與乳糜瀉風險有關的13個新變化
作者：Jacquelyn K. Beals, PhD
出處：WebMD醫學新聞
March 1, 2010 — 英國和荷蘭研究者進行的一個國際研究發現，有13種新變化與乳糜瀉風險有基因組顯著關聯，另外也發現13種被認為與疾病風險有關的變化。
與之前的乳糜瀉基因組關聯研究(GWASs)一致，確認了位於IL2–IL21的風險區域，追蹤發現了在HLA-DQA1和HLA-DQB1的因果變化，新發現的變化多數位於靠近免疫功能的基因。
乳糜瀉是一種自體免疫異常，特徵是小腸慢性發炎，因為曝露於大麥和裸麥所含有的麩質(一種麥類蛋白質)與類似蛋白質所引起。此疾病也稱為口炎性腹瀉（Celiac Sprue）、麩質腸病變(gluten enteropathy)、麩質耐受性不佳（gluten-intolerance），症狀可能包括慢性腹瀉、疲勞且無法茁壯，慢性發炎引起小腸內的手指狀絨毛萎縮，減少了營養吸收的表面積，乳糜瀉唯一有效的治療方式是無麩質飲食。
日前線上發表於Nature Genetics期刊的新版GWAS，描述了5個歐洲集團的乳糜瀉病患(n = 4533人)與對照組(n = 10,750人)的資料，在未涉及HLA區域、417個P GWAS < 10-4的單一核苷酸多型性(SNPs)中，選定進行複製的SNPs區域包括了之前已知的18個區域，以及113個新的區域，選定的SNPs與它們的P值包括：
* 來自14個之前已知的乳糜瀉風險位置的18個SNPs
* 來自7個新確認、PGWAS < 5 × 10-7區域的13個SNPs
* 來自新確認、5 × 10-7 < PGWAS < 5 × 10-5區域的86個SNPs
* 來自新確認、5 × 10-5 < PGWAS < 10-4區域的14個SNPs
在7個獨立世代、4,918名乳糜瀉病患與5,684名對照組進行追蹤，將範圍減少到14個之前報告過的SNPs，13個P 合併 < 5 × 10-8的新區域，以及P GWAS、P追蹤、或 P合併等值接近但未落入GWAS臨界值的13個「可能」區域，以探討顯著關聯。
這些變化強調的路徑包括胸腺中的T-細胞發展；病毒RNA的免疫偵測；T-細胞與B-細胞同時刺激或同時抑制；以及細胞激素、趨化素和它們的受體。
作者們指出，我們之前顯示，乳糜瀉風險區域和第一型糖尿病之間有不可忽視的重疊，乳糜瀉風險區域和類風濕性關節炎之間也是，新發現提供了實質的證據認為，有些風險區域與一種以上的慢性免疫相關疾病有關，研究者搜尋文獻以及人類基因圖流行病學資料庫之後發現，與乳糜瀉風險有關的27個SNPs中，有18個的基因組與一個以上的其他免疫相關發炎疾病有關。
我們特別有興趣的是，祖先為中國人者的全身性紅斑狼瘡(SLE)與ETS1基因變化有關聯，但是和歐洲人的SLE卻無關聯，不過，與歐洲人乳糜瀉最有關聯的SNP(如同目前的研究)只有70 kb來自與中國人最有關聯的SLE的SNP，這個變化和其他變化意味著，同一基因內性質不同的一般變化，可以視為造成不同種族的不同自體免疫疾病。
目前的研究不只檢視疾病風險關聯，也分析了血液樣本(n = 1469人)以確認靠近乳糜瀉風險變化位置的基因表現，檢測的38個位置中，有20個乳糜瀉風險變化與同一染色體的基因表現有關(P < .0028)，此資料表示，有些風險變化可能會透過改變基因表現之機轉影響乳糜瀉敏感性。
需注意，與乳糜瀉風險有關的變化超過半數與附近的基因表現改變有關，研究者建議，需要後續研究以明確確認每個會引起乳糜瀉的位置與它們的功能機轉。
Nat Genet. 線上發表於2010年2月28日。
13 New Variants Associated With Celiac Disease Risk
By Jacquelyn K. Beals, PhD
Medscape Medical News
March 1, 2010 — Thirteen new variants having genomewide significant association with risk for celiac disease were found in an international study headed by British and Dutch researchers. An additional 13 variants having suggestive association with disease risk were also found.
