糖耐量减低患者维生素D、维生素D受体基因FokI多态性与胰岛素抵抗的相关性研究

目的 探讨IGT者25羟基维生素D3（25-OH-VD3）、维生素D受体（VDR）基因FokI多态性与IR的相关性。 方法 选取IGT者（IGT组）94例及正常对照（NC）组54名,采用PCR-RLFP检测VDR基因FokI多态性,ELISA检测25-OH-VD3,比较各组基因型及等位基因频率。 结果 ⑴与NC组比较,IGT组血清25-OH-VD3较低[（22.05±2.37） vs （32.04± 2.64） ng/ml,P〈0.05];⑵与NC比较,IGT组“f”等位基因频率升高（46.8% vs 25.9%,FF：30.9% vs 57.4%;Ff： 46.9% vs 33.3%;ff：22.3% vs 9.3%,P〈0.05）。与FF基因型比较,Ff/ff基因型患IGT危险增加（OR=2.613,95%CI=1.239～5.512,P=0.018;OR=4.490,95%CI=1.496～13.473,P=0.010）。与F型比较,携带“f”等位基因患IGT风险增加（OR=2.465,95%CI=1.188～5.116,P=0.023）。Ff、ff基因型与FF型比较,HOMA-IR增高（P〈0.05）;VDR基因FokI位点ff基因型者较其它两种基因型IR更明显（P〈0.01）;⑶Logistic回归分析显示,VDR基因FokI ff与IR呈正相关（OR=1.761,95%CI：1.050～2.970,P〈0.05）,25-OH-VD3与IR呈负相关（β=-1.187,OR=0.461,95%CI：0.187～0.741,P〈0.05）。 结论 血清25-OH-VD3水平与IR呈负相关,VDR基因FokI可能与IGT者IR有关。     

初治肺结核患者维生素D与其受体基因多态性位点FokI的相关性分析

目的分析初治肺结核患者血清维生素D(VD)与维生素D受体(VDR)基因多态性位点Fok I的相关性。方法对我院随机选取的180位初治肺结核患者和100位正常对照的血清VD水平,VDR基因多态性位点Fok I基因型进行检测,比较和分析2组血清VD水平与VDR基因Fok I多态性差异以及相关性。结果初治肺结核患者血清VD水平明显低于正常对照组(P0.0001);初治肺结核组VD营养缺乏率(70.5%)明显高于正常对照组(47.0%),VDR基因多态性位点Fok I的三种基因型(纯合子FF,纯合子ff和杂合子Ff)在两组内的分布差异具有统计学意义(P=0.033),初治肺结核组纯合子ff及等位基因f比率明显高于正常对照组(P0.05);初治肺结核患者基因型ff组VD水平明显低于基因型FF组和基因型Ff组(P0.05)。结论初治肺结核患者血清VD水平明显下降,VDR基因多态性位点Fok I基因型ff为肺结核易感基因。     

维生素D受体基因多态性与新疆维吾尔族人群结核病易感性的相关性研究

目的研究维生素D受体(VDR)基因多态性与新疆维吾尔族人群结核病易感性的相关性。方法采用病例对照研究,选取224例新疆维吾尔族结核患者和225例有分枝杆菌感染史的同民族健康者分别作为病例组和对照组。用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)分析方法分别检测维生素D受体基因的多态性,内切酶分别为FokI和TaqI,并进行基因分型。统计学分析结果采用χ2检验,P值为0.05。结果FokI分析,分为FF、Ff、ff三种基因型,其在病例组和对照组中分别为36%、57%、7%和40%、54%、6%。FF基因型的分布在病例组与对照组中的差异性无统计学意义(χ2=0.872,P>0.05)。TaqI分析,分为TT、Tt、tt三种基因型,其在病例组和对照组中分别为68.8%、29.4%、1.8%和75.6%、22.2%、2.2%。TT基因型在病例组与对照组中的差异性也无统计学意义(χ2=2.588,P>0.05)。结论维生素D受体基因中FokI与TaqI多态性与新疆维吾尔族人群结核病易感性无明显相关性。     

