Nosikov V V
State Research Center, GosNIIgenetika, Moscow, 117545 Russia.
Mol Biol (Mosk). 2004 Jan-Feb;38(1):150-64.
In ethnic Russians, MHC (HLA) was shown to be the major locus determining the predisposition to type 1 diabetes mellitus (T1DM). To map the regions linked to T1DM, families with concordant or discordant sib pairs were selected from the Russian population of Moscow. With these families, linkage to T1DM was demonstrated for CTLA4 (IDDM12, 2q32.1-q33), which codes for a T-cell surface antigen, and PDCD2 (IDDM8, 6q25-q27), which is homologous to the mouse programmed cell death activator gene. With polymorphic microsatellites, regions 3q21-q25 (IDDM9) and 10p12.2 (IDDM10) were also linked to T1DM. Case/control and family studies of the polymorphic markers from region 11p13 revealed a new T1DM-associated locus in the vicinity of the catalase gene (CAT); linkage to this locus was not reported earlier for other populations. Diabetic polyneuropathy (DPN) proved to be associated with single-nucleotide polymorphisms Ala(-9)Val (SOD2), Arg213Gly (SOD3), and T(-262)C (CAT) and with a polymorphic microsatellite of the NOS2 promoter. Hence oxidative stress, which results from hyperglycemia, increased mitochondrial production of superoxide radicals, and insufficient activities of antioxidative enzymes, was assumed to play an important part in DPN development in T1DM. Diabetic nephropathy (DN) showed no association with the antioxidative enzyme genes. However, the association was observed for the insertion/deletion (I/D) polymorphism of ACE and the ecNOS34a/4b polymorphism of NOS3, two genes involved in controlling vascular tonicity, and for the I/D polymorphism of APOB and the epsilon 2/epsilon 3/epsilon 4 polymorphism of APOE, two genes involved in lipid transport. In addition, polymorphic microsatellites of chromosome 3q21-q25 proved to be closely associated with DN. The tightest association was established for D3S1550, carriers of allele 12 or genotype 12/14 having high risk of DN (OR = 4.85 and 6.25, respectively). Region 3q21-q25 was assumed to contain a major gene determining DN development, while the other DN-associated genes mostly affect the progression of DN.
在俄罗斯族中，主要组织相容性复合体（MHC，即人类白细胞抗原，HLA）被证明是决定1型糖尿病（T1DM）易感性的主要基因座。为了绘制与T1DM相关的区域，从莫斯科的俄罗斯人群中选取了同胞对患T1DM情况一致或不一致的家庭。利用这些家庭，证实了细胞毒性T淋巴细胞相关抗原4（CTLA4，位于IDDM12，2q32.1 - q33，编码一种T细胞表面抗原）以及程序性细胞死亡蛋白2（PDCD2，位于IDDM8，6q25 - q27，与小鼠程序性细胞死亡激活基因同源）与T1DM存在连锁关系。通过多态性微卫星，还发现3q21 - q25区域（IDDM9）和10p12.2区域（IDDM10）与T1DM有关联。对11p13区域多态性标记的病例/对照研究和家系研究揭示了过氧化氢酶基因（CAT）附近一个新的T1DM相关基因座；此前在其他人群中未报道过该基因座与T1DM的连锁关系。糖尿病性多发性神经病变（DPN）被证明与单核苷酸多态性丙氨酸（-9）缬氨酸（SOD2）、精氨酸213甘氨酸（SOD3）和胸腺嘧啶（-262）胞嘧啶（CAT）以及一氧化氮合酶2（NOS2）启动子的一个多态性微卫星有关。因此，由高血糖导致的氧化应激、线粒体超氧阴离子自由基产生增加以及抗氧化酶活性不足，被认为在T1DM患者DPN的发生中起重要作用。糖尿病肾病（DN）与抗氧化酶基因无关联。然而，观察到与血管紧张性控制相关的两个基因，即血管紧张素转换酶（ACE）的插入/缺失（I/D）多态性和一氧化氮合酶3（NOS3）的内皮型一氧化氮合酶34a/4b多态性有关联，以及与脂质转运相关的两个基因，即载脂蛋白B（APOB）的I/D多态性和载脂蛋白E（APOE）的ε2/ε3/ε4多态性有关联。此外，3q21 - q25染色体的多态性微卫星被证明与DN密切相关。其中D3S1550的关联最为紧密，等位基因12的携带者或基因型12/14的个体患DN的风险较高（优势比分别为4.85和6.25）。假定3q21 - q25区域包含一个决定DN发生的主要基因，而其他与DN相关的基因大多影响DN的进展。
