2型糖尿病易感基因SNP位点对生活方式干预降低血糖应答效果的修饰效应

doi:10.16288/j.yczz.19-304

遗传 ›› 2020, Vol. 42 ›› Issue (5): 483-492.doi: 10.16288/j.yczz.19-304

2型糖尿病易感基因SNP位点对生活方式干预降低血糖应答效果的修饰效应

王玉琢¹, 张一鸣², 董晓莲², 王学才², 朱建福², 王娜¹, 江峰¹, 陈跃³, 姜庆五¹, 付朝伟¹()

^1. 复旦大学公共卫生学院流行病学教研室,公共卫生安全教育部重点实验室,国家卫生健康委员会卫生技术评估重点实验室(复旦大学),上海 200032
^2. 浙江省德清县疾病预防控制中心,德清县 313200
^3. 加拿大渥太华大学医学院,渥太华 K1N6N5;

收稿日期:2019-12-05 修回日期:2020-02-26 出版日期:2020-05-20 发布日期:2020-03-01
通讯作者: 付朝伟 E-mail:fcw@fudan.edu.cn
作者简介:王玉琢,在读硕士研究生,专业方向：遗传流行病学、慢性病流行病学。E-mail: wyzsally0323@163.com
基金资助:
国家自然科学基金项目编号(81473038);上海市公共卫生重点学科建设计划项目编号(15GWZX0801);上海市公共卫生高端海外研修计划项目资助编号(GWTD2015S04)

Modification effects of T2DM-susceptible SNPs on the reduction of blood glucose in response to lifestyle interventions

Yuzhuo Wang¹, Yiming Zhang², Xiaolian Dong², Xuecai Wang², Jianfu Zhu², Na Wang¹, Feng Jiang¹, Yue Chen³, Qingwu Jiang¹, Chaowei Fu¹()

^1. Department of Epidemiology, School of Public Health, Key Laboratory of Public Health Safety of Ministry of Education, Key Laboratory of Health Technology Assessment, National Health Commission, Fudan University, Shanghai 200032, China
^2. Deqing County Center for Disease Prevention and Control, Deqing County 313200, China
^3. Faculty of Medicine, University of Ottawa, Ottawa K1N6N5, Canada

Received:2019-12-05 Revised:2020-02-26 Online:2020-05-20 Published:2020-03-01
Contact: Fu Chaowei E-mail:fcw@fudan.edu.cn
Supported by:
Supported by the National Natural Science Foundation of China No(81473038);Shanghai Leading Academic Discipline Project of Public Health No(15GWZX0801);Shanghai 3-Year Public Health Action Plan No(GWTD2015S04)

摘要/Abstract

摘要：

近年来的研究发现,一些2型糖尿病(type 2 diabetes mellitus, T2DM)易感基因位点不仅与T2DM的发病风险有关,还会影响生活方式干预效果。为进一步探究T2DM易感基因单核苷酸多态性(single nucleotide polymorphism, SNP)位点对生活方式干预降低高危人群血糖应答效果的修饰作用,本课题组在德清农村社区开展了生活方式干预试验(2017年6月~12月,对干预组的研究对象进行强化生活方式干预,对照组仅接受常规健康知识宣教),并对研究对象进行SNP基因分型。研究发现,对于rs9502570,干预组中的CC+CT基因型人群的空腹血糖降低值显著高于TT基因型(P=0.031);干预组中CC+CT基因型人群的糖化血红蛋白值降低值为0.03%,TT基因型人群的糖化血红蛋白值升高了0.27% (P=0.012);CC+CT和TT基因型干预组和对照组的空腹血糖和糖化血红蛋白前后差值差之间也有统计学差异(均为P<0.001)。对于rs10811661,干预组中TT基因型人群的空腹血糖降低值显著高于CC+CT基因型(P=0.021);TT和CC+CT基因型干预组和对照组的空腹血糖前后差值差之间亦有统计学差异(P<0.001)。上述研究结果表明,rs9502570、rs10811661两个位点会在一定程度上修饰高危人群对T2DM生活方式干预降低血糖的应答效果,为今后进一步研制糖尿病高危人群个体化干预措施提供了客观依据。

关键词: 2型糖尿病, 生活方式干预, 高危人群, 单核苷酸多态性

Abstract:

In recent years, it has been demonstrated that some susceptible gene loci of type 2 diabetes mellitus (T2DM) are not only associated with the susceptibility risk of T2DM, but also the modifying effects of lifestyle interventions. To further explore the modifying effects of the single nucleotide polymorphism (SNP) on the onset of T2DM and the reduction of blood glucose in response to lifestyle interventions among the high-risk population, we performed a lifestyle intervention study in two Deqing rural communities during the period from June to December in 2017. The intensive lifestyle interventions were conducted among the study subjects of the intervention group while those in the control group only received conventional and general health education. All participants were genotyped by the MassARRY system. This study showed that for SNP rs9502570, fasting blood glucose showed a significantly greater reduction for individuals with CC + CT genotype than those with TT genotype (P=0.031). In the intervention group, the glycated hemoglobin A1C (HbA1C) decreased by 0.03% for those with CC+CT genotype, while HbA1C increased by 0.27% for those with TT genotype (P=0.012). The difference in the reduction of fasting blood glucose and HbA1c between the intervention and control groups was also statistically significant between individuals with TT and those with CC+CT genotype. For SNP rs10811661, the reduction of fasting blood glucose was significantly higher in people with TT genotype than those with CC + CT genotype (0.44 mmol/L vs 0.12 mmol/L, P=0.021). The difference in reduction of fasting blood glucose between the intervention group and control group was also statistically significant between TT and CC+CT genotype (P<0.001). In summary, the SNP genotypes of both rs9502570 and rs10811661 could modify the effects of lifestyle interventions on reducing fasting blood glucose and HbA1C among the high risk rural population for T2DM. The present study has provided supporting evidence for future development of individualized intervention measures for high-risk population of T2DM.

