Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas Austin College of Natural Sciences, Austin, Texas 78723, USA.
Am J Med Genet A. 2012 May;158A(5):1124-34. doi: 10.1002/ajmg.a.35313. Epub 2012 Apr 11.
We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ≤ 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring.
我们评估了四个叶酸介导的一碳代谢途径基因（MTHFD1、SHMT1、MTHFR 和 DHFR）中的 35 个变体，作为圆锥动脉干缺陷的风险因素。排除了诊断为单基因疾病或染色体非整倍体的病例。对照是根据其对活产婴儿总数的贡献，从区域医院中随机选择的。对于每个基因型（纯合变体或杂合子，与纯合野生型相比）和每个较少见等位基因的增加（对数相加模型），计算了比值比（OR）和 95%置信区间（CI）。还在对数相加模型下评估了每个变体与三种叶酸摄入变量（母亲多维维生素使用、母亲膳食叶酸摄入和综合母亲叶酸摄入）之间的相互作用。一般来说，我们没有发现明显的关联。MTHFD1 rs11627387 的 A 等位基因与西班牙裔母亲（OR=1.7，95%CI=1.1-2.5）和西班牙裔婴儿（OR=1.7，95%CI=1.2-2.3）的圆锥动脉干缺陷风险增加 1.7 倍有关。MTHFR rs1801133 的 T 等位基因与膳食叶酸摄入量≤第 25 百分位数的西班牙裔女性的风险增加 2.8 倍有关。MTHFR rs1801131 的 C 等位基因与膳食叶酸摄入量>第 25 百分位数的女性的风险增加两倍（OR=2.0，95%CI=1.0-3.9）有关。我们的研究表明，MTHFD1 rs11627387 可能通过西班牙裔人群中母亲和后代基因型的影响与圆锥动脉干缺陷的风险相关。MTHFR 基因的母体功能变体可能与膳食叶酸摄入相互作用，并改变后代的圆锥动脉干缺陷风险。
