1.The Association Study Of Polymorphisms In The PAX4 Gene With Type 1 Diabetes In Chinese Han Population 2.The Effect Of Molecular Genetics On The Association Of Low Birth Weight And Impaired Glucose Metabolism

BackgroundsType 1 diabetes(T1D) can be viewed as the result of an imbalance between autoimmune p cell destruction and p cell regeneration.So alterations in genes invovled in the autoimmune destruction or islet cell development and regeneration should play a role in the pathology of T1D.Pax4(the paired box 4),a member of the Pax family of homeodomain transcription factors,is essential to the differentiation and function ofβcells.Recently,Biasom-Lauber reported a dominant effect of a non-synonymous single nucleotide polymorphism(SNP) in PAX4(rs712701) on the T1D susceptibility in both Swiss and German populations,in which C allele was associated with susceptibility. However,this effect has not been found in studies by Hermann and Maier.In present study,we aimed to evaluate whether the paired box gene 4(PAX4) may play a role in the pathogenesis of type 1 diabetes(T1D) in Chinese Han population.MethodsOne hundred and thirty-four cases with T1D and 324 non-diabetic control subjects were selected randomly from Han Chinese.Three single nucleotide polymorphisms (SNPs) rs712701,rs2233580,rs2233575 were genotyped by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and analyzed their association with T1D.All statistical analyses were performed using the SPSS statistical package,version 11.5. A P value of less than 0.05 was considered statistically significant.Results1.Genotype distributions for all the SNPs studied were found to be consistent with HWE in non-diabetic controls.No difference was found in genotype or allele frequencies between patients and non-diabetic controls in all three SNPs.2.There were four common haplotypes with a frequency of at least 3%:A-G-A, G-G-A,G-G-C和G-A-A.All the haplotypes had similar frequencies in non-diabetic control subjects and T1D patients. 3.The association between genotypes and phenotypes in non-diabetic control subjects were analyzed.In SNP rs2233575,we found that the carriers with AA and GA genotypes had lower plasma insulin level than the subjects with GG genotype(5.7 vs 7.0μmol/L, P=0.048)ConclusionsThe present study identified that the PAX4 gene was not associated with the risk of T1D in a Han Chinese sample,suggesting that it may not influence T1D risk in this population.SNP rs2233575 in the promoter region of the PAX4 gene might be associated with fasting insulin level.This is the first study on the PAX4 gene in a Chinese population. BackgroundsNumerous epidemiological studies demonstrated a strong association between low birth weight and the later development of the impaired glucose metabolism.According to the fetal insulin hypothesis,low birth weight and type 2 diabetes(T2D) shared the same insulin-resistant genotype.Common polygenic genetic factors that increase insulin resistance would produce two phenotypes-a small,thin baby in utero and an adult with insulin resistance and increased risk of impaired glucose metabolism.The present study was to study the effect of diabetes-susceptibility genes on the association of low birth weight and impaired glucose metabolism(IGM).This would be the first genetic study of birth weight in Chinese.MethodsOne thousand,one hundred and eighty one subjects born in Peking Union Medical College Hospital from 1921 to 1954 were recruited.Four diabetes-susceptibility genes, TCF7L2(transcription factor 7 like 2),SLC30A8(solute carrier family 30,member 8), KCNQ1(potassium voltage-gated channel,KQT-like subfamily,member 1) and PANK4 (pantothenate kinase 4) were selected as candidates genes.Genotyping of the variants was performed using Taqman allelic discrimination assay.All statistical analyses were performed using the SPSS statistical package,version 11.5. A P value of less than 0.05 was considered statistically significant.Results1.Multiple variable logistic regression analyses with adjustment for age,sex and BMI, SNPrs2074196TT(P＝0.016,OR＝0.628,95%CI 0.430-0.917),rs2234895AA(P＝0.007,OR＝0.706,95%CI 0.549-0.907),rs290487 CT(P＝0.022,OR＝0.752, 95%CI 0.590-0.960) and rs7535528 AA(P＝0.007,OR＝0.574,95%CI 0.384-0.858) genotypes appeared protective effect on IGM.SNP rs2074196 in gene KCNQ1 was associated fasting insulin and HOMA-IS,carriers with GG genotype had significant lower fasting insulin(FINS) and HOMA-IS than those with TT and TG genotypes;SNP rs290487 in gene TCF7L2 was associated with HOMA-IR,the carriers with CT genotype had significant lowerHOMA-IR levels than those with other genotypes(P=0.046).2.SNP rs2074196 in gene KCNQ1 was associated with birth weight after adjustment for sex,gestational weeks,parity and maternal age,the per-risk allele effect size estimate of the association was 40g.3.Stratified by birth weight,the associations between IGM and SNPs rs290487 in gene TCF7L2,rs2074196,rs2237895 in gene KCNQ1,and rs7535528 in gene PANK4 were only found in subject whose birth weight larger than(or equal to) 3000g;the association between impaired glucose metabolism and SNP rs2466293 in gene SLC30A8 and rs11196218 in gene TCF7L2 were found to be associated with IGM in those whose birth weight smaller than 3000g.And in subject whose birth weight larger than(or equal to) 3000g,subjects with CC genotype in rs290487 had higher HOMA-IR than subjects with CT and TT;subjects with GG in rs2074196 had lower HOMA-IS than GT and TT.Conclusions1.Impaired glucose metabolism were associated with SNPs rs290487 in gene TCF7L2, rs7535528 in gene PANK4,and rs2074196,rs2237895 in gene KCNQ1;no association was found with SNPs rs11196218 in gene TCF7L2,rs1980789 in gene PANK4,and rs13266634,rs2466293 in gene SLC30A8.2.The was the first study about the role of genes in birth weight in Chinese.SNP rs2074196 in gene KCNQ1 was associated with birth weight after adjustment for sex, gestational weeks,parity and maternal age,the per-risk allele effect size estimate of the association was 40g.3.There were interactions between the effects of genes and birth weighton on impaired glucose metabolism.