新加坡华人全基因组关联研究中已知2型糖尿病易感基因座的联合效应：新加坡华人健康研究
Joint effects of known type 2 diabetes susceptibility loci in genome-wide association study of Singapore Chinese: the Singapore Chinese health study.
作者信息
Chen Zhanghua, Pereira Mark A, Seielstad Mark, Koh Woon-Puay, Tai E Shyong, Teo Yik-Ying, Liu Jianjun, Hsu Chris, Wang Renwei, Odegaard Andrew O, Thyagarajan Bharat, Koratkar Revati, Yuan Jian-Min, Gross Myron D, Stram Daniel O
机构信息
Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
出版信息
PLoS One. 2014 Feb 10;9(2):e87762. doi: 10.1371/journal.pone.0087762. eCollection 2014.
BACKGROUND
Genome-wide association studies (GWAS) have identified genetic factors in type 2 diabetes (T2D), mostly among individuals of European ancestry. We tested whether previously identified T2D-associated single nucleotide polymorphisms (SNPs) replicate and whether SNPs in regions near known T2D SNPs were associated with T2D within the Singapore Chinese Health Study.
METHODS
2338 cases and 2339 T2D controls from the Singapore Chinese Health Study were genotyped for 507,509 SNPs. Imputation extended the genotyped SNPs to 7,514,461 with high estimated certainty (r(2)>0.8). Replication of known index SNP associations in T2D was attempted. Risk scores were computed as the sum of index risk alleles. SNPs in regions ± 100 kb around each index were tested for associations with T2D in conditional fine-mapping analysis.
RESULTS
Of 69 index SNPs, 20 were genotyped directly and genotypes at 35 others were well imputed. Among the 55 SNPs with data, disease associations were replicated (at p<0.05) for 15 SNPs, while 32 more were directionally consistent with previous reports. Risk score was a significant predictor with a 2.03 fold higher risk CI (1.69-2.44) of T2D comparing the highest to lowest quintile of risk allele burden (p = 5.72 × 10(-14)). Two improved SNPs around index rs10923931 and 5 new candidate SNPs around indices rs10965250 and rs1111875 passed simple Bonferroni corrections for significance in conditional analysis. Nonetheless, only a small fraction (2.3% on the disease liability scale) of T2D burden in Singapore is explained by these SNPs.
CONCLUSIONS
While diabetes risk in Singapore Chinese involves genetic variants, most disease risk remains unexplained. Further genetic work is ongoing in the Singapore Chinese population to identify unique common variants not already seen in earlier studies. However rapid increases in T2D risk have occurred in recent decades in this population, indicating that dynamic environmental influences and possibly gene by environment interactions complicate the genetic architecture of this disease.
背景
全基因组关联研究（GWAS）已在2型糖尿病（T2D）中鉴定出遗传因素，大多是在欧洲血统个体中。我们在新加坡华人健康研究中测试了先前鉴定的与T2D相关的单核苷酸多态性（SNP）是否能重复出现，以及已知T2D SNP附近区域的SNP是否与T2D相关。
方法
对来自新加坡华人健康研究的2338例病例和2339例T2D对照进行了507,509个SNP的基因分型。通过推算将基因分型的SNP扩展到7,514,461个，估计确定性较高（r²>0.8）。尝试重复已知索引SNP与T2D的关联。风险评分计算为索引风险等位基因的总和。在条件精细定位分析中，测试每个索引周围±100 kb区域内的SNP与T2D的关联。
结果
在69个索引SNP中，20个直接进行了基因分型，另外35个的基因型推算效果良好。在有数据的55个SNP中，15个SNP的疾病关联得到了重复（p<0.05），另外32个在方向上与先前报告一致。风险评分是一个显著的预测指标，将风险等位基因负担的最高五分位数与最低五分位数相比，T2D风险的风险比为2.03倍，置信区间为1.69 - 2.44（p = 5.72×10⁻¹⁴）。索引rs10923931周围的2个改良SNP以及索引rs10965250和rs1111875周围的5个新候选SNP在条件分析中通过了简单的Bonferroni校正，具有显著性。尽管如此，这些SNP仅解释了新加坡T2D负担的一小部分（疾病易感性量表上为2.3%）。
结论
虽然新加坡华人的糖尿病风险涉及遗传变异，但大多数疾病风险仍无法解释。新加坡华人人群正在进行进一步的遗传研究，以鉴定早期研究中未发现的独特常见变异。然而，近几十年来该人群的T2D风险迅速增加，这表明动态环境影响以及可能的基因与环境相互作用使这种疾病的遗传结构变得复杂。
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