内蒙古地区老年女性维生素D受体基因Fok1多态性与骨质疏松的关系

目的 探讨维生素D受体(VDR)基因Fok1多态性与内蒙古地区汉族老年女性骨质疏松(OP)的关系.方法 应用聚合酶链反应-限制性片段长度多态性技术(PCR-RFLP),对70例对照者和32例OP患者的VDR基因Fok1多态性进行分析,并分别计算两组人群Fok1基因型和等位基因的分布频率.结果 对照组人群Fok1多态性FF、Ff、ff基因型的分布频率分别为38.57%、50%、11.43%.OP组分别为21.88%、43.75%、34.37%.两组人群基因型的分布频率差异有显著性(χ2=8.211,P<0.05).结论 老年女性VDR基因Fok1多态性与OP相关.     

新疆哈萨克族人群结核病易感基因的病例对照研究

目的研究自然抗性相关巨噬细胞蛋白1(NRAMPl)基因3′端非编码区(3′UTR)和维生素D受体(VDR)基因FokI、TaqI位点多态性与新疆哈萨克族人群结核病易感性的关联;分析NRAMPl基因和VDR基因交互作用对新疆哈萨克族人群结核病易感性的影响。方法采用病例对照研究方法,选取新疆哈萨克族活动性肺结核病患者213例,同地区同种族健康者211例。用聚合酶链反应 限制性片断长度多态性(PCR RFLP)分析方法对NRAMP1基因3′UTR、VDR基因FokI和TaqI多态性位点基因分型,采用χ2检验分析3个位点多态性与新疆哈萨克族结核病易感性的关系,相乘模型分析NRAMPl基因和VDR基因交互作用。结果1. NRAMPl基因3′UTR位点在病例组和对照组中TGTG/TGTG、TGTG/del和TGTGdel/del基因型频率分别为64.8%、29.6%、5.6%和79.1%、19.5%、1.4%。TGTGdel等位基因组间分布差异有统计学意义(χ2=13.737,P<0.01)。2. VDR基因FokI位点在病例组和在对照组中FF、Ff和ff基因型频率分别为33.8%、45.1%、21.1%和47.9%、41.7%、10.4%。f等位基因频率组间分布差异有统计学意义(χ2=13.868,P<0.01);TaqI位点TT、Tt和tt基因型组间分布差异无统计学意义;等位基因T和t组间分布差异无统计学意义(χ2=1.267,P>0.05);D'=0.477,r2=0.01,两位点不存在连锁不平衡。3. NRAMP1基因和VDR基因存在正交互作用,ORint=1.62。结论1. TGTG/del和TGTGdel/del基因型、TGTG缺失等位基因可能是新疆哈萨克族人群结核病易感基因。2. VDR基因中FokI多态性与新疆哈萨克族结核病易感性有关联,等位基因f可能是新疆哈萨克族结核病易感基因。3. NRAMP1和VDR基因间交互作用可能增加新疆哈萨克族人群结核病的发病风险。     

维生素D受体基因多态性与酒精性肝病的相关性

目的: 探讨维生素D受体(vitamin D receptor,VDR)基因多态性与酒精性肝病易感性之间的关系.方法: 采用半巢式聚合酶链式反应-限制性片段长度多态性(semi-nested PCR-RFLP)技术检测50例酒精性肝病患者和72例健康志愿者VDR多态性的基因型, 并比较甘肃汉族人群和酒精性肝病患者之间VDR基因多态性、基因型频率、等位基因频率的差异与酒精性肝病相关性的分析.结果: 共检出3种VDR基因型, 即BB、Bb、b b. 病例组b b基因型频率显著高于对照组(χ2 = 7.16, P = 0.028, OR = 2.698, 95% CI:1.167-6.235); b等位基因的频率病例组显著高于对照组(χ2 = 11.64, P = 0.001, OR = 3.071,95% CI: 1.583-3.958). 通过多因素非条件Logistic回归模型, 发现携带bb基因型的个体暴露于酒精后容易发展成酒精性肝病, bb基因型可能是酒精性肝病发生的一种易患因素( OR = 2.272, OR 95% CI: 0.971-5.318).结论: 维生素D受体基因BsmⅠ酶切位点基因型与酒精性肝病之间存在相关性, bb基因型可能是酒精性肝病发生的一种易患基因.     

