The insulin/insulin-like growth factor (IGF) system and related pathways such as growth hormone, and leptin signaling have a key role in cancer development. It is unclear how germline variation in these pathways affects breast cancer risk. We conducted gene-based analyses of 184 genes in the insulin/IGF, growth hormone, and leptin pathways to identify genetic variation associated with risk of breast cancer overall, and for estrogen receptor (ER) subtypes. Tag single-nucleotide polymorphisms (SNPs) for each gene were selected and genotyped on a customized Illumina SNP array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 91,627 SNPs genotyped or imputed in 3,663 breast cancer cases, (1,983 ER-positive and 1,098 ER-negative) and 4,687 controls from the African American Breast Cancer Epidemiology and Risk consortium, a collaborative project of four large studies of breast cancer in African-American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multiethnic Cohort). We used a multi-locus adaptive joint test to determine the association of each gene with overall breast cancer and ER subtypes. The most significant gene associations (P ≤ 0.01) were BAIAP2 and CALM2 for overall breast cancer; BAIAP2 and CSNK2A1 for ER+ breast cancer; and BRAF, BAD, and MAPK3 for ER- breast cancer. The association of BAD with ER- breast cancer was explained by a two-SNP risk model; all other associations were best explained by one-SNP risk models. In total, six genes and seven SNPs had suggestive associations with overall breast cancer or ER subtypes in African-American women.

中文翻译：

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非洲裔美国女性中与乳腺癌相关的胰岛素，类胰岛素生长因子，生长激素和瘦素途径的遗传变异：AMBER联盟。

胰岛素/胰岛素样生长因子（IGF）系统和相关途径（例如生长激素和瘦素信号传导）在癌症发展中具有关键作用。目前尚不清楚这些途径中的种系变异如何影响乳腺癌风险。我们对胰岛素/ IGF，生长激素和瘦素途径中的184个基因进行了基于基因的分析，以确定与总体风险和雌激素受体（ER）亚型相关的遗传变异。选择每个基因的标签单核苷酸多态性（SNP），并在定制的Illumina SNP阵列上进行基因分型。使用1000个基因组单倍型进行插补。分析包括3,663例乳腺癌病例（1,983 ER阳性和1,098 ER阴性）中91,627个SNP的基因分型或估算，以及来自非裔美国人乳腺癌流行病学和风险协会的4,687例对照，这是一项针对非裔美国女性进行的四项大型乳腺癌研究的合作项目（Carolina乳腺癌研究，黑人女性健康研究，Women's Circle of Health研究和多种族队列研究）。我们使用多位点适应性联合测试来确定每个基因与整体乳腺癌和ER亚型的关联。对于整个乳腺癌，最显着的基因关联（P≤0.01）是BAIAP2和CALM2。BAIAP2和CSNK2A1用于ER +乳腺癌；以及BRAF，BAD和MAPK3用于ER-乳腺癌。BAD与ER-乳腺癌的相关性通过两个SNP风险模型进行了解释。所有其他关联都可以通过单SNP风险模型得到最好的解释。总共有六个基因和七个SNP与非裔美国女性的总体乳腺癌或ER亚型相关。