研究發現的遺傳變異與疾病之間的顯著關聯有助於：1)
臨床護理：新藥靶標和疾病生物標誌物的鑑定，可以提高藥物開發的成功率，減 少開發新藥物的時間和成本；3)精準醫療：根據個體基因型預測疾病風險，及早 發現、預防或優化治療方案，提高患者預後(Tam et al., 2019; Tang, 2019; Viatte &
Barton, 2017)。儘管目前已經確定了多種基因在預測患者治療狀態中的效果，但 未完全闡明其中一些基因在類風濕性關節炎發病機轉中的作用，因此類風濕性關 節炎的大型遺傳學關聯性研究仍十分重要(Karami, Aslani, Jamshidi, Garshasbi, &
Mahmoudi, 2019)。
類風濕性關節炎是一高度異質性的疾病所以不容易預測，而異質性有部分是 因為遺傳因素(Yamamoto et al., 2015)，未來能利用東亞或其他地區資料對本研究 結果進行比對或驗證(Validation)，進一步探討多基因組合、添加其他風險因素（例 如環境因素、生物標誌物和臨床預測因子）能提高預測模型的功能，應用於臨床 診斷與醫療發展(Yarwood et al., 2016)。類風濕性關節炎對社會經濟層面的影響足 以構成重大的公共衛生議題(Minichiello et al., 2016)，辨識出更多風險位點變異對 疾病的影響，可能是未來預防類風濕性關節炎的關鍵。
圖一、品質控管流程圖
圖二、曼哈頓圖
圖三、本研究不同p 值篩選出的顯著位點量
2435
220
36 0
0 500 1000 1500 2000 2500 3000
p=0.01 p=0.001 p=0.0001 p=0.00001 顯
著 位 點( 個)
表一、人口學變項分布
病例組(n=137) 對照組(n=15,785)
N % N %
性別
男性 48 35.0 7883 49.9
女性 89 65.0 7902 50.1
類風濕性關節炎 家族病史
有 14 10.2 304 1.9
無 123 89.8 15481 98.1
年齡(歲)
<30 0 0.0 0 0.0
30-40 14 10.2 3828 24.3
40-50 32 23.4 3941 25.0
50-60 35 25.5 3956 25.1
60-70 53 38.7 3910 24.8
≧70 3 2.2 150 1.0
平均值±標準差 54.12±10.64 49.67±11.35
表二、36 個顯著單核苷酸多型性位點
rs12611515 NCKAP5 2 133541575 0.5713 1.90E-05
rs349135 ARAP3 5 141066161 1.692 2.30E-05
rs78849619 TMEM192 4 166038634 1.782 2.60E-05
rs10191147 NCKAP5 2 133542545 0.5773 2.63E-05
rs75895670 LSAMP 3 117334083 2.039 2.83E-05
rs1461957 SRP9 1 225965832 1.946 2.94E-05
rs76488461 intergenic 6 156973759 1.986 3.10E-05
rs3823055 PLG 6 161138917 1.671 3.28E-05
rs10199481 NCKAP5 2 133577528 0.5852 3.62E-05
rs2378013 intergenic 1 218951464 0.5215 3.70E-05
rs4682542 ZBTB20 3 114247125 1.999 4.13E-05
rs3757017 PLG 6 161158734 0.5949 4.13E-05
rs13062127 YEATS2 3 183503634 1.909 4.46E-05
rs1582626 intergenic 2 186199224 1.66 4.98E-05
rs14224 PLG 6 161137779 1.648 4.98E-05
rs17026435 intergenic 4 150683768 1.811 5.25E-05
rs2295368 PLG 6 161139502 1.645 5.32E-05
rs1594307 PLG 6 161141184 1.652 5.36E-05
rs17638386 FSTL5 4 162596227 2.007 5.40E-05
rs6745548 intergenic 2 186187392 1.647 5.77E-05
rs9295131 PLG 6 161136294 1.64 5.84E-05
rs1465620 PLG 6 161136485 1.637 6.20E-05
rs10511370 LSAMP 3 117325977 1.989 6.47E-05
rs850908 intergenic 2 186220642 1.657 6.78E-05
rs783147 PLG 6 161137990 1.629 7.77E-05
rs783146 PLG 6 161138848 1.631 7.92E-05
rs6677132 SRP9 1 225967597 1.709 8.19E-05
rs7601203 TBC1D8 2 101727601 1.687 8.62E-05
rs80200347 intergenic 4 12677786 2.302 8.76E-05
rs10210192 OLA1 2 174924658 1.638 8.94E-05
rs2649086 intergenic 1 5782769 1.62 8.97E-05
rs61294929 intergenic 6 157038510 2.007 9.33E-05
SNP: Single Nucleotide Polymorphism; CHR: Chromosome; BP: base pair *Affx-20961401 目前無對應的基因
