Hugot Jean-Pierre, Zaccaria Isabelle, Cavanaugh Juleen, Yang Huiying, Vermeire Séverine, Lappalainen Maarit, Schreiber Stefan, Annese Vito, Jewell Derek P, Fowler Elizabeth V, Brant Steven R, Silverberg Mark S, Cho Judy, Rioux John D, Satsangi Jack, Parkes Miles
INSERM Avenir U763; AP-HP; Université Paris 7, Hôpital Robert Debré, Paris, France.
Am J Gastroenterol. 2007 Jun;102(6):1259-67. doi: 10.1111/j.1572-0241.2007.01149.x. Epub 2007 Feb 23.
Crohn's disease (CD) has been associated with CARD15/NOD2 mutations in Caucasians. The R702W, G908R, and 1007fs mutations represent 82% of the mutated chromosomes. The relative risk of developing CD in homozygous or compound heterozygous people has been estimated as between 10 and 40 times that of the general population. This high risk may support the opinion that CARD15/NOD2 variants are strong CD risk factors at the individual and population levels.
The allele and genotype frequencies were calculated for the R702W, G908R, and 1007fs mutations in 3,575 Caucasian healthy controls recruited by 15 groups distributed on three continents. Geographic homogeneity was tested and the observed proportion of double mutants was compared with the expected value using chi2 tests.
The allele frequencies of the R702W, G908R, and 1007fs mutations were 4.3% (3.6-4.9), 1.2% (0.8-1.6), and 2.3% (1.8-2.8), respectively, with large geographic fluctuations of the G908R, 1007fs, and wild-type alleles (P<0.0001). At the population level, no simple relationship was observed between mutation frequencies and the disease incidences in the studied populations. At the individual level, no significant deficit of double-dose mutation carriers among healthy controls was found, providing strong evidence that the penetrances of the most at-risk genotypes are low.
Altogether, these data confirm that CARD15/NOD2 acts in interaction with other unknown risk cofactors.
在白种人中，克罗恩病（CD）与CARD15/NOD2突变有关。R702W、G908R和1007fs突变占突变染色体的82%。据估计，纯合子或复合杂合子人群患CD的相对风险是普通人群的10至40倍。这种高风险可能支持以下观点，即CARD15/NOD2变体在个体和人群水平上是CD的强风险因素。
计算了分布在三大洲的15个研究组招募的3575名白种健康对照者中R702W、G908R和1007fs突变的等位基因和基因型频率。检验了地理同质性，并使用卡方检验将观察到的双突变体比例与预期值进行比较。
R702W、G908R和1007fs突变的等位基因频率分别为4.3%（3.6 - 4.9）、1.2%（0.8 - 1.6）和2.3%（1.8 - 2.8），G908R、1007fs和野生型等位基因存在较大的地理波动（P<0.0001）。在人群水平上，未观察到突变频率与所研究人群中疾病发病率之间的简单关系。在个体水平上，未发现健康对照者中双剂量突变携带者有明显不足，这有力地证明了风险最高的基因型的外显率较低。
总之，这些数据证实CARD15/NOD2与其他未知的风险辅助因子相互作用。
