Background/Purpose:

Few SNPs and susceptibility genes have been identified in previous genome-wide and candidate gene association studies for knee radiographic osteoarthritis (OA). Nearly all studies have been conducted in European Caucasian and Asian populations with few data published on genetics of knee OA in African-Americans. For this reason we have performed a genome-wide association study (GWAS) of knee OA in African Americans.    

Methods:

In total, 1217 African-American participants from two cohorts, the Johnston County Osteoarthritis Project (JoCo , 590 subjects) and the Osteoarthritis Initiative (OAI, 627 subjects), were included in the analysis. This sample size provides 80% power to detect odds ratios of 1.55-1.70 for minor allele frequencies ranging from 0.10-0.50. Knee OA cases were defined as having a Kellgren-Lawrence (KL) grade of 2 or higher in at least one knee, whereas controls were defined as having KL grade of 0 or 1 in both knees. Genome wide genotyping was completed using the Illumina 2.5M platform for OAI and Illumina Infinium 1M-Duo array for JoCo.  Imputation was conducted with Minimach using the combined 1000 Genome CEU and YRI reference panels. Single marker analysis was conducted using logistic regression with adjustment for age, sex, body mass index (BMI) and principal components. We combined GWAS results from the two data sets using the meta-analyses as implemented in the METAL software program. 

Results:  

No SNP reached the significant level at 10e-8. However, we identified 24 SNPs with P-value less than 5×10-6. Among the 24 SNPs, three are located in the coding regions of genes (FLJ2052, RRAGD and ATP8A2).   FLJ 2052 codes a hypothetical protein, whose biological function is unknown. RRAGD (Ras-Related GTP Binding D) codes a monomeric guanine nucleotide-binding protein. By binding GTP or GDP, small G proteins act as molecular switches in numerous cell processes and signaling pathways. ATP8A2(ATPase Class I Type 8A Member 2) codes a member of ATPase. It is well known that ATPases import and export many of the metabolites necessary for cell metabolism. However, the molecules carried by ATP8A2 are unknown. None of these genes has been implicated in OA development in Caucasian populations.

Conclusion:

We identified three genes associated with knee OA with P-value < 5x10-6 in African Americans. RRAGD and ATP8A2are both involved in various cell processes and signaling pathways. Further analysis, including pathway analysis, will be performed to determine if these biological pathways or protein networks have a role to play in knee osteoarthritis.

Table 1    Samples in each cohort

		N_samples	Age Mean (sd)	BMI Mean (sd)	Sex %women
JoCo_AA	Case	293	63.98 (10.78)	34.70 (8.76)	68.94
	Control	297	58.55 (9.63)	30.14 (6.27)	61.95
	All	590	61.24 (10.57)	32.40 (7.93)	65.42
OAI_AA	Case	449	59.63 (8.37)	31.92 (4.58)	69.71
	Control	178	57.38 (8.25)	29.04 (4.59)	61.24
	All	627	58.99 (8.39)	31.10 (4.76)	67.30

Table 2    Top hits from GWAS META-analysis (p-value< 0.000005)

CHR	POS	SNP	Gene	Allele1	Allele2	Direction	Study	Beta	SE_Beta	P-value
5	16608874	rs890824	FLJ2052	t	c	—	META	–	–	3.93E-06
							JoCo	-0.7948	0.2234	0.000374
							OAI	-0.5875	0.1972	0.002898
6	90120883	rs1407192	RRAGD	c	g	—	META	–	–	3.77E-06
							JoCo	-0.6490	0.2142	0.002448
							OAI	-0.7592	0.2167	0.00046
13	26095937	rs34622730	ATP8A2	a	g	++	META	–	–	4.34E-06
							JoCo	0.4618	0.1509	0.002212
							OAI	0.5141	0.1498	0.000599

---

« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-association-study-of-knee-radiographic-osteoarthritis-in-african-american-populations/