维生素D受体基因多态性与汉族儿童氟斑牙易感性的关系研究

目的 观察维生素D受体(VDR)基因多态性在汉族儿童中的分布情况,探讨VDR基因多态性与汉族儿童氟斑牙易感性的关系.方法 2008年10月至2009年3月,Dean法检查安徽省凤台县关店乡8～12岁儿童氟斑牙患病情况,选择氟斑牙儿童101例及对照儿童102例,采集外周静脉血提取DNA,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法测定两组儿童VDR Apa I、Bsm I、Fok I和Taq I的基因型,观察汉族儿童VDR各基因型分布情况,并分析两组间基因型分布的差异.结果 汉族儿童中存在VDR基因多态性.且基因型的分布以Aa、bb、Ff、TT居多,分别占51.7%(105/203)、89.7%(182/203)、52.7%(107/203)、93.1%(189/203);aa、Bb、FF、Tt次之,分别占39.9%(81/203)、7.9%(16/203)、31.5%(64/203)、6.9%(14/203);AA、BB、ff、tt最少,分别占8.4%(17/203)、2.4%(5/203)、15.8%(32/203)、0(0/203).VDR Apa I基因型分布频率为:氟斑牙患者AA占7.9%(8/101),Aa占55.4%(56/101),aa占36.7%(37/101);对照组AA占8.8%(9/102),Aa占48.0%(49/102),aa占43.3%(44/102);两组基因型分布比较,差异无统计学意义(χ2=1.13,P>0.05).VDR Bsm I基因型分布频率为:氟斑牙患者BB占3.0%(3/101),Bb占5.9%(6/101),bb占91.1%(92/101);对照组BB占2.0%(2/102),Bb占9.8%(10/102),bb占88.2%(90/102);两组基因型分布比较,差异无统计学意义(χ2=0.55,P>0.05).VDR Fok I基因型分布频率为:氟斑牙患者FF占28.7%(29/101),Ff占56.4%(57/101),ff占14.9%(15/101);对照组FF占34.3%(35/102),Ff占49.0%(50/102),ff占16.7%(17/102);两组基因型分布比较,差异无统计学意义(χ2=1.14,P>0.05).VDR Taq I基因型分布频率为:氟斑牙患者TT占93.1%(94/101),Tt占6.9%(7/101);对照组Tr占93.1%(95/102),Tt占6.9%(7/102);未发现tt型;两组基因型分布比较,差异无统计学意义(χ2=0.00,P>0.05).结论 汉族儿童中存在VDR基因多态性,但VDR Apa I、Bsm I、Fok I和Taq I 4个酶切位点的多态性与所调查儿童氟斑牙发生无明显关系.     

上海地区汉族人群维生素D受体基因多态性与1型糖尿病的相关性研究

目的 探讨上海地区汉族人群维生素D受体(VDR)基因多态性与1型糖尿病(T1DM)的关系. 方法 采用病例对照研究方法,运用PCR-RFLP方法测定80例T1DM患者(T1DM组)与80位正常对照者(NC组)的VDR-FoKΙ位点基因型. 结果 与NC组相比,T1DM组FF基因型频率(48.75%)、F等位基因频率(71.25%)明显增加;GAD65抗体阳性的T1DM组FF基因型频率(56%)、F等位基因频率(75%)也明显增加(P均<0.05). 结论 VDR-FoKΙ可能是上海地区汉族人群T1DM的易感基因,VDR-FoKΙ位点基因多态性也可能与GAD65抗体阳性的T1DM相关.     