表三、東亞與歐洲族群信賴區間估計(36 個顯著單核苷酸多型性位點) SNP: Single Nucleotide Polymorphism
*Affx-20961401 目前無對應的基因
表四、顯著風險位點與性狀關聯
SNP Traits
rs14224 脂蛋白(Lipoprotein) rs2295368 脂蛋白(Lipoprotein) rs783147 脂蛋白(Lipoprotein)
Gene Traits
PLG 脂蛋白(Lipoprotein)、血液蛋白(Blood protein) NCKAP5 多發性硬化症(Multiple sclerosis)
LSAMP 血液蛋白(Blood protein) OLA1 血液蛋白(Blood protein)
YEATS2 C-反應蛋白(C-reactive protein, CRP)
TBC1D8 脂蛋白(Lipoprotein)、白血球計數(WBC count) SNP: Single Nucleotide Polymorphism
表五、59 個未顯著但在 GWAS Catalog 的類風濕性關節炎風險位點
SNP P value 研究樣本來源*
rs3890745 0.03 歐洲(3,393 cases, 12,460 controls; 3,929 cases, 5,807 controls) rs11900673 0.03519 日本(4,074 cases, 16,891 controls; 5,277 cases, 21,684 controls)
rs7731626 0.04598 歐洲(14,361 cases, 42,923 controls; 3,775 cases, 5,801 controls) 東亞(4,873 cases, 17,642 controls; 6,871 cases, 6,392 controls) rs840016 0.08078 歐洲(5,539 cases, 20,169 controls; 6,768 cases, 8,806 controls) rs2240335 0.09951 韓國(801 cases, 757 controls; 718 cases, 719 controls)
rs16867384 0.1306 歐洲(4,418 cases, 3,300 controls)
rs2867461 0.1429 日本(4,074 cases, 16,891 controls; 5,277 cases, 21,684 controls) rs7579944 0.1655 歐洲(4,418 cases, 3,300 controls)
rs9296015 0.1939 日本(1,247 cases, 1,486 controls; 4,168 cases, 5,003 controls) rs1875463 0.201 歐洲(13,838 cases, 33,742 controls)
rs7765379 0.2062 韓國(801 cases, 757 controls; 718 cases, 719 controls) rs10174238 0.2255 歐洲(4,595 cases, 19,704 controls)
rs660895 0.2388 歐洲(3,297 cases, 15,870 controls)
rs1854853 0.2402 漢族(952 cases, 943 controls; 2,132 cases, 2,553 controls) rs10484565 0.2875 歐洲(833 cases, 1,740 controls; 608 cases, 908 controls)
rs9784858 0.3047 歐洲(833 cases, 1,740 controls; 608 cases, 908 controls) rs9275334 0.3253 歐洲(833 cases, 1,740 controls; 608 cases, 908 controls) rs3998159 0.3396 歐洲(833 cases, 1,740 controls; 608 cases, 908 controls)
rs802791 0.3529 歐洲(4,595 cases, 19,704 controls)
rs3957146 0.3548 歐洲(833 cases, 1,740 controls; 608 cases, 908 controls) rs7454108 0.3556 歐洲(833 cases, 1,740 controls; 608 cases, 908 controls) rs4921283 0.3652 歐洲(3,911 cases, 10,398 controls)
rs9271348 0.3944 歐洲(1,148 cases, 6,008 controls; 774 cases, 1,079 controls) rs13015080 0.4009 日本(31 mild cases, 282 moderate cases, 131 severe cases)
rs3806624 0.4053 南美(916 cases, 1,392 controls) 東亞(4,873 cases, 17,641 controls) 歐洲(19,234 cases, 61,654 controls)
rs3129890 0.4262 歐洲(833 cases, 1,740 controls; 608 cases, 908 controls) rs6457620 0.4265 歐洲(3,393 cases, 12,460 controls; 3,929 cases, 5,807 controls)