Consistent with previous genomewide association studies (GWASs) of celiac disease, which identified a risk locus in IL2–IL21, and follow-ups that found causal variants in HLA-DQA1 and HLA-DQB1, most of the newly discovered variants lie near genes with immune functions.
Celiac disease is an autoimmune disorder characterized by chronic inflammation of the small intestine resulting from exposure to gluten (a wheat protein) and similar proteins in barley and rye. Symptoms of the disease — also called celiac sprue, gluten enteropathy, or gluten intolerance — may include chronic diarrhea, fatigue, and failure to thrive. The chronic inflammation causes atrophy of the finger-like villi that line the small intestine, decreasing the surface area for nutrient absorption. The only treatment effective for celiac disease is a gluten-free diet.
The new GWAS, published online yesterday in Nature Genetics, drew on data from 5 European collections of patients with celiac disease (n = 4533) and control patients (n = 10,750). Of 417 single nucleotide polymorphisms (SNPs) with P GWAS < 10?4 that did not involve HLA sites, the SNPs chosen for replication included 18 that were previously known and 113 that were newly identified. The selected SNPs and their P values included:
18 SNPs from 14 previously known risk loci for celiac disease
13 from 7 newly identified regions having PGWAS < 5 × 10?7
86 from newly identified regions for which 5 × 10?7 < PGWAS < 5 × 10?5
14 from newly identified regions for which 5 × 10?5 < PGWAS < 10?4
Follow-up was carried out in 7 independent cohorts with 4918 patients with celiac disease and 5684 control individuals. This reduced the field to the 14 previously reported SNPs, 13 new loci with P combined < 5 × 10?8, and 13 "suggestive" loci with P GWAS, P follow-up, or P combined values that approached (but did not fall within) GWAS threshold for significant association.
The pathways highlighted by the variants involve T-cell development in the thymus; immune detection of viral RNA; T- and B-cell costimulation or coinhibition; and cytokines, chemokines, and their receptors.
"We previously showed that there is considerable overlap between risk loci for celiac disease and type 1 diabetes, as well as between risk loci for celiac disease and rheumatoid arthritis," note the authors. The new findings provide "substantial evidence" that some risk loci are associated with more than one of the chronic immune-mediated diseases. Searching the literature and the Human Genome Epidemiology database, the investigators found that 18 of the 27 SNPs associated with risk for celiac disease at the genomewide level are associated with 1 or more other immune-mediated or inflammatory diseases.
Of particular interest was that genetic variation in ETS1 has an association with systemic lupus erythematosus (SLE) in people of Chinese origin but is not implicated in SLE in Europeans. However, the SNP most strongly associated with celiac disease in European populations (as in the present study) lies only 70 kb from the SNP most strongly associated with SLE in Chinese populations. This and other observations suggest that "distinct common variants within the same gene can predispose to different autoimmune diseases across different ethnic groups."
The present study not only examined disease risk associations but also analyzed blood samples (n = 1469) to determine expression of genes near loci with celiac risk variants. In 20 of the 38 loci tested, celiac risk variants correlated with expression of the gene on the same chromosome (P < .0028). The data "indicate that some risk variants might influence celiac disease susceptibility through a mechanism of altered gene expression."
Noting that more than half the variants associated with celiac disease risk correlate with changes in the expression of nearby genes, the investigators recommend that "[f]urther research is needed to definitively determine at each locus both the variants that can cause celiac disease and their functional mechanisms."
Nat Genet. Published online February 28, 2010.