HLA-G基因14bp插入/缺失多态性与系统性红斑狼疮的相关性

目的检测系统性红斑狼疮（systemic lupus erythematosus,SLE）患者人白细胞抗原G（human leukocyte antigen G,HLA-G）14bp插入/缺失多态性的基因型分布,明确其多态性与SLE易感性的关系。方法采用聚合酶链反应（polymerase chain reaction,PCR）检测231例SLE患者及367名健康体检者的HLA-G14bp插入/缺失多态性的基因型分布,并分析不同基因型SLE患者的临床特征。结果SLE患者及健康体检者的HLA-G14bp插入/缺失多态性基因型和等位基因分布处于Hardy-Weinberg平衡（SLE组：χ2=1.383,P=0.501;健康体检组：χ2=0.095,P=0.953）。该多态性等位基因及基因型频率在SLE组和健康体检组间分布无统计学差异（P均〉0.05）。进一步分析HLA-G14bp多态性与SLE患者的临床特征发现,不同HLA-G14-bp基因型SLE患者之间临床症状、疾病活动性积分（systemic lupus erythematosus disease activity index,SLEDAI）亦均无统计学差异（P均〉0.05）;但抗Histone抗体阳性SLE患者-14bp/-14bp基因型频率、抗U1-snRNP抗体阳性SLE患者＋14bp/-14bp基因型频率均明显增高（P值分别为0.002及0.036）。结论HLA-G14bp插入/缺失多态性与SLE易感性无关,但可能参与SLE自身抗体（抗Histone抗体及抗U1-snRNP抗体）的生成。     

维生素D受体Bsm I基因多态性及VDR mRNA表达与系统性红斑狼疮的相关性

目的检测维生素D受体（VDR）Bsm I基因多态性与系统性红斑狼疮（SLE）的相关性,以及对SLE患者VDR mRNA表达的影响。方法应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析技术检测VDR Bsm I多态性位点和基因型在242例系统性红斑狼疮患者和162例健康对照组中的分布情况,并分析与SLE发病的相关性及对SLE患者临床的影响。同时应用实时定量聚合酶链反应（RT-PCR）技术检测VDR mRNA在48例SLE患者和38例健康对照组的表达。结果 VDR Bsm I多态性等位基因B和b频率在SLE组和健康对照组差异无统计学意义（P=0.166）,但B等位基因阳性的SLE患者（BB基因型和Bb基因型患者）肾脏损害的发生率较B等位基因阴性SLE患者明显升高（bb基因型患者,P=0.044）。VDR mRNA在48例SLE患者表达下调,其⊿Ct值（⊿Ct值越大,表达量越小）为9.26±2.37,高于健康对照组的7.82±3.05（P=0.026）。而在SLE患者,B等位基因阳性患者的VDR mRNA的⊿Ct值为9.53±0.53,明显高于B等位基因阴性患者的7.77±4.30（t=2.502,P=0.016）。结论 VDR Bsm I基因多态性与SLE发病易感性无关,但B等位基因阳性患者更容易发生肾脏损害,此可能与B等位基因下调SLE患者的VDR mRNA表达有关。     

Vitamin D receptor gene start codon polymorphism (FokI) and bone mineral density in healthy male subjects

OBJECTIVE: The genetic factors determining peak bone mineral density (BMD) in men are not well characterized. Recent studies have investigated the relationship between the start codon polymorphism (SCP) of the vitamin D receptor (VDR) gene and BMD in different populations. We have now examined the relationship between SCP of the VDR gene and BMD in a group of healthy Caucasian men from the north-east of England. SUBJECTS: Ninety-six healthy men (median age 50, range 40.0-77.0 years). MEASUREMENTS: Analysis of the FokI genotypes of SCP of the VDR and measurements of BMD at the femoral neck and lumbar spine were performed. RESULTS: FF, Ff and ff VDR FokI genotypes were found to have the highest, intermediate and the lowest lumbar spine BMD, respectively (Mean +/- SD, for FF 1.07 +/- 0.14, Ff 1.05 +/- 0.16 and ff 0.95 +/- 0.10 g/cm2). There was a significant difference in spine BMD between FF and ff genotypes (P < 0.05, analysis of variance [ANOVA]), but no such difference was apparent between Ff and ff (P > 0.05, ANOVA). Interestingly, there was no association between FokI polymorphism and femoral neck BMD (Mean +/- SD, for FF 0.85 +/- 0.12, Ff 0.87 +/- 0.15 and ff 0.83 +/- 0.15 g/cm2). The distribution of FokI VDR genotypes approached Hardy-Weinberg equilibrium and was similar to that reported for women from different ethnic groups, as the prevalence of FF and ff genotypes was 44% and 16%, respectively. CONCLUSION: The study shows that in this population of healthy men there is a weak association between lumbar spine bone mineral density and FokI restriction fragment length polymorphism at the translation initiation site of the vitamin D receptor gene.     