Key words: type 2 diabetes mellitus, lifestyle intervention, high-risk population, single nucleotide polymorphism

王玉琢, 张一鸣, 董晓莲, 王学才, 朱建福, 王娜, 江峰, 陈跃, 姜庆五, 付朝伟. 2型糖尿病易感基因SNP位点对生活方式干预降低血糖应答效果的修饰效应[J]. 遗传, 2020, 42(5): 483-492.

Yuzhuo Wang, Yiming Zhang, Xiaolian Dong, Xuecai Wang, Jianfu Zhu, Na Wang, Feng Jiang, Yue Chen, Qingwu Jiang, Chaowei Fu. Modification effects of T2DM-susceptible SNPs on the reduction of blood glucose in response to lifestyle interventions[J]. Hereditas(Beijing), 2020, 42(5): 483-492.

图/表 6

表1

43个基因位点的基本信息"

基因	SNP	染色体	碱基	MAF	P_HWE	成功分型率(%)
FSCN3-PAX4	rs10229583	7	G/A	0.171	1.000	92.9
CDKN2A	rs10811661	9	T/C	0.417	1.000	92.6
GRK5	rs10886471	10	C/T	0.217	0.515	93.7
CDC123	rs10906115	10	A/G	0.361	0.688	94.2
CDC123	rs11257655	10	T/C	0.472	0.636	91.1
ZFAND6-FAH	rs11634397	15	A/G	0.069	0.792	97.0
HHEX	rs1111875	10	A/G	0.346	0.335	94.4
FAM58A	rs12010175	X	G/A	0.157	0.000	96.6
GCKR	rs1260326	2	T/C	0.357	0.399	95.8
RPS3AP49-MC4R	rs12970134	18	G/A	0.167	1.000	91.6
SLC30A8	rs13266634	8	C/T	0.2849	0.013	90.5
KCNK16	rs1535500	6	G/T	0.4035	0.363	97.0
ARAP1	rs1552224	11	T/G	0.071	0.375	93.7
FAF1	rs17106184	1	G/A	0.102	0.290	94.4
PTPRD	rs17584499	9	C/T	0.118	0.251	97.5
PPARG	rs1801282	3	C/G	0.046	1.000	97.8
AP3S2和C15orf38-AP3S2	rs2028299	15	A/C	0.18	0.233	94.0
KRT18P24-CHCHD2P9	rs17791513	9	A/G	0.07	0.637	97.8
KCNQ1	rs2237892	11	C/T	0.399	0.302	93.2
RPSAP52	rs2261181	12	C/T	0.121	0.217	91.9
RNA5SP94-MIR4432	rs243021	2	T/C	0.354	0.410	95.2
PROX1	rs340874	1	A/G	0.376	0.746	94.4
GLP1R	rs3765467	6	C/T	0.076	0.252	94.4
EIF3EP3-COBLL1	rs3923113	2	T/G	0.143	0.409	95.5
HNF1B	rs4430796	17	A/G	0.316	1.000	93.6
HNF4A	rs4812829	20	G/A	0.456	0.222	97.3
HHEX	rs5015480	10	T/C	0.206	0.686	93.3
KCNJ11	rs5215	11	T/C	0.344	0.414	96.0
KRT18P48-DUSP9	rs5945326	X	A/G	0.167	0.000	96.6
IGF2BP2	rs6769511	3	T/C	0.29	0.765	95.3
MAEA	rs6815464	4	C/G	0.42	0.209	92.2
GCKYKT6	rs6975024	7	T/C	0.142	0.324	97.0
ARL15	rs702634	5	A/G	0.132	0.018	97.5
GLIS3	rs7041847	9	G/A	0.406	0.164	94.9
HMG20A	rs7178572	15	A/G	0.422	1.000	97.1
UBE2E2	rs7612463	3	C/A	0.228	0.729	91.6
TCF7L2	rs7903146	10	C/T	0.36	1.000	94.2
PSMD6-PRICKLE2-AS1	rs831571	3	C/T	0.412	0.395	94.0
NPM1P47-C2CD4B	rs7172432	15	A/G	0.395	0.201	97.1
ZFAND3	rs9470794	6	T/C	0.27	0.526	91.1
RREB1	rs9502570	6	T/C	0.421	0.091	93.6
FTO	rs9936385	16	T/C	0.117	0.000	97.9
MACF1	rs2296172	1	A/G	0.1853	0.007	97.0

