Center for Oral Health Research in Appalachia (COHRA) Genomic Studies of Oral Health and Disease

The purpose of this project is to identify the genetic factors contributing to dental caries in children and adults. The datasets come from the Center for Oral Health Research in Appalachia (COHRA), which has the long-term goal of determining the sources of oral health disparities in a high risk, Northern Appalachian population so that effective preventive interventions can be designed and targeted. The specific aims of this project are to perform genome-wide association scans of dental caries of the (1) primary dentition in children, and (2) permanent dentition in adults, to identify novel risk variants and to replicate previously nominated risk variants. This project brings together samples from three cohorts: COHRA1 is a cross-sectional cohort comprising members of 862 northern Appalachian families; approximately 80% of the cohort has been previously genotyped by the Center for Inherited Disease Research with support from NIDCR using the Illumina Quad W array (see dbGaP Study Accession: phs000095.v3.p1). Dental SCORE is a cross-sectional cohort comprising approximately 550 unrelated individuals who underwent the same data collection protocol as COHRA1. COHRA2 is an ongoing longitudinal cohort that recruited approximately 1100 northern Appalachian women during pregnancy, and followed them and their children through their children's early childhood; the current project period will continue data collect though age 6 of the child. Phenotypes for this project were derived from intra-oral examinations performed by trained and calibrated research hygienists. In brief, each tooth was recorded as present or absent, and each surface of each present tooth was scored for evidence of decay. From these data, dental caries indices were generated. This project contains two phases of genotyping: (1) Collection of exome SNP Chip data for the previously genotyped COHRA1 samples, and (2) Collection of whole-genome SNP Chip data for the remaining COHRA1 samples and all Dental SCORE and COHRA2 samples. These data will support efforts to test hypotheses regarding the causal relationships of risk factors contributing to the unusually high rates of caries formation in the Appalachian population. Ultimately, these data may inform the development of an integrated model of caries risk, in which the effects of genetics, oral ecology, diet, and other environmental/psychosocial factors and behaviors are modeled in concert to explain the disparities, including the high rate of caries onset before age 6. The gene-mapping aims of this project, which seek to identify the genetic factors that contribute to caries risk, are a requisite step in realizing this integrated model.]]>
COHRA1: Inclusion criteria - Households with one biological parent-child pair living together with the child being between ages 1 and 18 years; all members of eligible households were offered admission into the study regardless of biological or legal relationships and regardless of oral health conditions. Exclusion criteria - Individuals with neurological impairment, physical or intellectual handicap, or psychosis, and households for which the adult or child of the biological parent-child pair had either a reduced capacity to resist infection or form blood clots due to reasons such as leukemia, cancer, unstable diabetes, transplant, blood clotting disorder, corticosteroid use, immunosuppressive therapy, blood thinning medications, or HIV. COHRA2: Inclusion criteria - Pregnant Caucasian women between the 12th and 29th weeks of pregnancy who were at least 18 years of age and fluent in English. Exclusion criteria - Women who were carrying a multiple pregnancy, had tuberculosis, were immunocompromised, or did not have telephone. Additionally, women were excluded based on pregnancy outcomes such as premature delivery or development of serious medical issues in the mother or baby.Heart SCORE:Inclusion criteria - Adult participants to be ages 45 to 75 years. Exclusion criteria -Pregnancy and comorbidities that limited life expectancy to less than 5 years.Dental SCORE: Participants enrolled in the Heart SCORE study were eligible to participate in this ancillary study.]]>
1999: Center for Oral Health Research in Appalachia (COHRA) was established as a consortium between the University of Pittsburgh and West Virginia University to address oral health disparities in rural Appalachia. 2003: Recruitment for the COHRA1 family-based sample was initiated in West Virginia. 2004: Recruitment for the COHRA1 family-based sample was initiated in Pennsylvania. 2007: Recruitment for the Dental SCORE sample was initiated in Pittsburgh, Pennsylvania. 2009: Genotyping was performed for approximately 80% of the COHRA1 sample by the Center for Inherited Disease Research (CIDR) at Johns Hopkins University. 2011: Recruitment for the COHRA2 mother-baby sample was initiated in West Virginia. Three in-person assessments took place during the first year of participation including a prenatal visit (12-29 weeks of pregnancy), pre-tooth visit (baby age 2-3 months), and 1-year visit. Annual in-person visits took place at child ages 2 to 6 years. Telephone interviews occurred once prenatally, and postnatally at baby ages 10 weeks and 6 months, and every 6 months thereafter. 2012: Recruitment for the COHRA2 mother-baby sample was initiated in Pittsburgh, Pennsylvania. Longitudinal assessments took place as in West Virginia with two additional in-person visits occurring at birth and one month after the eruption of the baby's first tooth. 2017: New recruitment for the COHRA2 sample closed; longitudinal follow-up continued. 2018: Genotyping of COHRA1, Dental SCORE, and COHRA2 for the current project performed by the Center for Inherited Disease Research (CIDR) of Johns Hopkins University. ]]>

本项目旨在明确影响儿童与成人龋齿发生的遗传因素。本项目数据集源自阿巴拉契亚口腔健康研究中心（Center for Oral Health Research in Appalachia, COHRA），该中心的长期目标是明确高风险北阿巴拉契亚人群中口腔健康差异的成因，从而设计并实施针对性的有效预防干预措施。