Association between vitamin D receptor FokI. Polymorphism and serum parathyroid hormone level in patients with chronic renal failure

We investigated the relationship between vitamin D receptor (VDR) start codon polymorphism and serum levels of PTH, calcidiol, and calcium in 64 Spanish patients with chronic renal failure (CRF). An exon 2 fragment of the VDR gene was amplified by PCR, and cleaved with the restriction enzyme FokI. The alleles were identified according to the digestion pattern obtained as F (absence of restriction site) and f (presence of restriction site). Genotype frequencies in the patient population were 54.7% FF, 28.1% Ff and 17.2% ff, vs 46.7% FF, 43.3% Ff and 10% ff in a healthy control population. The difference between the two populations was statistically significant (p<0.01). Within the patient population, mean serum PTH level in the FF group was significantly higher (159.77+/-25.69 pg/ml) than in both the Ff and ff groups (106.67+/-19.07 and 77.55+/-15.85 pg/ml, respectively; p<0.05). However there were no significant differences in serum levels of calcidiol or calcium among genotypes. These results suggest that FokI polymorphisms of the VDR gene may determine parathyroid response in CRF patients.     

Vitamin D receptor genotype is associated with fat-free mass and sarcopenia in elderly men

We investigated the association of vitamin D receptor (VDR) genotype with fat-free mass (FFM) in a cohort of 302 older (aged 58-93 years) Caucasian men who underwent body composition analysis by dual-energy X-ray absorptiometry, and completed questionnaires addressing comorbidities, physical activity, and dietary intake. All participants were genotyped for a VDR translation start site (FokI) polymorphism [FF (37.7%), Ff (48.4%), and ff (13.9%)] and the previously studied BsmI polymorphism [BB (24.9%), Bb (37.7%), and bb (37.4%)]. The BsmI polymorphism was not associated with FFM in any analysis; however, the FokI polymorphism was significantly associated with total FFM, appendicular FFM, and relative (kg/m(2)) appendicular FFM (all p <.05), with the FF group demonstrating significantly lower FFM than the Ff and ff groups (e.g., total FFM: FF = 57.6 +/- 0.4, Ff = 59.4 +/- 0.4, ff = 59.4 +/- 0.7 kg; p <.02). Age-adjusted logistic regression revealed a 2.17-fold higher risk for sarcopenia (defined previously as appendicular FFM <7.26 kg/m(2)) in FF homozygotes (95% CI [confidence interval] = 1.19-3.85; p =.03) compared to men with one or more f alleles. The VDR translation start site (FokI) polymorphism is significantly associated with FFM and sarcopenia in this cohort of older Caucasian men.     

VDR起始密码子区突变与北方汉族人群乳腺癌易感性的关系研究

目的探讨维生素D受体（VDR）起始密码子区FokⅠ突变与中国北方汉族人群乳腺癌发病的相关性。方法提取81例乳腺癌患者及78例健康对照者外周血基因组DNA（gDNA）,应用聚合酶链反应—限制性片段长度多态性检测并分析DNA FokⅠ多态性在两组中的分布。结果健康对照组FokⅠ多态位点FF、Ff、ff基因型频率,等位基因F、f分布频率分别为33.33%、56.41%、10.26%、61.5%、38.5%;病例组分别为19.75%、59.26%、20.99%、49.4%、50.6%,组间比较均有统计学差异（P均〈0.05）。Ff、ff基因型人群乳腺癌患病风险的OR值分别为1.30和1.84（P均〈0.01）。结论 VDR等位基因f有可能成为乳腺癌的遗传标志基因。     

Vitamin D receptor FokI,TaqI, and ApaI polymorphisms and susceptibility to systemic lupus erythematosus: an updated meta-analysis

This study aimed to explore whether vitamin D receptor (VDR) polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE). Meta-analyses were conducted to determine the associations between the VDR FokI, TaqI, and ApaI polymorphisms and SLE in all subjects and each ethnic group. A total of 12 studies were considered in the meta-analysis, which involved 1974 patients and 2506 controls. Meta-analysis of the VDR FokI polymorphism showed no association between SLE and the FokI F allele in all study subjects (OR?=?1.047, 95% CI?=?0.781–1.403, p?=?0.758). However, the meta-analysis showed a significant association between SLE and the VDR FokI F allele in the Arab population (OR?=?1.721, 95% CI?=?1.417–2.088, p?<?0.001). Analysis using the recessive and dominant models and homozygote contrast showed the same pattern for the VDR FokI F allele in Europeans, Asians, and Arabs. This meta-analysis showed that polymorphisms in VDR FokI, TaqI, and ApaI are not associated with SLE susceptibility in overall, European and Asian populations. However, the VDR FokI polymorphism is associated with SLE susceptibility in the Arab population.     

Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves' disease.

Recent studies have shown that related genetic influences on bone mineral density (BMD) and bone turnover are related to allelic variations in the vitamin D receptor (VDR) gene. Osteoporosis as a complication of hyperthyroidism is characterized by increased rates of both bone formation and bone resorption. In addition, VDR gene polymorphism influences susceptibility to some autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) and multiple sclerosis (MS). In the gene encoding the VDR, we investigated the distribution of a VDR-FokI polymorphism that changes the predicted protein sequence. The subjects were 131 female Japanese patients with Graves' disease and 150 female controls. The distribution of genotype frequencies differs between Graves' disease and controls (chi2 = 5.99, degrees of freedom = 2, p = 0.0386). We found overexpression of F allele (69% vs. 61%, p = 0.0472) and homozygote FF (48% vs. 33%, p = 0.0118) in Graves' disease patients compared with controls. We also correlated a VDR-FokI polymorphism with BMD in the distal radius and biochemical markers of bone turnover in patients with Graves' disease in remission. Although generally, no significant association was seen between age-adjusted BMD and genotype, patients in remission for fewer than 5 years showed significantly lower age-adjusted BMD in Ff heterozygotes than in ff homozygotes (z = 1.14 ff vs. z = -0.43 Ff, p < 0.05). Moreover, serum concentrations of bone alkaline phosphatase were significantly greater in Ff homozygotes than in FF homozygotes (78 +/- 12 vs. 59 +/- 10, p < 0.05). The genotypes did not differ in serum concentrations of osteocalcin, urinary hydroxyproline, or urinary deoxypyridinoline. Our results indicate, for the first time, an association between Graves' disease and a VDR polymorphism in the Japanese and suggest that a VDR-FokI polymorphism may affect bone mineral metabolism and can predict risk of osteoporosis as a complication of Graves' disease in patients in remission.     

Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves' disease.

Recent studies have shown that related genetic influences on bone mineral density (BMD) and bone turnover are related to allelic variations in the vitamin D receptor (VDR) gene. Osteoporosis as a complication of hyperthyroidism is characterized by increased rates of both bone formation and bone resorption. In addition, VDR gene polymorphism influences susceptibility to some autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) and multiple sclerosis (MS). In the gene encoding the VDR, we investigated the distribution of a VDR-FokI polymorphism that changes the predicted protein sequence. The subjects were 131 female Japanese patients with Graves' disease and 150 female controls. The distribution of genotype frequencies differs between Graves' disease and controls (chi2 = 5.99, degrees of freedom = 2, p = 0.0386). We found overexpression of F allele (69% vs. 61%, p = 0.0472) and homozygote FF (48% vs. 33%, p = 0.0118) in Graves' disease patients compared with controls. We also correlated a VDR-FokI polymorphism with BMD in the distal radius and biochemical markers of bone turnover in patients with Graves' disease in remission. Although generally no significant association was seen between age-adjusted BMD and genotype, patients in remission for >5 years showed significantly lower age-adjusted BMD in Ff heterozygotes than in ff homozygotes (Z = 1.14 ff vs. Z = -0.43 Ff, p < 0.05). Moreover, serum concentrations of bone alkaline phosphatase were significantly greater in Ff homozygotes than in FF homozygotes (78 +/- 12 vs. 59 +/- 10, p < 0.05). The genotypes did not differ in serum concentrations of osteocalcin, urinary hydroxyproline, or urinary deoxypyridinoline. Our results indicate, for the first time, an association between Graves' disease and a VDR polymorphism in the Japanese and suggest that a VDR-FokI polymorphism may affect bone mineral metabolism and can predict risk of osteoporosis as a complication of Graves' disease in patients in remission.