Gallagher Carla J, Keene Keith L, Mychaleckyj Josyf C, Langefeld Carl D, Hirschhorn Joel N, Henderson Brian E, Gordon Candace J, Freedman Barry I, Rich Stephen S, Bowden Donald W, Sale Michèle M
Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
Diabetes. 2007 Mar;56(3):675-84. doi: 10.2337/db06-0303.
The estrogen receptor-alpha gene (ESR1) was selected as a positional candidate under a type 2 diabetes linkage peak at 6q24-27. A total of 42 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 380 African-American type 2 diabetic case subjects with end-stage renal disease (ESRD) and 276 African-American control subjects. A total of 22 ancestry informative markers were also genotyped, and the program Admixmap was used to adjust allelic and haplotypic association tests for individual estimates of admixture. The most significant association with type 2 diabetes-ESRD was with rs1033182 in intron 2 (P = 0.013, admixture-adjusted P(a) = 0.021). Genotyping 17 SNPs across a region of ESR1 intron 1-intron 2 in an expanded population of 851 case and 635 control subjects supported association with rs1033182 (P = 0.004, P(a) = 0.027) and with an independent six-SNP haplotype of high linkage disequilibrium spanning 6.4 kb (P < 0.0001, P(a) < 0.0001). The same 17 ESR1 SNPs were genotyped in 300 European-American type 2 diabetes-ESRD case subjects and 310 European-American control subjects. Two intron 2 SNPs, rs2431260 (P = 0.015) and rs1709183 (P = 0.019), and a four-SNP haplotype containing these SNPs (P = 0.033) were associated with type 2 diabetes and/or ESRD. Results suggest that intron 1 and intron 2 of the ESR1 gene may contain functionally important regions related to type 2 diabetes or ESRD risk.
雌激素受体α基因（ESR1）被选为位于6q24 - 27的2型糖尿病连锁峰下的位置候选基因。在380例患有终末期肾病（ESRD）的非裔美国2型糖尿病病例受试者和276例非裔美国对照受试者中，对总共42个ESR1单核苷酸多态性（SNP）进行了基因分型。还对总共22个祖先信息标记进行了基因分型，并使用Admixmap程序针对个体混合估计调整等位基因和单倍型关联测试。与2型糖尿病 - ESRD最显著的关联是与内含子2中的rs1033182（P = 0.013，混合调整后P(a) = 0.021）。在851例病例和635例对照受试者的扩大群体中，对ESR1内含子1 - 内含子2区域的17个SNP进行基因分型，支持了与rs1033182的关联（P = 0.004，P(a) = 0.027）以及与一个跨越6.4 kb的高连锁不平衡的独立六SNP单倍型的关联（P < 0.0001，P(a) < 0.0001）。在300例欧美2型糖尿病 - ESRD病例受试者和310例欧美对照受试者中对相同的17个ESR1 SNP进行了基因分型。两个内含子2 SNP，rs2431260（P = 0.015）和rs1709183（P = 0.019），以及包含这些SNP的一个四SNP单倍型（P = 0.033）与2型糖尿病和/或ESRD相关。结果表明，ESR1基因的内含子1和内含子2可能包含与2型糖尿病或ESRD风险相关的功能重要区域。