表1

表2

表3

表4

附表1

附表2

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变量	干预组(n=377)	对照组(n=306)	总计(n=683)	P值
人口学和社会经济学特征
年龄(岁)	64.02±10.66	65.09±9.17	64.46±12.73	0.211
性别(男)	169(44.9)	162(52.8)	331(48.5)	0.025
文化程度(初中及以上)	106(28.2)	35(11.3)	141(20.6)	<0.001
自评收入				0.096
低	64(17.0)	69(22.6)	133(19.5)
中	291(77.3)	213(69.5)	504(73.8)
高	22(5.8)	24(7.9)	46(6.7)
务农(是)	58(15.5)	81(26.5)	139(20.4)	<0.001
已婚(是)	297(78.7)	244(79.8)	541(79.2)	0.082
有农村合作医疗保险	364(96.5)	298(97.5)	662(96.9)	0.446
体检指标
腰围(cm)	82.67±8.91	89.58±8.43	85.84±9.34	<0.001
收缩压(mmHg)	138.29±16.25	130.27±15.71	134.60±16.48	<0.001
舒张压(mmHg)	80.92±8.57	81.15±8.50	81.02±8.53	0.697
空腹血糖(mmol/L)	5.59±0.80	5.40±0.99	5.50±0.89	0.003
糖化血红蛋白(%)	5.61±0.67	5.52±0.52	5.57±0.61	0.047
总胆固醇(mmol/L)	4.64±1.12	4.56±0.74	4.60±0.96	0.265
甘油三酯(mmol/L)	1.50±1.61	1.75±1.06	1.62±1.39	0.009
超重(BMI≥25 kg/m²)	112(29.7)	257(83.9)	369(54.0)	<0.001
健康相关因素
吸烟	103(27.4)	88(28.9)	191(28.0)	0.773
饮酒	97(25.8)	80(26.3)	177(25.9)	0.870
规律体育运动	47(12.1)	43(14.1)	81(11.9)	0.394
饮茶	279(74.0)	101(33.0)	380(55.6)	<0.001
食物偏好				<0.001
素为主	56(14.9)	25(8.2)	81(11.9)
荤为主	15(3.9)	9(3.1)	24(3.5)
均衡	306(81.2)	256(83.6)	562(82.3)
糖尿病家族史	22(5.8)	22(7.1)	44(6.4)	0.277
高血压	137(36.3)	94(30.8)	231(33.8)	0.116

指标	TT(n=186)				CC+CT(n=497)				P³
指标	干预组(n=100)	对照组(n=86)	d	P¹	干预组(n=277)	对照组(n=220)	d	P²	P³
空腹血糖前后差值(mmol/L)	-0.01±1.40^*	-0.15±0.77	0.14±1.13	0.418	0.31±1.22	0.05±1.04	0.26±1.09	0.011	<0.001
糖化血红蛋白值前后差值(%)	-0.27±1.20^*	0.02±0.47	-0.29±0.89	0.034	0.03±1.98	0.12±0.50	-0.09±1.34	0.225	<0.001

指标	TT(n=210)				CC+CT(n=473)				P³
指标	干预组(n=124)	对照组(n=86)	d	P¹	干预组(n=253)	对照组(n=220)	d	P²	P³
空腹血糖前后差值(mmol/L)	0.44±1.09*	0.04±0.92	0.40±1.02	0.006	0.12±1.35	-0.04±1.03	0.16±1.22	0.15	<0.001
糖化血红蛋白值前后差值(%)	-0.03±0.86	0.15±0.45	-0.18±0.66	0.08	-0.05±1.13	0.09±0.51	-0.14±0.98	0.083	0.341

指标	TT(n=186)				CC+CT(n=497)				P³
指标	干预组(n=100)	对照组(n=86)	d	P¹	干预组(n=277)	对照组(n=220)	d	P²	P³
空腹血糖前后差值(mmol/L)	-0.01±1.40^*	-0.15±0.77	0.14±1.13	0.562	0.31±1.22	0.05±1.04	0.26±1.09	0.008	<0.001
糖化血红蛋白值前后差值(%)	-0.27±1.20^*	0.02±0.47	-0.29±0.89	0.045	0.03±1.98	0.12±0.50	-0.09±1.34	0.122	<0.001

指标	TT(n=210)				CC+CT(n=473)				P³
指标	干预组(n=124)	对照组(n=86)	d	P¹	干预组(n=253)	对照组(n=220)	d	P²	P³
空腹血糖前后差值(mmol/L)	0.44±1.09^*	0.04±0.92	0.40±1.02	0.002	0.12±1.35	-0.04±1.03	0.16±1.22	0.224	<0.001
糖化血红蛋白值前后差值(%)	-0.03±0.86	0.15±0.45	-0.18±0.66	0.12	-0.05±1.13	0.09±0.51	-0.14±0.98	0.120	0.066

2型糖尿病易感基因SNP位点对生活方式干预降低血糖应答效果的修饰效应

Modification effects of T2DM-susceptible SNPs on the reduction of blood glucose in response to lifestyle interventions

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