Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas 78245, USA.
Am J Hum Biol. 2011 Jan-Feb;23(1):118-25. doi: 10.1002/ajhb.21114.
To identify genetic variation influencing serum bilirubin levels in American Indians, we performed genome-wide screening and association analyses in the Strong Heart Family Study. Bilirubin is an endogenous antioxidant that has demonstrated an inverse relationship with cardiovascular disease. Genetic variation within the promoter region of uridine diphosphate glucuronosyltransferase (UGT1A1) on chromosome 2q has been associated with elevated serum bilirubin levels in European populations. However, no study has investigated the UGT1A1 promoter in American Indians.
Statistical analyses were carried out with 3,484 participants aged 14 to 93 years recruited from three geographic areas in the United States; Arizona, Oklahoma, and North and South Dakota.
Variance components linkage analysis detected a quantitative trait locus (QTL) for bilirubin on chromosome 2q in the combined centers (LOD = 6.61, P = 4.24 × 10⁻⁶) and in Oklahoma (LOD = 5.65, P = 4.57 24 × 10⁻⁵). Genetic association of the UGT1A1 promoter polymorphism was significant for all geographic locations. After adjustment using conditional linkage for UGT1A1 promoter variance, the linkage signal dropped to 1.10 in the combined sample and to 3.32 (P = 0.02) in Oklahoma, indicating this polymorphism is not completely responsible for the linkage signal in American Indians. We also detected suggestive linkage signals in the Dakotas on chromosome 10p12 (LOD = 2.18) and in the combined centers (LOD = 2.24) on chromosome 10q21.
Replication of a serum bilirubin QTL on chromosome 2q in American Indians implicates UGT1A1 but further genotyping is warranted to identify additional causative polymorphisms. Evidence also supports a potential novel locus for bilirubin on chromosome 10.
为了鉴定影响美洲印第安人血清胆红素水平的遗传变异，我们在美国印第安人强心脏家族研究中进行了全基因组筛查和关联分析。胆红素是一种内源性抗氧化剂，与心血管疾病呈负相关。在欧洲人群中，位于 2 号染色体上的尿苷二磷酸葡萄糖醛酸基转移酶（UGT1A1）启动子区域内的遗传变异与血清胆红素水平升高有关。然而，尚无研究调查过美洲印第安人UGT1A1 启动子。
对来自美国三个地理区域（亚利桑那州、俄克拉荷马州以及北达科他州和南达科他州）的 3484 名 14 至 93 岁的参与者进行了统计分析。
方差成分连锁分析在联合中心（LOD = 6.61，P = 4.24 × 10⁻⁶）和俄克拉荷马州（LOD = 5.65，P = 4.57 × 10⁻⁵）检测到胆红素的 2 号染色体 q 区的数量性状基因座（QTL）。UGT1A1 启动子多态性的遗传关联在所有地理位置上均具有统计学意义。在使用 UGT1A1 启动子方差条件性连锁进行调整后，联合样本中的连锁信号降至 1.10，在俄克拉荷马州降至 3.32（P = 0.02），表明该多态性并非完全负责美洲印第安人中的连锁信号。我们还在达科他州的 10p12 染色体（LOD = 2.18）和联合中心的 10q21 染色体（LOD = 2.24）上检测到了提示性连锁信号。
在美洲印第安人中复制 2 号染色体上的血清胆红素 QTL 提示 UGT1A1 参与其中，但进一步的基因分型是必要的，以鉴定其他致病多态性。证据还支持胆红素在 10 号染色体上的潜在新基因座。
