Jaakkola E, Crane A M, Laiho K, Herzberg I, Sims A-M, Bradbury L, Calin A, Brophy S, Kauppi M, Kaarela K, Wordsworth B P, Tuomilehto J, Brown M A
Wellcome Trust Centre for Human Genetics, Oxford, UK.
Rheumatology (Oxford). 2004 Jan;43(1):32-8. doi: 10.1093/rheumatology/keg457. Epub 2003 Jul 30.
To determine whether genetic polymorphisms in or near the transforming growth factor beta1 (TGFB1) locus were associated with susceptibility to or severity of ankylosing spondylitis (AS).
Five intragenic single-nucleotide polymorphisms (SNP) and three microsatellite markers flanking the TGFB1 locus were genotyped. Seven hundred and sixty-two individuals from 184 multiplex families were genotyped for the microsatellite markers and two of the promoter SNPs. One thousand and two individuals from 212 English and 170 Finnish families with AS were genotyped for all five intragenic SNPs. A structured questionnaire was used to assess the age of symptom onset, disease duration and disease severity scores, including the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index).
A weak association was noted between the rare TGFB1 +1632 T allele and AS in the Finnish population (P = 0.04) and in the combined data set (P = 0.03). No association was noted between any other SNPs or SNP haplotype and AS, even among those families with positive non-parametric linkage scores. The TGFB1 +1632 polymorphism was also associated with a younger age of symptom onset (English population, allele 2 associated with age of onset greater by 4.2 yr, P = 0.05; combined data set, allele 2 associated with age of onset greater by 3.2 yr, P = 0.02). A haplotype of coding region SNPs (TGFB1 +869/+915+1632 alleles 2/1/2) was associated with age of symptom onset in both the English parent-case trios and the combined data set (English data set, haplotype 2/1/2 associated with age of onset greater by 4.9 yr, P = 0.03; combined data set, haplotype 2/1/2 associated with greater age of onset by 4.2 yr, P = 0.006). Weak linkage with AS susceptibility was noted and the peak LOD score was 1.3 at distance 2 cM centromeric to the TGFB1 gene. No other linkage or association was found between quantitative traits and the markers.
This study suggests that the polymorphisms within the TGFB1 gene play at most a small role in AS and that other genes encoded on chromosome 19 are involved in susceptibility to the disease.
确定转化生长因子β1（TGFB1）基因座内或其附近的基因多态性是否与强直性脊柱炎（AS）的易感性或严重程度相关。
对TGFB1基因座的5个基因内单核苷酸多态性（SNP）和3个侧翼微卫星标记进行基因分型。对来自184个多基因家族的762名个体进行微卫星标记和两个启动子SNP的基因分型。对来自212个英国家庭和170个芬兰AS家庭的1002名个体进行所有5个基因内SNP的基因分型。使用结构化问卷评估症状发作年龄、病程和疾病严重程度评分，包括巴斯强直性脊柱炎疾病活动指数（BASDAI）和巴斯强直性脊柱炎功能指数（BASFI）。
在芬兰人群（P = 0.04）和合并数据集中（P = 0.03），罕见的TGFB1 +1632 T等位基因与AS之间存在弱关联。在任何其他SNP或SNP单倍型与AS之间未发现关联，即使在那些非参数连锁评分呈阳性的家族中也是如此。TGFB1 +1632多态性还与症状发作年龄较小有关（英国家庭，等位基因2与发作年龄大4.2岁相关，P = 0.05；合并数据集，等位基因2与发作年龄大3.2岁相关，P = 0.02）。编码区SNP的单倍型（TGFB1 +869/+915+1632等位基因2/1/2）在英国家庭父母-病例三联体和合并数据集中均与症状发作年龄有关（英国家庭数据集，单倍型2/1/2与发作年龄大4.9岁相关，P = 0.03；合并数据集，单倍型2/1/2与发作年龄大4.2岁相关，P = 0.006）。观察到与AS易感性的弱连锁，在距TGFB1基因着丝粒2 cM处的峰值LOD评分为1.3。在数量性状与标记之间未发现其他连锁或关联。
本研究表明，TGFB1基因内的多态性在AS中至多起很小的作用，并且19号染色体上编码的其他基因参与了该疾病的易感性。
