利用可改變與不可改變因子進行台灣族群第二型糖尿病及B型肝炎病毒感染的SNP分析

Association of Single Nucleotide Polymorphisms with Type 2 Diabetes and Hepatitis B Virus Infection among Taiwanese Adults Based on Modifiable and Nonmodifiable Risk Factors

符歐思(OSWALD NDI NFOR)

指導教授 ： 廖勇柏

中山醫學大學/健康管理學院/公共衛生學系博士班/博士(2018年)

摘要

第二型糖尿病 (type 2 diabetes; T2D)和B型肝炎病毒 (hepatitis B virus infection; HBV)感染在全球皆是重要的公共衛生議題，而基因與環境因素一直是增加疾病易感性的重要因子。近年來，GWAS研究已經證實了在不同種族中有許多與疾病相關的基因多型性 (Single nucleotide polymorphisms; SNP)位點、且每個基因型在不同族群中也有獨特的影響，然而，台灣卻鮮少有SNP變異與非傳染性疾病的相關性研究。因此，本研究利用台灣人體生物資料庫探討在台灣族群中CDKAL1基因與NTCP基因變異對T2D和HBV的影響。
CDKAL1基因位於第六條染色體上、與胰島素反映受損有關，且CDKAL1基因在歐洲及亞洲族群中都已經被證實是第二型糖尿病的相關基因。本研究第一階段利用台灣人體生物資料庫的資料，共有9908位年齡介於30至70歲的參與者納入研究，探討在不同BMI分層中CDKAL1 rs10946398與第二型糖尿病的相關性。研究結果顯示，以AA型為參考組，帶有rs10946398的CC型和CA型會顯著增加罹患第二型糖尿病的機會；過重及肥胖的女性相較於正常BMI的女性，其OR值皆較高。儘管如此，結果僅在CC型及C等位基因中較為顯著。
NTCP基因是B型肝炎病毒感染的功能性受體，在亞洲族群中，有許多研究都已經證實NTCP rs2296651的主要功能是HBV的易感性。因此，本研究第二階段透過台灣人體資料庫收集之基因與社會學變項資料，共有10017位參與者納入研究，並利用性別及女性是否停經分層來探討rs2296651與HBV感染之間的相關性。NTCP rs2296651基因型在HBV感染的參與者中，頻率分別是女性GG型為0.85、AG型為0.15及AA型為0，男性GG型為0.82、AG型為0.18及AA型為0。調整干擾因子後，透過多變項邏輯斯迴歸進行分析，結果發現，男性帶有C等位基因HBV感染的機會為0.77 (95% CI 0.589-0.999)，女性帶有C等位基因帶有HBV感染的機會為0.98 (95%CI 0.792-1.202)；且女性未停經者HBV感染的機會為0.87 (CI 0.634-1.188)、已停經者HBV感染的機會為0.59 (0.357-0.965)。研究結果發現， NTCP 基因的rs2296651變異在台灣女性族群中能顯著降低HBV感染的風險。
總體來說，本研究針對台灣HBV和T2D相關變異的分佈提供了額外的見解，我們的研究結果顯示，CDKAL1 rs10946398與第二型糖尿病之間的顯著相關性，且相較於AA型，帶有CC型及CA型的過重和肥胖女性都有較高的機會得到第二型糖尿病；另外，我們也建議NTCP rs2296651的基因型變異對HBV來說具有保護效果。本研究結果可以做為未來更大型研究的參考並加以驗證。

關鍵字

第二型糖尿病 ； CDKAL1基因 ； NCTP基因 ； 身體質量指數 ； B型肝炎病毒 ； 臺灣人體生物資料庫

並列摘要

Type 2 diabetes (T2D) and hepatitis B virus (HBV) infection are serious health issues in all countries including Taiwan. Genetic and environmental factors are among several factors thought to increase susceptibility to these diseases. Recent genome-wide association studies (GWAS) have recognized several loci associated with several disease conditions in different ethnic groups. Each genotype has a distinctive effect in different populations. There are relatively few reports about the association of polymorphic variants with non-communicable diseases in Taiwan. This thesis was performed to determine whether specific polymorphic variants in CDKAL1 and NTCP genes are associated with susceptibility to T2D and HBV in Taiwan. This was realized using genotypic data contained in Taiwan Biobank.
CDKAL1 gene is located on chromosome 6 and is associated with impaired insulin response. It is a T2D-associated gene particularly in European and Asian populations. In the first phase of this study, genetic data from 9908 participants (aged 30-70 years) in Taiwan Biobank were used to estimate the association between CDKAL1 rs10946398 and T2D risk based on BMI. Results showed that rs10946398 CC and CA genotypes were associated with increased the risk of T2D. The ORs were higher in women who were overweight and obese than in those with normal weight. Nonetheless, significant results were prominent only among those with CC genotype and C allele.
NTCP is a functional receptor for hepatitis B virus infection. NTCP rs2296651 is an Asian-specific variant responsible for HBV susceptibility. In the second phase of this study, complete genetic and sociodemographic data from 10017 participants in Taiwan Biobank were used to estimate the relationship between rs2296651 and HBV infection under stratification by sex and menopausal status. Among individuals with HBV infection, the frequencies of GG, AG, and AA genotypes of rs2296651 were 0.85, 0.15 and 0 in women and 0.82, 0.18 and 0 in men, respectively. The multivariate-adjusted odds ratios of HBV infection was 0.77 (95% CI 0.589-0.999) in men and 0.98 (95%CI 0.792-1.202) in women with NTCP rs2296651. The adjusted odds ratio was 0.87 (CI 0.634-1.188) in pre-menopausal and 0.59 (0.357-0.965) in post-menopausal women with NTCP rs2296651. We found that genetic variation in the HBV receptor gene NTCP was significantly associated with a decreased risk of HBV infection in Taiwanese women.
Overall, these results have provided additional insights into the distribution of HBV- and T2D-associated variants in Taiwan. Our data show that there is a significant association between CDKAL1 rs10946398 and type 2 diabetes. Overweight and obese women with CC and CA genotypes had higher odds ratios than normal women. Our data also suggested a protective association between NTCP rs2296651 and HBV. These results should serve as an incentive for larger dedicated studies.

並列關鍵字

Type 2 diabetes ； CDKAL1 ； NCTP ； Body mass index ； hepatitis B virus ； Taiwan Biobank

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