rs744600 0.428 歐洲(4,595 cases, 19,704 controls) rs1571878 0.432 歐洲(9,585 cases, 33,742 controls)
rs7574865 0.4387 歐洲(5,539 cases, 20,169 controls; 6,768 cases, 8,806 controls) rs6596147 0.4438 歐洲(868 cases, 1,194 controls)
rs11937061 0.448 歐洲(1,157 cases; 526 cases)
表五、59 個未顯著但在 GWAS Catalog 的類風濕性關節炎風險位點(續)
SNP P value 研究樣本來源*
rs657075 0.4596 南美(916 cases, 1,392 controls) 東亞(4,873 cases, 17,641 controls) 歐洲(19,234 cases, 61,654 controls)
rs6457617 0.5032 歐洲(400 cases, 400 controls; 410 cases, 394 controls) rs6931277 0.5039 歐洲(833 cases, 1,740 controls; 608 cases, 908 controls) rs12525220 0.5298 漢族(952 cases, 943 controls; 2,132 cases, 2,553 controls) rs12529514 0.5341 日本(4,074 cases, 16,891 controls; 5,277 cases, 21,684 controls)
rs934734 0.5474 歐洲(5,539 cases, 20,169 controls; 6,768 cases, 8,806 controls) rs17604670 0.5702 歐洲(868 cases, 1,194 controls)
rs11571302 0.5763 歐洲(9,585 cases, 3,742 controls)
rs6568431 0.6031 歐洲(3,911 cases, 10,398 controls; 13,641 cases, 36,509 controls) rs615672 0.6035 歐洲(1,860 cases, 2,938 controls)
rs3093024 0.655 日本(2,303 cases, 3,380 controls; 4,768 cases, 17,359 controls) rs3093023 0.6666 歐洲(5,539 cases, 20,169 controls; 6,768 cases, 8,806 controls) rs231735 0.6706 歐洲(2,418 cases, 4,504 controls; 2,604 cases, 2,882 controls) rs2233424 0.684 南美(916 cases, 1,392 controls)
東亞(4,873 cases, 17,641 controls) 歐洲(19,234 cases, 61,654 controls)
rs6910071 0.7024 歐洲(5,539 cases, 20,169 controls; 6,768 cases, 8,806 controls) rs9268839 0.7596 歐洲(14,361 cases, 42,923 controls; 3,775 cases, 5,801 controls)
東亞(4,873 cases, 17,642 controls; 6,871 cases, 6,392 controls) rs3087243 0.7731 歐洲(5,539 cases, 20,169 controls; 6,768 cases, 8,806 controls) rs3731714 0.7763 歐洲(3,921 cases, 11,232 controls)
rs2561477 0.7891 南美(916 cases, 1,392 controls) 東亞(4,873 cases, 17,641 controls) 歐洲(19,234 cases, 61,654 controls)
rs9268557 0.8286 歐洲(833 cases, 1,740 controls; 608 cases, 908 controls) rs3763309 0.8424 歐洲(3,034 cases, 5,271 controls; 4,726 cases, 2,625 controls) rs10499194 0.9447 歐洲(397 cases, 1,211 controls; 875 cases, 832 controls)
rs6448119 0.9448 歐洲(1,921 cases, 1,079 controls; 887 cases, 1,218 controls) rs26232 0.9556 歐洲(5,539 cases, 20,169 controls; 6,768 cases, 8,806 controls) rs3816587 0.9575 歐洲(1,860 cases, 2,938 controls)
rs2062583 0.9664 韓國(801 cases, 757 controls; 718 cases, 719 controls)
rs13192471 0.9883 日本(2,303 cases, 3,380 controls; 4,768 cases, 17,359 controls)
*Retrieved from GWAS Catalog (https://www.ebi.ac.uk/gwas/)
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附錄一、2010 年 ACR/EULAR 聯合發表類風濕性關節炎診斷分類標準