Ke Hao

Incorporating Individual Error Rate into Association Test of Unmatched Case-Control Design

Objectives: Genotyping error commonly occurs and could reduce the power and bias statistical inference in genetics studies. In addition to genotypes, some automated biotechnologies also provide quality measurement of each individual genotype. We studied the relationship between the quality measurement and genotyping error rate. Furthermore, we propose two association tests incorporating the genotyping quality information with the goal to improve statistical power and inference. Methods: 50 pairs of DNA sample duplicates were typed for 232 SNPs by BeadArray technology. We used scatter plot, smoothing function and generalized additive models to investigate the relationship between genotype quality score (q) and inconsistency rate (ĩ) among duplicates. We constructed two association tests: (1) weighted contingency table test (WCT) and (2) likelihood ratio test (LRT) to incorporate individual genotype error rate (Εi), in unmatched case-control setting. Results: In the 50 duplicates, we found q and ĩ were in strong negative association, suggesting the genotypes with low quality score were more likely to be mistyped. The WCT improved the statistical power and partially corrects the bias in point estimation. The LRT offered moderate power gain, but was able to correct the bias in odds ratio estimation. The two new methods also performed favorably in some scenarios when Εi was mis-specified. Conclusions: With increasing number of genetic studies and application of automated genotyping technology, there is a growing need to adequately account for individual genotype error rate in statistical analysis. Our study represents an initial step to address this need and points out a promising direction for further research.

Single-nucleotide polymorphisms of the KCNS3 gene are significantly associated with airway hyperresponsiveness

Airway hyperresponsiveness (AHR) is one of the major clinical symptoms and intermediate phenotypes of asthma. A recent genome-wide search for asthma quantitative trait loci has revealed a significant linkage signal between a p-terminal region of chromosome 2 and AHR. Thus, the gene encoding the potassium voltage-gated channel delayed-rectifier protein S3 (KCNS3) in this region is considered a positional candidate for asthma. We have evaluated a total of 12 single-nucleotide polymorphisms (SNPs) of the KCNS3 gene in a validation panel of 48 lymphoblastoid cell line DNA samples of Chinese origin. Three SNPs were found to be polymorphic and were tested. Two independent sets (an initial screening set and a replication set) of cases and controls from the original linkage study sample were collected. In the initial screening set, two SNPs (rs1031771 and rs1031772) showed suggestive association and were further confirmed by the replication set. In combined single-SNP analysis, the rs1031771 G allele (odds ratio=1.42, P=0.006) and rs1031772 T allele (odds ratio=1.40, P=0.018) were associated with a significantly higher risk of AHR. Haplotype analysis also detected significant association (P=0.006). Our findings suggest that SNPs located at the 3′ downstream region of KCNS3 have a significant role in the etiology of AHR.

β2 Adrenergic Receptor Gene Arg16Gly Polymorphism is Associated with Therapeutic Efficacy of Benazepril on Essential Hypertension in Chinese

Background: There is considerable variability in individual response to antihypertensive agents. The reason for this is not known, but may be related to individual genetic variability. This study examined whether the therapeutic efficacy of benazepril on essential hypertension is modified by β2 adrenergic receptor gene (ADRB2) Arg16Gly (R16G) polymorphism. Methods and Results: We conducted a family‐based study of 321 and 610 hypertensive subjects from Yuexi and Huoqiu Counties of Anhui, China, respectively. Both systolic and diastolic blood pressures (SBP and DBP) before and after a 15‐day benazepril treatment were measured. ADRB2 R16G genotypes were determined for all subjects. ADRB2 G16 allele frequency was found to be 41.0% and. 47.4% in Huoqiu and Yuexi, respectively. In Yuexi family‐based association test (FBAT) revealed that the G16 allele was associated with a greater DBP decrease in response to a 15‐day benazepril treatment (Z = 2.12, P = 0.03), and the data were consistent with a dominant inheritance model. A similar trend was observed in Huoqiu Chinese, but the magnitudes of effects were smaller and did not reach statistical significance. The FBAT results were further confirmed by using a generalized estimating equation model. Conclusion: Our family‐based study provided the first evidence that ADRB2 R16G polymorphism may play an important role in DBP response to benazepril treatment, although the magnitude of the effect appears to be modified by other risk factors such as plasma lipid and glucose profiles.

Hypertensive patients from two rural Chinese counties respond differently to benazepril: the Anhui Hypertension Health Care Study.

PURPOSEnEssential hypertension, as a complex disorder with unknown etiology cause, is a major public health problem worldwide. Patients need constant drug therapy to maintain their blood pressure in a normal range. However, the current facts suggest that the treatment is not optimized in a large number of patients, and as a result they are at risk for compliance resulting in uncontrolled blood pressure. Genetic and environmental factors associated with individual variation in response to anti-hypertensive drug remain largely unknown.nnnMETHODSnIn order to illustrate the existence and to attempt to identify the factors modifying drug effect, we conducted a large-scale follow-up study in two Chinese rural counties differing in both genetic background and residential environment. Hypertensive patients were treated with benazepril, a commonly used angiotensin converting enzyme inhibitor, for 15 days, and the end-point effect was evaluated.nnnRESULTSnWe found that there were large and significant differences in drug response between subjects from two counties, even after adjustment for known factors. The responses to benazepril, measured in diastolic blood pressure drop, in male patients from Yuexi was twice as effective as their counterparts from Huoqiu.nnnCONCLUSIONSnThese results suggest that adjustment of treatment regimen is necessary to improve efficacy, and it could be done at the population level to make it more feasible and affordable.