本项目的具体研究目标为：对（1）儿童乳牙列、（2）成人恒牙列的龋齿开展全基因组关联扫描（genome-wide association scans），以识别全新的龋齿风险变异，并验证此前已被提名的风险变异。

本项目整合了三个队列的样本：COHRA1为横断面队列（cross-sectional cohort），涵盖862个北阿巴拉契亚家庭的成员；该队列中约80%的样本已在美国国家口腔与颅面研究所（NIDCR）资助下，由遗传性疾病研究中心（Center for Inherited Disease Research, CIDR）使用伊利米纳（Illumina）Quad W基因芯片完成基因分型（genotyped）（详见dbGaP研究编号：phs000095.v3.p1）。Dental SCORE为横断面队列，包含约550名无关个体（unrelated individuals），其数据采集方案（data collection protocol）与COHRA1完全一致。COHRA2为正在进行中的纵向队列（longitudinal cohort），于妊娠期间招募了约1100名北阿巴拉契亚女性，并对其及子女进行随访至子女幼儿期；本项目的执行周期将延续至子女年满6岁时。

本项目的表型（phenotypes）数据源自经过培训且校准合格的研究型口腔卫生师开展的口腔内检查（intra-oral examinations）。简言之，每颗牙齿均被记录为存在或缺失，每颗存留牙齿的每个牙面均被评分以判断是否存在龋损。基于上述数据，可生成龋齿指数（dental caries indices）。

本项目包含两个阶段的基因分型工作：（1）为此前已完成基因分型的COHRA1样本采集外显子组SNP芯片（exome SNP Chip）数据；（2）为剩余COHRA1样本以及全部Dental SCORE与COHRA2样本采集全基因组SNP芯片（whole-genome SNP Chip）数据。

上述数据将为验证相关假说提供支持，该假说围绕阿巴拉契亚人群异常高发的龋齿形成的风险因素因果关系展开。最终，本项目数据可助力构建龋齿风险整合模型，该模型将协同模拟遗传因素、口腔生态（oral ecology）、饮食及其他环境/社会心理因素（psychosocial factors）与行为的影响，以解释口腔健康差异——包括6岁前高发的龋齿发病情况。本项目的基因定位（gene-mapping）目标，即明确龋齿风险相关遗传因素，是实现该整合模型的必要前提。

### COHRA1队列
纳入标准（inclusion criteria）：居住在一起的亲生父母-子女对家庭，且子女年龄为1至18岁；符合上述条件的家庭所有成员均可参与本研究，无论其生物学或法律亲属关系，也无论其口腔健康状况。
排除标准：存在神经功能障碍（neurological impairment）、躯体或智力障碍（intellectual handicap）、精神病（psychosis）的个体；以及亲生父母-子女对中的成人或子女因白血病、癌症、不稳定型糖尿病、移植手术、凝血功能障碍（blood clotting disorder）、糖皮质激素使用（corticosteroid use）、免疫抑制治疗（immunosuppressive therapy）、抗凝药物（blood thinning medications）或人类免疫缺陷病毒（Human Immunodeficiency Virus, HIV）感染等原因，导致抗感染能力下降（reduced capacity to resist infection）或血凝块形成能力受损的家庭。

### COHRA2队列
纳入标准：妊娠12至29周、年龄至少18岁且英语流利的白人女性（Caucasian women）。
排除标准：多胎妊娠（multiple pregnancy）、结核病（tuberculosis）、免疫功能低下（immunocompromised）或无电话的女性。此外，若出现早产（premature delivery），或母亲或婴儿发生严重疾病，该女性也将被排除。

### Heart SCORE队列
纳入标准：年龄45至75岁的成年参与者。
排除标准：妊娠及预期寿命不足5年的合并症患者。

### Dental SCORE队列
参与Heart SCORE研究的参与者可纳入本附属研究（ancillary study）。

1999年：阿巴拉契亚口腔健康研究中心（COHRA）由匹兹堡大学与西弗吉尼亚大学联合成立，旨在解决农村阿巴拉契亚地区的口腔健康差异问题。
2003年：西弗吉尼亚州启动COHRA1家系样本（family-based sample）招募（recruitment）工作。
2004年：宾夕法尼亚州启动COHRA1家系样本招募工作。
2007年：宾夕法尼亚州匹兹堡启动Dental SCORE样本招募工作。
2009年：约翰·霍普金斯大学遗传性疾病研究中心（CIDR）为约80%的COHRA1样本完成基因分型。
2011年：西弗吉尼亚州启动COHRA2母婴队列样本招募工作。参与首年共开展三次面对面评估（in-person assessments）：产前访视（prenatal visit）（妊娠12-29周）、出牙前访视（pre-tooth visit）（婴儿2-3月龄）及1岁访视（1-year visit）；在子女2至6岁期间开展年度面对面访视（annual in-person visits）。产前开展1次电话访谈（telephone interviews），产后（postnatally）分别于婴儿10周龄、6月龄时开展电话访谈，此后每6个月开展1次。
2012年：宾夕法尼亚州匹兹堡启动COHRA2母婴队列样本招募工作。纵向评估流程与西弗吉尼亚州一致，额外增加两次面对面访视：分娩时访视及婴儿第一颗牙齿萌出（eruption of the baby's first tooth）后1个月访视。
2017年：COHRA2样本新招募工作结束，纵向随访持续进行。
2018年：约翰·霍普金斯大学遗传性疾病研究中心（CIDR）为本项目完成COHRA1、Dental SCORE及COHRA2样本的基因分型工作。