rs498422 — LOC101929163 LOC101929163 Variant

LOC101929163 rs498422 — An HLA-Region Variant Associated with Non-Obstructive Azoospermia in East Asian Men

Non-obstructive azoospermia (NOA) is the complete absence of sperm in semen due to a failure of sperm production in the testes — the most severe form of male infertility, affecting roughly 1% of all men and approximately 10% of infertile men. Unlike obstructive azoospermia (where a physical blockage prevents sperm from reaching the ejaculate), NOA reflects a fundamental spermatogenic failure¹¹ spermatogenic failure
inability of the testes to produce mature sperm through the meiotic and mitotic divisions of spermatogenesis. Genetic factors account for a substantial proportion of NOA cases. Chromosome abnormalities (e.g. Klinefelter syndrome, Y microdeletions) are the most common causes, but common variants of modest effect — particularly in the HLA region — have also been implicated.

The Mechanism

rs498422 lies in an intronic region of LOC101929163 (also annotated as TSBP1-AS1), a non-coding antisense RNA gene situated on chromosome 6p21.32 between TSBP1 (testis-expressed basic protein 1) and BTNL2 (butyrophilin-like protein 2). This locus sits within the extended major histocompatibility complex (MHC)²² major histocompatibility complex (MHC)
the HLA region, spanning ~4 Mb on chromosome 6p21, encoding immune-recognition proteins and dozens of regulatory genes. The precise causal mechanism is not established. The intronic position suggests the G allele may tag a haplotype that influences the expression of nearby genes, particularly TSBP1 (expressed in testis) or BTNL2 (a co-stimulatory molecule involved in immune regulation). Given the strong immune-regulatory role of the HLA region, one leading hypothesis is that certain MHC haplotypes alter testicular immune tolerance — creating a milieu in which the immune system fails to appropriately protect germ cells from autoimmune attack.

The Evidence

The primary evidence comes from a landmark genome-wide association study by Zhao et al. 2012³³ genome-wide association study by Zhao et al. 2012
A genome-wide association study reveals that variants within the HLA region are associated with risk for nonobstructive azoospermia. Am J Hum Genet, 2012, conducted in Han Chinese men across three independent stages: discovery (802 NOA cases, 1,863 controls), northern China replication (818 cases, 1,755 controls), and central/southern China replication (606 cases, 958 controls), totalling 2,226 cases and 4,576 controls. rs498422 at the C6orf10/BTNL2 region reached a combined p-value of 2.43 × 10⁻¹², with an odds ratio of 1.42 — a statistically robust finding that survived genome-wide significance thresholds after multiple-testing correction.

A subsequent case-control study and meta-analysis by Zou et al. 2017⁴⁴ case-control study and meta-analysis by Zou et al. 2017
Association and meta-analysis of HLA and non-obstructive azoospermia in the Han Chinese population. Andrologia, 2017 in 603 NOA cases and 610 controls replicated the association (OR 1.40, p = 0.006). A meta-analysis across five studies confirmed that the three HLA-region loci including rs498422 are consistently associated with NOA susceptibility (p < 0.01 across all), leading the authors to propose these variants as potential diagnostic markers for male infertility risk.

A replication study in Japanese men by Jinam et al. 2013⁵⁵ replication study in Japanese men by Jinam et al. 2013
HLA-DPB1*04:01 allele is associated with non-obstructive azoospermia in Japanese patients. Hum Genet, 2013 (443 patients, 544 controls) showed that the correlated marker rs3129878 (in linkage disequilibrium with rs498422) was associated with NOA in a Japanese population, though HLA-DPB1*04:01 emerged as the primary independently associated allele in that cohort. This confirms the broader HLA-region involvement in NOA across East Asian populations.

Critical limitation: All replication data are from East Asian populations (Han Chinese and Japanese). The G allele of rs498422 is approximately three times more common in East Asians (~18%) than in Europeans (~6%), and the MHC haplotype structure differs substantially between populations. No replication data exist for European, African, South Asian, or Latino men. Until independent replication in non-East-Asian populations is published, this association should be considered population-specific and the evidence classified as emerging for general population use.

Practical Actions

For men of East Asian ancestry, carrying G alleles at rs498422 modestly elevates the prior probability of spermatogenic impairment. The OR of 1.42 means that, in the context of an infertility evaluation, this genotype adds modest incremental information — it does not diagnose NOA or predict it with high certainty, but it can inform how aggressively to investigate spermatogenesis, particularly in the context of other risk factors such as a history of orchitis, cryptorchidism, or prior chemotherapy.

Semen analysis remains the essential diagnostic test. Men with G alleles who are pursuing fertility and have not had a semen analysis should consider obtaining one. If NOA is diagnosed, the presence of this risk genotype does not change management — NOA is evaluated with hormonal testing, testicular biopsy, and potential surgical sperm retrieval regardless of genotype.

Interactions

rs498422 is in linkage disequilibrium with rs3129878 (HLA-DRA) and rs7194, two other HLA-region variants associated with NOA. In the Zhao et al. 2012 GWAS, rs498422 and rs3129878 showed independent signals after conditioning on each other, suggesting they may tag distinct functional effects within the MHC. A 2019 fine-mapping study (Huang et al., PMID 30502936) identified additional loci (rs7194, rs4997052) within the MHC class I region, suggesting that multiple independent signals in the HLA region collectively contribute to NOA susceptibility — possibly through different immune mechanisms acting on spermatogenesis. Men who carry risk alleles at multiple HLA-region NOA loci may have cumulatively higher risk, though formal compound analysis of this specific combination has not been published.