rs498422 — LOC101929163 LOC101929163 Variant

Intronic variant in TSBP1-AS1 (LOC101929163), a non-coding antisense RNA in the HLA region between TSBP1 and BTNL2 on chromosome 6p21.32; the G allele is associated with increased risk of non-obstructive azoospermia in Han Chinese men, with an odds ratio of approximately 1.42 in a large multi-stage GWAS

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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.

Genotype Interpretations

What each possible genotype means for this variant.

TT Common Genotype Normal

Common genotype — no elevated NOA risk from this HLA-region variant

The TT genotype is the reference state at rs498422. In the landmark Zhao et al. 2012 GWAS (2,226 Han Chinese NOA cases, 4,576 controls), TT homozygotes served as the baseline group from which risk was measured for G allele carriers. No elevated spermatogenic risk attributable to this specific variant has been documented in TT individuals.

Note that NOA has many other genetic and non-genetic causes. The absence of G alleles at rs498422 does not exclude other HLA-region variants (rs3129878, rs7194, rs4997052) or non-HLA genetic causes of male infertility. A normal result at this locus simply removes one known HLA-region contributor from consideration.

GT One Risk Allele Intermediate

One G allele — modestly elevated NOA risk signal, particularly relevant in East Asian men

The G allele at rs498422 acts in an additive fashion — GT heterozygotes have an intermediate risk between TT (baseline) and GG (highest risk). An odds ratio of 1.42 means that, in a population where NOA affects roughly 1% of all men, G allele carriers would have approximately 1.4% risk from this locus alone — a modest absolute increase. This variant is best interpreted as one contributor to a polygenic risk landscape rather than a deterministic marker.

Evidence strength caveat: all key studies were conducted in Han Chinese or Japanese men. The European G allele frequency is only ~6%, and no replication data exist for non-East-Asian populations. If you are of non-East-Asian ancestry, the applicability of this risk estimate to your personal biology is uncertain.

GG Two Risk Alleles High Risk

Two G alleles — highest NOA risk signal at this locus; very rare genotype, especially in Europeans

GG homozygosity at rs498422 represents the highest-risk genotype at this HLA-region NOA locus. The G allele tags an MHC haplotype in the TSBP1/BTNL2/C6orf10 region that is believed to affect testicular immune regulation or the expression of nearby testis-expressed genes, though the precise molecular mechanism is not established.

For East Asian men, where the G allele is more common (~18%), GG homozygosity is less rare (~3.2% of East Asian men). For men of European ancestry, where the G allele frequency is ~6%, GG homozygosity occurs in under 0.4% of men. If you are of European or other non-East-Asian ancestry, note that no replication study has confirmed this association outside East Asian populations; the risk estimate should be interpreted with caution.

NOA evaluation and management is the same regardless of genotype. If sperm production failure is confirmed, surgical sperm retrieval (testicular sperm extraction, TESE) combined with IVF/ICSI remains the primary path to biological parenthood. The genetic risk marker does not predict success of TESE.