弗雷明汉心脏研究中与糖尿病相关性状的全基因组关联研究。
Genome-wide association with diabetes-related traits in the Framingham Heart Study.
作者信息
Meigs James B, Manning Alisa K, Fox Caroline S, Florez Jose C, Liu Chunyu, Cupples L Adrienne, Dupuis Josée
机构信息
General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
出版信息
BMC Med Genet. 2007 Sep 19;8 Suppl 1(Suppl 1):S16. doi: 10.1186/1471-2350-8-S1-S16.
BACKGROUND
Susceptibility to type 2 diabetes may be conferred by genetic variants having modest effects on risk. Genome-wide fixed marker arrays offer a novel approach to detect these variants.
METHODS
We used the Affymetrix 100K SNP array in 1,087 Framingham Offspring Study family members to examine genetic associations with three diabetes-related quantitative glucose traits (fasting plasma glucose (FPG), hemoglobin A1c, 28-yr time-averaged FPG (tFPG)), three insulin traits (fasting insulin, HOMA-insulin resistance, and 0-120 min insulin sensitivity index); and with risk for diabetes. We used additive generalized estimating equations (GEE) and family-based association test (FBAT) models to test associations of SNP genotypes with sex-age-age2-adjusted residual trait values, and Cox survival models to test incident diabetes.
RESULTS
We found 415 SNPs associated (at p < 0.001) with at least one of the six quantitative traits in GEE, 242 in FBAT (18 overlapped with GEE for 639 non-overlapping SNPs), and 128 associated with incident diabetes (31 overlapped with the 639) giving 736 non-overlapping SNPs. Of these 736 SNPs, 439 were within 60 kb of a known gene. Additionally, 53 SNPs (of which 42 had r2 < 0.80 with each other) had p < 0.01 for incident diabetes AND (all 3 glucose traits OR all 3 insulin traits, OR 2 glucose traits and 2 insulin traits); of these, 36 overlapped with the 736 other SNPs. Of 100K SNPs, one (rs7100927) was in moderate LD (r2 = 0.50) with TCF7L2 (rs7903146), and was associated with risk of diabetes (Cox p-value 0.007, additive hazard ratio for diabetes = 1.56) and with tFPG (GEE p-value 0.03). There were no common (MAF > 1%) 100K SNPs in LD (r2 > 0.05) with ABCC8 A1369S (rs757110), KCNJ11 E23K (rs5219), or SNPs in CAPN10 or HNFa. PPARG P12A (rs1801282) was not significantly associated with diabetes or related traits.
CONCLUSION
Framingham 100K SNP data is a resource for association tests of known and novel genes with diabetes and related traits posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. Framingham 100K data replicate the TCF7L2 association with diabetes.
背景
2型糖尿病易感性可能由对风险有适度影响的基因变异所致。全基因组固定标记阵列提供了一种检测这些变异的新方法。
方法
我们在1087名弗雷明汉后代研究家庭成员中使用了Affymetrix 100K SNP阵列，以研究与三种糖尿病相关的定量血糖性状（空腹血糖（FPG）、糖化血红蛋白A1c、28年时间平均FPG（tFPG））、三种胰岛素性状（空腹胰岛素、HOMA胰岛素抵抗和0 - 120分钟胰岛素敏感性指数）以及糖尿病风险的遗传关联。我们使用加性广义估计方程（GEE）和基于家系的关联检验（FBAT）模型来检验SNP基因型与性别 - 年龄 - 年龄²调整后的残差性状值之间的关联，并使用Cox生存模型来检验糖尿病发病情况。
结果
我们发现415个SNP在GEE中与六个定量性状中的至少一个相关（p < 0.001），在FBAT中有242个（18个与GEE重叠，共639个非重叠SNP），128个与糖尿病发病相关（31个与639个重叠），得出736个非重叠SNP。在这736个SNP中，439个位于已知基因距离60 kb范围内。此外，53个SNP（其中42个相互之间r² < 0.80）对于糖尿病发病以及（所有3个血糖性状或所有3个胰岛素性状，或2个血糖性状和2个胰岛素性状）的p < 0.01；其中，36个与其他736个SNP重叠。在100K SNP中，一个（rs7100927）与TCF7L2（rs7903146）处于中度连锁不平衡（r² = 0.50），并与糖尿病风险相关（Cox p值0.007，糖尿病的加性风险比 = 1.56）以及与tFPG相关（GEE p值0.03）。没有常见的（MAF > 1%）100K SNP与ABCC8 A1369S（rs757110）、KCNJ11 E23K（rs5219）处于连锁不平衡（r² > 0.05），也没有与钙蛋白酶10或肝细胞核因子α中的SNP处于连锁不平衡。PPARG P12A（rs1801282）与糖尿病或相关性状无显著关联。
结论
弗雷明汉100K SNP数据是用于已知和新基因与糖尿病及相关性状关联测试的资源，可在http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007网站查询。弗雷明汉100K数据重复了TCF7L2与糖尿病的关联。
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