Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Diabetologia. 2012 Nov;55(11):2970-84. doi: 10.1007/s00125-012-2656-4. Epub 2012 Aug 16.
AIMS/HYPOTHESIS: Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs.
We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (F(st)s) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within ± 250 kb around each EuA SNP in AfAs.
Allele frequency differences ranged from 0.6% to 54%. F(st) exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were <2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p = 5.8 × 10(-8); MTNR1B, p = 8.5 × 10(-9); and FADS1, p = 2.2 × 10(-4)) or FI (GCKR, p = 5.9 × 10(-4)). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r(2) <0.2), suggesting allelic heterogeneity for association with FG at these loci.
CONCLUSIONS/INTERPRETATION: Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping.
目的/假设：高血糖在非裔美国人（AfA）中不成比例地发生。我们在来自候选基因关联资源的五个队列中的 5984 名非糖尿病 AfA 中检验了与欧洲血统（EuA）人群中鉴定的血糖特征相关的 18 个单核苷酸多态性（SNP）的可转移性。
我们对 AfA 中的 SNP 与空腹血糖（FG）或胰岛素（FI）的关联进行了荟萃分析。我们：（1）计算等位基因频率差异、连锁不平衡（LD）的变化、固定指数（F（st））和整合单倍型评分（iHS）；（2）在 AfA 中检验 EuA SNP；（3）在 AfA 中每个 EuA SNP 周围±250 kb 处进行探测。
等位基因频率差异范围从 0.6%到 54%。在 6/16 个位点上，F（st）超过 0.15，表明种群分化程度中等。所有 iHSs 均小于 2，表明没有近期的正向选择。对于 18 个 SNP，当比较 EuA 与 AfA 时，所有方向的效应均相同，关联的 95%置信区间重叠。在 18 个基因座中，有 17 个基因座的至少一个 SNP 与 AfA 中的 FG 呈名义相关。有 4 个基因座与 FG（GCK，p=5.8×10(-8)；MTNR1B，p=8.5×10(-9)；和 FADS1，p=2.2×10(-4)）或 FI（GCKR，p=5.9×10(-4)）显著相关。在 GCK 和 MTNR1B 中，EuA 和 AfA 的 SNP 代表了相同的信号，而在 FADS1 和 GCKR 中，EuA 和最佳 AfA 的 SNP 相关性较弱（r(2)<0.2），表明这些基因座与 FG 相关的等位基因异质性。
结论/解释：很少有血糖 SNP 显示出从 EuA 到 AfA 的严格可转移性证据。在考虑到不同祖先群体的 LD 变化后，在 AfA 中以及在与 EuA 相关的 SNP 中，有 4 个基因座与 FG 显著相关，出现了新的信号，有助于精细映射。
